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M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
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Review
Hereditary ovarian carcinoma: Heterogeneity, molecular genetics,
pathology, and management
Henry T. Lyncha,*, Murray Joseph Caseyb, Carrie L. Snydera, Chhanda Bewtrac,
Jane F. Lyncha, Matthew Buttsa, Andrew K. Godwind
a
Department of Preventive Medicine and Public Health, Creighton University School of Medicine, 2500 California Plaza, Omaha,
NE 68178, USA
b
Department of Gynecology and Obstetrics, Creighton University Medical Center, Omaha, NE 68131, USA
c
Department of Pathology, Creighton University Medical Center, Omaha, NE 68131, USA
d
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
A R T I C L E
I N F O
A B S T R A C T
Article history:
Hereditary ovarian cancer accounts for at least 5% of the estimated 22,000 new cases of this
Received 2 February 2009
disease during 2009. During this same time, over 15,000 will die from malignancy ascribed
Received in revised form
to ovarian origin. The bulk of these hereditary cases fits the hereditary breast–ovarian can-
3 February 2009
cer syndrome, while virtually all of the remainder will be consonant with the Lynch syn-
Accepted 6 February 2009
drome, disorders which are autosomal dominantly inherited. Advances in molecular
Available online 21 February 2009
genetics have led to the identification of BRCA1 and BRCA2 gene mutations which predispose to the hereditary breast–ovarian cancer syndrome, and mutations in mismatch repair
Keywords:
genes, the most common of which are MSH2 and MLH1, which predispose to Lynch syn-
Hereditary ovarian cancer
drome. These discoveries enable relatively certain diagnosis, limited only by their variable
Review
penetrance, so that identification of mutation carriers through a comprehensive cancer
Ovarian cancer
family history might be possible. This paper reviews the subject of hereditary ovarian can-
Hereditary breast-ovarian
cer, with particular attention to its molecular genetic basis, its pathology, and its pheno-
cancer syndrome
typic/genotypic heterogeneity.
Lynch syndrome
ª 2009 Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies.
1.
Introduction
During this year, approximately 22,000 new cases of ovarian
cancer will be diagnosed in the United States and more than
15,000 women may die from malignancies ascribed to ovarian
origin ( Jemal et al., 2008). About 90% of cancers believed to
arise in the ovaries are carcinomas, with the remaining primary ovarian malignancies being closely split between stromal and germ cell origin (Auersperg et al., 2001; Ozols et al.,
2005). Familial ovarian cancer confers a 4.6 relative risk (RR)
(95% confidence interval [CI] ¼ 2.1–8.7) of this disease in the
proband’s mother and a 1.6 RR (95% CI ¼ 0.2–5.9) in the proband’s sister (Ziogas et al., 2000). This translates to a lifetime
risk estimate of about 2.5% for the sister of an ovarian cancer
patient and a 7.0% risk for the patient’s mother.
The present communication will focus on ovarian carcinoma arising in women with inherited susceptibilities, which
are estimated to account for some 5–15% of ovarian cancer
* Corresponding author. Tel.: þ1 402 280 2942; fax: þ1 402 280 1734.
E-mail address: [email protected] (H.T. Lynch).
1574-7891/$ – see front matter ª 2009 Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies.
doi:10.1016/j.molonc.2009.02.004
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M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
and thus as many as some 3300 new cases of the cancer in the
United States within the next year. Many such cancers may be
preventable (Boyd, 1998; Claus et al., 1996; Pal et al., 2005;
Rubin et al., 1998).
With emerging evidence, so-called ‘‘ovarian’’ carcinomas
are now believed to predominantly arise de novo by malignant
transformation of the ovarian surface epithelium, and/or the
serous epithelium of the fallopian tube, especially the distal
portion (Auersperg et al., 2001; Bassis, 1960; Casey and Bewtra, 2004; Gray and Barnes, 1962; Lauchlan, 1972; Lynch
et al., 1986; Parmley and Woodruff, 1974; Piek et al., 2004;
Woodruff, 1979). The biological mechanism for this transformation remains elusive, although mounting evidence indicates that it likely involves a multi-step process with the
accumulation of genetic lesions in at least three classes of
genes, namely proto-oncogenes, tumor suppressor genes,
and mutator genes.
Epithelial ovarian cancer, along with related Müllerian
duct adenocarcinomas of the peritoneum and fallopian
tube, carries the highest fatality to case ratio for all gynecologic malignancies diagnosed in the U.S.A. and is the fifth
leading cause of cancer death in women. Because the majority of patients with epithelial ovarian cancer are diagnosed at
an advanced stage and because the efficacy of standard therapy is limited in such advanced cases, primary and secondary prevention strategies are critical to reduction of both
cancer incidence and mortality. The development of effective
prevention methods depends on the identification of the anatomic origins of disease as well as specific carcinogenic
mechanisms.
At least two defined inheritable genetic aberrations are
known to predispose to ovarian cancer. Mutations in the
breast cancer-associated genes BRCA1 and BRCA2 account
for approximately 90% of the ovarian cancers in the hereditary breast–ovarian cancer (HBOC) syndrome (Easton et al.,
1995, 1997; Ford et al., 1994; Narod et al., 1995a,b; Schubert
et al., 1997), and some 65–85% of all hereditary ovarian cancers (Bewtra et al., 1992; Malander et al., 2006; Rubin et al.,
1998); mutations in at least four mismatch repair (MMR)
genes (MLH1, MSH2, MSH6 and PMS2) (National Center for
Biotechnology Information [NCBI], 2008) in the Lynch syndrome account for another 10–15% of hereditary ovarian
carcinomas (Bewtra et al., 1992; Lynch et al., 1998;
Malander et al., 2006).
Hereditary ovarian cancer syndromes appear to be genotypically and phenotypically heterogeneous diseases,
characterized by variable clinical courses. Prevention of
hereditary ovarian carcinoma depends on knowledgeable
physicians understanding the natural history of these
hereditary syndromes in which ovarian cancer is an integral lesion. Comprehensive family histories are currently
fundamental for the diagnosis of hereditary cancer syndromes, thereby enabling clinical management, research
and, ultimately, the prevention of ovarian-like carcinomas
in genetically susceptible individuals. Today’s epidemiological, clinical, and pathological investigations and the
current search for molecular pathways in sporadic and
hereditary ovarian carcinogenesis are basic for the prophylaxis, early detection, treatment, and final elimination of
these cancers in the future.
2.
Historical breakthroughs in hereditary ovarian
cancer
2.1.
Hereditary Breast–Ovarian Cancer (HBOC)
syndrome
Hereditary transmission of an autosomal dominant trait predisposing women to both breast and ovarian cancers was first
published in the early 1970s by Lynch’s group at Creighton
University (Lynch et al., 1972, 1974; Lynch and Krush, 1971).
In 1990, Hall et al. (1990) reported linkage between a site in
chromosome 17q and site-specific breast cancer arising in disproportionately larger than expected numbers of young
women in some cancer prone families. Less than a year later,
Narod et al. (1991) demonstrated that this same genetic locus
was linked to cancers in the HBOC syndrome described twenty
years earlier by Lynch et al. (Lynch et al., 1972, 1974; Lynch and
Krush, 1971; Narod et al., 1991) (Figure 1). This gene, located at
chromosome 17q21 (National Center for Biotechnology Information, 2008) was termed BRCA1 and subsequently cloned
by Miki et al. (1994). A second gene locus at chromosome
13q12.3 (National Center for Biotechnology Information,
2008) was linked to breast cancers in several other families,
designated as BRCA2, and cloned by Wooster et al. (1994,
1995). Data from the Breast Cancer Linkage Consortium
(Ford et al., 1998) showed that 90% of families afflicted with
four or more breast cancers and even one ovarian cancer in
the linear pedigree were linked to either BRCA1 (Figure 2) or
BRCA2 (Figure 3).
2.2.
The Lynch syndrome
More than 40 years ago, Lynch and co-workers (Lynch et al.,
1966; Lynch and Krush, 1967) were responsible for defining
and bringing to attention a familial syndrome characterized
by autosomal dominant transmission of susceptibility to colorectal cancer (CRC) with predilection to the right of the splenic
flexure in younger than expected adult patients (mean <45
years of age) but with no excess of adenomatous colon polyps.
As experience continued to accumulate regarding families
with predilections to hereditary nonpolyposis colorectal cancer (HNPCC) it became evident that members of these kindreds were prone to an excess of primary synchronous and
metachronous CRCs and to primary tumors of other organs
as well, including especially carcinomas of the endometrium
and ovary, stomach, small bowel, hepatobiliary tract, pancreas, renal pelvis, ureter and brain tumors, particularly glioblastomas (Aarnio et al., 1999; Lynch et al., 2006a, 2008;
Lynch and de la Chapelle, 1999; Lynch and Lynch, 1979; Myrhoj
et al., 1997).
Emerging data from several centers have now demonstrated that among female members of Lynch syndrome families, the cumulative lifetime risk (to age 70 years) for primary
endometrial cancer is greater than their risk for CRC (Dunlop
et al., 1997; Quehenberger et al., 2005; Vasen et al., 2001). In
several of these studies the lifetime risk and standardized
incidence ratios (SIRs) for primary ovarian cancer, compared
to population risk, exceed that of all other primary extracolonic malignancies besides endometrial cancer in the women
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
= Ovarian Cancer
Figure 1 – The pedigree of one of the families involved in the linkage studies that demonstrated that the 17q12–q23 locus for early-onset breast cancer was also associated with hereditary ovarian cancer
(Narod et al., 1991).
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Figure 2 – Pedigree of an HBOC family with multiple occurrences of ovarian cancer in concert with carcinoma of the breast wherein a BRCA1 mutation was found. Note also the strikingly early onset of
ovarian cancer shown in III-2 with onset at age 33, along with early onset in additional individuals shown in the pedigree.
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
= Ovarian Cancer
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
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= Ovarian Cancer
Figure 3 – Pedigree depicting an HBOC family with a known BRCA2 mutation. Notable are the two individuals with ovarian and breast cancer
(II-2, II-3).
of Lynch syndrome kindreds (Aarnio et al., 1999; Vasen et al.,
1999; Watson and Lynch, 2001). Aarnio et al. (1999) calculated
an SIR of 13 (95% CI ¼ 5.3–25) compared with their populationbased data and a 12% cumulative lifetime risk for ovarian cancer in Finnish women from Lynch syndrome families who
were carriers of MLH1 or MSH2 mutations. In their recent
study of pooled data from four large hereditary cancer registries in Europe and the United States, Watson et al. (2008)
determined a 6.7% lifetime risk for ovarian cancer in proven
or probable MSH2 and MLH1 mutation carriers from Lynch
syndrome families. Data from The Netherlands Hereditary
Nonpolyposis Colorectal Cancer Registry and the Clinical
Genetics Centre of the Radiumhospital in Oslo were analyzed
by Vasen et al. (2001), who reported a cumulative lifetime risk
(to age 70 years) of 10.4% for ovarian cancer in MSH2 mutation
carriers, which would exceed a 3.4% lifetime risk for ovarian
cancer in the carriers of MLH1 mutations in women from
Lynch syndrome families. In the families associated with
MLH1 mutations the mean age at which ovarian cancer was
diagnosed in carriers was 51 years (range, 35–75 years), and
in families associated with MSH2 mutations the mean age of
ovarian cancer diagnosis was 45 years (range, 37–58 years)
(Vasen et al., 2001) (see Figures 4 and 5).
3.
Genetics of hereditary ovarian cancer
3.1.
Hereditary ovarian cancer linked to mutations in
BRCA1 and BRCA2
The estimated risk for developing ovarian cancer during the
lifetime of women selected from HBOC syndrome families
who inherit cancer-associated mutations in BRCA1 has been
estimated to be as low as 11% to as high as 66% (Brose et al.,
2002; Easton et al., 1993, 1995; Ford et al., 1994, 1998; King
et al., 2003; Milne et al., 2008; Satagopan et al., 2002; Struewing
et al., 1997). The lifetime risk for ovarian cancer in BRCA2
mutation carriers from HBOC syndrome families has been
estimated between 10% and 20% (King et al., 2003; Satagopan
et al., 2002; Struewing et al., 1997). Antoniou et al. (2003) estimated average cumulative lifetime risks for ovarian cancer
in BRCA1 carriers to be 39% and 11% in BRCA2 carriers, unselected for family histories using pooled data from 22 published
studies.
3.1.1. Specific BRCA1 and BRCA2 mutations carried in closed
populations
Certain relatively closed and geographically confined populations carry well-defined mutations (founder mutations). Some
populations are known to be particularly susceptible to ovarian cancer because of founder mutations in BRCA1 and/or
BRCA2. The most studied of these populations are Ashkenazi
Jews (Jewish families who trace their ancestries to Eastern
Europe) in North America and Israel, with specific founder
mutations 185delAG and 5382insC in the BRCA1 gene and
6174delT in the BRCA2 gene. The lifetime ovarian cancer risk
associated with carriers of one or another of these Ashkenazi
mutations was 23% in a study by the New York Breast Cancer
Study Group (King et al., 2003). Of 92 consecutive Ashkenazi
women diagnosed with ovarian cancer in the New York
area, Tobias’s group found that 14 carried the 185delAG mutation and 2 carried the 5382insC mutation in BRCA1, while 7
carried a 6174delT mutation in BRCA2, for a 25% (23/92) incidence of these known cancer-associated mutations (Tobias
et al., 2000). A New England study of 32 Jewish women with
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Figure 4 – Pedigree of a family showing the Lynch syndrome as evidenced by early-onset colorectal cancer as shown in individual III-3, in whom the disease was diagnosed at 32 years of age with death at the same age.
Note also occurrences of carcinoma of the ovary and endometrium in individuals IV-9, IV-15, and IV-16. Individual III-7 was diagnosed with ovarian cancer; her mother (II-4) had ‘‘uterine cancer,’’ but we do not have
the pathology so we cannot exclude endometrial cancer.
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= Ovarian Cancer
Figure 5 – Pedigree of another example of a Lynch syndrome family with multiple occurrences of early-onset ovarian cancer. Note individual II-6 with carcinoma of the ovary and endometrium at age 46 years,
carcinoma of the cecum at age 47 years, and of the sigmoid colon at age 56 years. That individual has a daughter with early-onset ovarian cancer (III-13) and another daughter (III-16) with carcinoma of the
ovary, endometrium, and colon.
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ovarian cancer found that 8 carried a 185delAG mutation in
BRCA1 and 6 carried a 6174delT mutation in BRCA2, an incidence of 44% (14/32) for one or another of the known ovarian-associated genetic mutations carried in Ashkenazi
populations (Lu et al., 1999). Forty-eight per cent of 71 Jewish
ovarian carcinoma patients tested in Los Angeles carried one
of the three known Ashkenazi founder mutations; 31% (22/
71) of these patients carried a mutation in BRCA1 and 17%
(12/71) carried a mutation in BRCA2 (Cass et al., 2003).
A specific 999del5 mutation in BRCA2 accounts for 8.5% of
the breast cancer and 6.0–7.9% of the ovarian cancer in Iceland
(Johannesdottir et al., 1996; Rafnar et al., 2004). Rafnar et al.
(2004) of the Icelandic Genomics Corporation and colleagues
at the University of Iceland and Landspitali University Hospital in Reykjavik, estimated that inheritance of the 999del5
founder mutation conveys a highly significant 20.65 odds ratio
(OR) (95% CI ¼ 7.75–57.02) risk of developing ovarian cancer.
From the Icelandic Cancer Registry data, Tulinius et al.
(2002) calculated a significantly increased ovarian cancer risk
of OR ¼ 1.48 (95% CI ¼ 1.08–1.96) for first-degree relatives and
an increased ovarian cancer risk of OR ¼ 1.32 (95% CI ¼ 1.00
1.63) for second-degree relatives of affected probands carrying
this mutation.
Soegaard et al. (2008) examined BRCA1 and BRCA2 genes for
coding sequence mutations and large genomic rearrangements in 445 confirmed cases of ovarian cancer from Denmark. They focused upon associations between their clinical
characteristics in concert with their mutation status; they
then extended this to cancer risk for first-degree relatives as
well as clinicopathologic features of the tumors. Findings
showed pathogenic BRCA1 or BRCA2 mutations in 26 cases
(5.8%) of ovarian cancer patients, in which 5 differing mutations were identified in more than one individual, a finding
consonant with the possibility of ovarian cancer founder
mutations in Denmark. Mutation carriers were diagnosed at
a significantly earlier age than noncarriers (median, 49 and
61 years, respectively; p ¼ 0.0001). BRCA1 mutations were
carried by 23% of women diagnosed before the age of 40 years,
15% of those diagnosed at 40–49 years, 4% of those diagnosed
at 50–59 years, and 2% for women diagnosed when 60 years of
age or older ( p ¼ 0.00002). First-degree relatives of mutation
carriers had greater relative risks of both ovarian cancer
(RR ¼ 10.6, 95% CI ¼ 4.2 26.6; p < 0.0001) and breast cancer at
less than 60 years (RR ¼ 8.7, 95% CI ¼ 3.0–25.0; p < 0.0001).
3.2.
Ovarian cancer cluster region (OCCR) and BRCA2
mutation
The OCCR of the BRCA2 gene appears to predispose to an excess of ovarian cancer. Gayther et al. (1995, 1997) identified
truncating mutations clustered in a BRCA2 region of approximately 3.3 kb in exon 11 in families with the highest risk of
ovarian cancer in relation to breast cancer (p ¼ 0.0004). Based
on a subsequent study by Lubinski et al. (2004), this was found
to be attributable to both the relatively high risk of ovarian
cancer and the relatively low risk of breast cancer. Lubinski
et al. (2004) studied 440 families with 140 distinct BRCA2 mutations, which supported the assignment of the OCCR to the region spanned by nucleotides 3035 and 6629. Families with
mutations located within this region were approximately
twice as likely to contain women affected with ovarian cancer
as families with other mutations (OR ¼ 2.21; p ¼ 0.0002).
Thompson et al. (2001, 2002a) reported higher ratios of ovarian
to breast cancer in the central regions of BRCA1 and BRCA2
and confirmed reduced risk for ovarian cancer with 30 mutations in BRCA1.
Both the position of the mutation and the ethnic background of the family appear to contribute to the phenotypic
variation observed in families with BRCA2 mutations, and
therein Lubinski et al. (2004) concluded that their study provided ‘‘.compelling evidence that the risk of ovarian cancer
in all BRCA2 families is not uniform.’’ This lack of uniformity
of risk due to the OCCR may therefore be modified by ethnicity, yet-to-be-identified modifier genes, and/or environmental
exposures.
If further investigations such as these ultimately define
that specific mutations in BRCA1 and/or BRCA2 are associated
with significantly increased or decreased risks for ovarian carcinoma, the implications for genetic counseling and clinical
management are obvious.
3.3.
Hereditary ovarian cancers linked to mismatch
repair (MMR) genes
Replication errors in somatic DNA without chromosomal allelic loss of heterozygosity (LOH), demonstrated by PCR-based
amplification and electrophoretic mobility testing, were found
to manifest phenotypically as sequentially repeated banding
patterns (Ionov et al., 1993), now termed ‘‘microsatellite instability’’ (MSI). Such patterns are known to represent the possibility of significant nucleotide deletions and other nucleotide
rearrangements (van der Klift et al., 2005), and have been demonstrated by investigators at the Mayo Clinic Foundation and
the University of Helsinki in colon cancers from the majority
of Lynch syndrome patients (Aaltonen et al., 1993; Thibodeau
et al., 1993). Simultaneously, a collaborative international
group under the leadership of Peltomäki in Helsinki reported
linkage of HNPCC to a microsatellite marker (D2S123), that
previously was mapped in the region of chromosome 2p16–
15, in two large families subsequently determined to have
Lynch syndrome (Peltomäki et al., 1993). This genetic locus ultimately was mapped to chromosome 2p22–21 (NCBI, 2008),
cloned and recognized to be the human homologue, designated MSH2, of a bacterial MMR gene (MutS) (Fishel et al.,
1993; Green et al., 1994; Leach et al., 1993; Schmutte et al.,
1998). Rapidly thereafter, other MMR homologues were analyzed, and the next most frequent human MMR gene linked
to HNPCC was found in chromosome 3p21 (NCBI, 2008) and
designated MLH1 (Bronner et al., 1994; Lindblom et al., 1993;
Papadopoulos et al., 1994; Tannergård et al., 1994). Subsequently, mutations in these genes (MSH2 and MLH1), as well
as two other human mismatch repair genes, MSH6 in chromosome 2p21–16 and PMS2 in chromosome 7p22 (NCBI, 2008),
were linked to other cancers that have been found to be integral to Lynch syndrome (Akiyama et al., 1997; Miyaki et al.,
1997; Nakagawa et al., 2004; NCBI, 2008; Nicolaides et al.,
1994; Schmutte et al., 1998). Further research to characterize
the locations of MSH2 and MSH6 on chromosome 2p discovered that they map to a region within just 1 MB from one another (Schmutte et al., 1998).
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The genetic closeness in chromosome 2p of the MSH2 and
MSH6 loci implied that there may be a functional relationship
in somatic mismatch repair, which in vitro molecular chemistry research with HeLa cells has shown to involve a complex of
MSH2 and MSH6 proteins, termed hMutSa, that is necessary
for mismatch binding and repair (Drummond et al., 1995; Iaccarino et al., 1998; Palombo et al., 1995). Although the hMutSa
protein complex was necessary for repair of small base–base
and nucleotide loop repairs, in vitro experiments indicated
that it may not be needed or involved in the correction of larger
DNA defects that are manifested in colorectal cancers by high
microsatellite instability (MSI-H) but may be necessary for
mismatch repair in MSI-low tumors, such as those associated
with hereditary mutations in MSH6 (Drummond et al., 1995;
Genschel et al., 1998; Wu et al., 1999). For mismatch recognition, the MSH2 protein thus binds with the MSH6 protein to
form the hMutSa complex for the correction of single base
mispairs (Acharya et al., 1996; Peltomäki, 2003). Another mismatch repair complex, MutSb, first identified in the yeast Saccharomyces cerevisiae, involves proteins coded by MSH2 and
MSH3 (Acharya et al., 1996; Marsischky et al., 1996; Das Gupta
and Kolodner, 2000), and an hMutSb protein complex has
been demonstrated in several human cell lines, where it also
supports the repair of single nucleotide mispair and 2–8 nucleotide insertion/deletion, but was not active in mismatch repair
of larger defects (Genschel et al., 1998). Either the hMUSb protein complex of MSH2 and MLH3 or the hMUSa heterodimer of
MSH2 protein with MSH6 protein is necessary for recognition
and repair of insertion–deletion errors (Acharya et al., 1996;
Peltomäki, 2003). MSH2 protein is integral for mismatch recognition in both of these MMR complexes; however, the molecular deficiencies associated with inheritance of cancerassociated mutations in MLH1 so far are less well explored.
Several in vitro experiments have addressed problems of
defining the mechanism of defective MMR that accompanies
inheritance of mutated MLH1 in Lynch syndrome. One of these
investigations that bears mentioning was by Koi et al. (1994),
a group from the University of Michigan and the Institute of
Environmental Health Sciences, Research Triangle, North Carolina, who restored microsatellite stability by introducing
human chromosome 3 into HCT116 human colon cancer cell
lines that carried biallelic mutations in MLH1 and were
therefore deficient in MMR. This procedure also reduced intolerance of the HCT116 cell line to methyl-N0 -nitro-N-nitrosoguanidine, tolerance to which is accompanied by loss of
MMR (Koi et al., 1994). The work was followed by further experiments in which Carethers et al. (1996) showed that transfer of chromosome 3 into the MMR defective HCT116 cell line
with homologous MLH1 mutations corrected its failure to arrest cell growth in the G2 phase, a ‘‘checkpoint’’ at which
DNA damage may be repaired or replication of mutated DNA
prevented. Boland et al. (2008) recently offered evidence that
a complex of MLH1 and PMS2 proteins may be required for
MMR activity. This group found that transfer of chromosome
3 into HCT116 cells, previously deficient of both MLH1 and
PMS2 proteins in spite of already ‘‘robust presence’’ of PMS2
mRNA, led not only to increased MLH1 activity but also the expression of both MLH1 and PMS2 proteins. Although, germline
mutations in MSH3 have not been associated with CRC in the
classical Lynch syndrome (Huang et al., 2001); somatic
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mutations in MSH3, due to the loss of its MSH3 protein products, may be instrumental in potentiating further deleterious
mutations in other DNA repair genes. Thus, failure of the
MMR system in families with Lynch syndrome through inheritance of a deleterious MSH2, MLH1, or MSH6 mutation with
LOH or mutation of the normal allele results in unchecked
hypermutability with the accumulation of repeated nucleotide sequences phenotypically expressed as MSI, beginning
a cascade to ultimate tumorigenesis (Eshleman et al., 1995;
Ionov et al., 1993; Malkhosyan et al., 1996; Peltomäki, 2003).
European and multi-institutional studies have shown that
some 90% of American and European Lynch syndrome families tested with DNA- or RNA-based techniques carried mutations in MSH2 or MLH1 (Peltomäki et al., 1997; Peltomäki and
Vasen, 2004; van der Klift et al., 2005; Wagner et al., 2003; Wijnen et al., 1998), and absence of MSH2 and MLH1 functional
expression appears to be the fundamental defect in the majority of typical Lynch syndrome families, such as those families
that feature both CRC and endometrial carcinomas and meet
the Amsterdam criteria (Peltomäki and Vasen, 2004; Vasen
et al., 1999). Interestingly, in one of these studies, four of 48
nucleotide rearrangements found in Lynch syndrome families
were not actually within the genetic coding regions, but three
families carried nucleotide deletions immediately upstream
of MSH2, and one family carried a deletion upstream of
MSH6 in chromosome 2p, presumably, thereby affecting
MMR gene expression (van der Klift et al., 2005). At least 175
germline MSH2 and 225 MLH1 mutations associated with
Lynch syndrome had been registered in the International
Society of Gastrointestinal Hereditary Tumors database by
2003, accounting, respectively, for 39% and 50% of the MMR
germline mutations in 748 Lynch syndrome families, worldwide (Peltomäki and Vasen, 2004).
Hereditary transmission of MSH6 mutations is less common in Lynch syndrome families, accounting for only 7% in
the International Society of Gastrointestinal Hereditary
Tumors database (Peltomäki and Vasen, 2004), and although
germline mutations in MSH6 have been associated with an attenuated form of Lynch syndrome with later onset of tumors,
the 71% cumulative lifetime risk for endometrial carcinomas
seems to be greater in these kindreds than in those which
are associated with germline mutations in MLH1 and MSH2
(Hendriks et al., 2004; Peltomäki and Vasen, 2004; Wijnen
et al., 1999). Only 4% of the germline MMR gene mutations
recorded in the International Society of Gastrointestinal
Hereditary Tumors databases were in PMS2 and MLH3, and
these were reported only in atypical variants of the Lynch syndrome (Peltomäki and Vasen, 2004), such as Turcot syndrome,
characterized by brain tumors, usually glioblastomas, colonic
polyps and café au lait spots, lipomas and multiple basal cell
carcinomas of the scalp.
Although a few cases of homozygous inheritance of defective MSH2 and MLH1 have been reported in profoundly affected
children with neurofibromas, lymphomas, leukemia, café au
lait spots, and brain tumors (Ricciardone et al., 1999; Vilkki
et al., 2001; Wang et al., 1999; Whiteside et al., 2002); in the classical Lynch syndrome, a defective MSH2 or MLH1 and more
rarely a defective MSH6 is inherited and paired with its normal
‘‘wild-type’’ allele from the non-affected parent to be somatically replicated together until chance or an exogenous
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mutagen results in mutation or somatic loss of the wild-type
allele (LOH), initiating oncogenic transformation (Liu et al.,
1996; Nyström-Lahti et al., 1996; Wijnen et al., 1999). However,
contrary to their expectation, a collaborative group headed by
Aaltonen (Aaltonen et al., 1993) found no LOH at the D2S123 locus coinciding with the MSH2 site in chromosome 2p linked to
CRC in 14 tested tumors from three Lynch syndrome families,
leading them to speculate that for those who inherit a defective
gene at this locus, LOH may not be necessary for initiation of
carcinogenesis. Notwithstanding, MMR gene mutation or allelic LOH in turn adversely affect the interaction of these genes
and their proteins with MSH6, MSH3, and PMS2 protein products in mismatch repair (Aaltonen et al., 1993; Chang et al.,
2000; Plaschke et al., 2004; Schweizer et al., 2001). Thereafter,
the impaired MMR mechanism fails to correct DNA replication
errors induced by exogenous mutagens or occurring by chance
during mitosis and cell division (Ionov et al., 1993; Thibodeau
et al., 1993), resulting in hypermutability, an oncogenic cascade, and the accumulation of nucleotide sequences, more
or less phenotypically expressed as the nucleotide bands (Eshleman et al., 1995).
Early studies with various markers reported microsatellite
instability (MSI) in 8–17% of sporadic ovarian carcinomas
(Fujita et al., 1995; Han et al., 1993; Osborne and Leech, 1994).
In 1998 the U.S.A. National Cancer Institute (NCI) Workshop
on Microsatellite Instability proposed specific markers
(BAT25 and BAT26 for two mononucleotide repeats, and
D5S346, D2S123 and D17S250 for three dinucleotide repeats)
to be used in the recognition of tumors with defective MMR
(Boland et al., 1998). Sood et al. (2001) of the University of
Iowa studied 109 unselected ovarian cancers and reported
that only 28% of the non-serous tumors were microsatellite
stable (MSS), that is, showing normal nucleotide length at all
marker loci in the NCI panel, compared with 42% of the serous
carcinomas being stable at all marker loci. Using the NCI five
marker panel, Gras et al. (2001) at the Autonomous University
of Barcelona studied 52 sporadic ovarian tumors (35 malignant, 7 borderline, and 10 benign); they identified MSI in
only two of the 52 tumors (4%), one an endometrioid carcinoma and the other a clear cell carcinoma. This led Gras
et al. (2001) to expand their investigation to a total of 56 ovarian endometrioid and clear cell carcinomas in which 7 (12.5%)
were found to have MSI. A subsequent study by the Barcelona
group using the NCI panel found MSI in 3/17 (18%) of the endometrioid ovarian carcinomas and 1/16 (6%) of the clear cell
ovarian carcinomas that they studied (Catasús et al., 2004).
Testing in turn a series of 74 sporadic endometrioid ovarian
carcinomas for MSI with a four marker panel consisting of
BAT25, BAT26, DS5S346, and D17S250, Liu et al. (2004) found
high level MSI (MSI-H) in 20% of the tumors of which 9/15
(60%) were demonstrated to have lost MHL1 and/or MSH2 protein with immunohistochemical staining. Nine (12%) of the
endometrioid ovarian carcinomas studied by Liu et al. (2004)
showed low level MSI (MSI-L), and the remaining 50 tumors
(68%) were MSS. Though not reaching statistical significance,
the endometrioid ovarian carcinomas that showed MSI-H in
this series tended to be low grade tumors ( p ¼ 0.053).
Cai et al. (2004) used the NCI battery of markers to study 42
ovarian clear cell carcinomas from Yale University and the
University of Texas M.D. Anderson Cancer Center and found
that 6 tumors (14%) were MSI-H, 3 tumors (7%) were MSI-L
and the remaining 33 tumors (79%) were MSS. This group
found that 4/6 ovarian clear cell carcinomas with MSI-H demonstrated loss of MLH1 or MSH2 protein expression with immunohistochemical staining; whereas, none of the 3 clear
cell carcinomas with MSI-L and only 2/33 of the MSS clear
cell carcinomas demonstrated loss of MLH1 or MSH2 protein
expression (Cai et al., 2004). On the other hand, loss of MLH1
and MSH2 protein expression is highly predictive of MSI-H in
unselected sporadic ovarian carcinoma (Rosen et al., 2006).
Malander et al. (2006) tested 128 ovarian carcinomas from patients at the Lund University Hospital for MSI using the mononucleotide markers BAT25, BAT26, BAT40, BAT34C4 and the
dinucleotide markers D2S123 and D5S346 in immunohistochemical testing for expression of MSH2, MLH1, MSH6 and
PMS2 proteins. This Swedish group found that 3 of the 128
ovarian carcinomas (2.3%) lost MMR protein expression, and
each of these was MSI positive. Two of these ovarian tumors,
which showed loss of both MLH1 and PMS2 proteins, were
mucinous carcinomas, one of which was mixed with endometrioid elements; and one ovarian tumor, which showed loss of
MSH6 protein, was a clear cell carcinoma. Family histories
consistent with Lynch syndrome were obtained from the
patient with clear cell carcinoma and the patient with mixed
mucinous–endometrioid carcinoma (Malander et al., 2006),
the latter fulfilling the revised Amsterdam criteria for HNPCC
(Vasen et al., 1999). Rubin et al. (1998) examined 116 consecutive unselected ovarian cancer patients treated at the University of Pennsylvania for mutations in MSH2, MLH1, BRCA1 and
BRCA2. Among these ovarian cancer patients, 10 were found
to carry germline mutations in BRCA1, one patient carried
a germline mutation in BRCA2 and two patients carried MMR
gene mutations. One of these was an MSH2 mutation in
a 46-year-old woman who had survived colon cancer at age
29 years, and the other was a 64-year-old woman who carried
an MLH1 mutation and was diagnosed with synchronous
ovarian and endometrial carcinomas; however, neither of
these women’s families fulfilled the Amsterdam criteria for
HNPCC (Rubin et al., 1998; Vasen et al., 1999).
In 72 proven or probable mutation carriers, who were diagnosed with ovarian cancer from an international study of 261
Lynch syndrome families, reported by Watson et al. (2008), the
risk for this disease was significantly higher in families that
carried defective MSH2 compared with familial MLH1 mutations ( p < 0.006). A collaborating group from the Netherlands
and Norway, led by Wijnen et al. (1999), found that women
who carried MSH6 mutations were more than twice as likely
to have endometrial carcinomas and atypical endometrial hyperplasia (73%) than women who inherited defective MSH2
(29%) or MLH1 (31%); and, based on their finding of instability
of the mononucleotide TGFbR2(A)10 in colorectal and urothelial tumors, but not in endometrial or ovarian tumors, Wijnen
et al. hypothesized that there are different tumorigenic pathways toward endometrial and ovarian cancers in those who
inherit cancer-associated MSH6 mutations. Although this
group made no distinction between the various histological
types of ovarian cancer in their report, a study by Zhai et al.
(2008) recently reported that MSH6 protein expression is found
in significantly higher proportions of non-serous ovarian carcinomas (23.2%) than in ovarian serous carcinomas (8.7%).
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
Thus, it appears that studies to date indicate that MSI-H
and associated loss of MMR gene expression are found
more frequently in ovarian carcinomas of non-serous ovarian
histologies, particularly endometrioid and related clear cell
types, than in serous carcinomas, which are more common
in general populations. An international collaborative group
headed by Kuismanen et al. (2002)) of the University of Helsinki studied 44 colorectal cancers and 57 endometrial cancers from well characterized Lynch syndrome families that
carried either MSH2 or MLH1 mutations. Their investigations
showed that CRCs displayed more consistent patterns of oncogene instability, particularly TGFbR2 (Transforming Growth
Factor Beta Receptor II in chromosome 3p22) in 73% of the
CRCs compared with 18% of the endometrial cancers; while
endometrial cancers with the loss of PTEN (Phosphatase
and Tensin homologue, also known as MMAC1), a tumor suppressor gene at chromosome 10q23.3 (NCBI, 2008), was found
in 20% of endometrial cancers but only 5% of CRCs (Kuismanen et al., 2002). PTEN protein acts as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate
(PtdIns (3,4,5)P3 or PIP3). PTEN specifically catalyses the
dephosporylation of the 30 phosphate of the inositol ring in
PIP3, resulting in the biphosphate product PIP2 (PtdIns(4,5)P2).
This dephosphorylation is important because it results in inhibition of the AKT signaling pathway; so with loss or dysfunction of this gene and encoded protein, proliferation of
transformed cells continues unabated (Sakurada et al.,
1999). More than ten years ago, Peiffer et al. (1995) from the
University of Washington studied endometrial cancers using
39 microsatellite markers representing all human chromosomal arms except X and found that the most frequent LOH
was on chromosome 10q at the D10S610 marker site in the
10q23–26 region, which was found in 8/20 (40%) of the informative cases. Since then, several groups have reported
PTEN mutations and LOH at the PTEN locus in chromosome
10q of endometrioid tissues.
Risinger et al. (1997) found PTEN mutations in 34% (24/70) of
the endometrial cancers they studied. While Tashiro et al.
(1997) found PTEN mutations in 62% (16/26) of endometrioid
endometrial cancers, when they stratified for microsatellite
stability, PTEN mutations were found in 86% (12/14) of the
MSIþ endometrioid endometrial carcinomas but in just 33%
(4/12) of the MSS endometrioid endometrial carcinomas.
LOH of microsatellite markers surrounding the PTEN locus in
chromosome 10q was found in 48% (11/23) of the endometrial
cancers but only in 17% (6/35) of the CRCs tested by Kong et al.
(1997). Mutter et al. (2000) found PTEN mutations in 83% (25/30)
of the endometrioid endometrial carcinomas but in none of
the 10 normal endometria that they studied; and although
most of the endometrial carcinomas (23/30) showed mutations in only one PTEN allele, all seven of the 30 carcinomas
with LOH of markers within or flanking PTEN had mutations
in the remaining allele. Moreover, in this investigation by Mutter et al., there was complete loss of PTEN protein expression
in 61% (20/33) and moderate to mild diminutions of PTEN
expression in 97% (32/33) of the endometrioid endometrial
carcinomas; but only 2 of the 8 (25%) non-endometrioid carcinomas tested by Mutter et al. completely lost PTEN expression. According to their reported data there was moderate to
mild loss of PTEN expression in another 50% of the non-endo
107
metrioid carcinomas; although there was no significant difference between absent PTEN expression in endometrioid compared with any expression in non-endometrioid endometrial
carcinomas ( p ¼ 0.115) (Mutter et al., 2000). Taken all together,
the studies by Mutter et al. (2000) showing high PTEN mutation
rates, PTEN LOH, and absent or diminished PTEN expression
indicate probable biallelic inactivation of PTEN in most of
the endometrioid endometrial carcinomas.
LOH of PTEN has been reported by Obata et al. (1998) at the
University of Southampton in 43% of sporadic endometrioid
ovarian carcinomas (13/30), and 21% of the endometrioid
ovarian carcinomas (7/34) had somatic mutations in PTEN.
PTEN mutations were accompanied with allelic LOH in 6 of
these 7 endometrioid ovarian carcinomas, and two somatic
mutations were demonstrated and expected to be on separate
alleles in the remaining endometrioid carcinoma (Obata et al.,
1998). One predominantly mucinous ovarian carcinoma with
foci of endometrioid differentiation showed LOH in chromosome 10q and a PTEN mutation (Obata et al., 1998). Though
less frequently, LOH in chromosome 10q has been reported
in ovarian clear cell carcinomas (8–14%) (Catasús et al., 2004;
Obata et al., 1998) than in ovarian serous carcinomas (28%)
(Obata et al., 1998), Obata et al. (1998) found no PTEN mutations in 8 clear cell and 25 serous ovarian carcinomas. Tashiro
et al. (1997) of Johns Hopkins University found no PTEN mutations in 12 serous carcinomas of the ovary. In sporadic endometrioid ovarian carcinomas studied at the Autonomous
University of Barcelona, Catasús et al. (2004) demonstrated
MSI in 3/17 (17.5%) and PTEN mutations in 3/21 (14%) of the
tumors. This group found MSI in 1/16 (6%) ovarian clear cell
carcinomas and in 1/10 (10%) mixed endometrioid–clear cell
carcinomas; and PTEN mutations were found in 1/18 (5.5%)
clear cell carcinomas and 1/15 (6.5%) of the mixed endometrioid–clear cell carcinomas. What is most interesting, however, is that in the tested tumors 3/5 (60%) of the
endometrioid ovarian carcinomas that carried PTEN mutations showed MSI (Catasús et al., 2004). PTEN mutations
have been reported in other human malignancies (Li et al.,
1997). Of most importance to our current discussion, PTEN
mutations are frequently found in endometrioid endometrial
carcinomas (Kong et al., 1997; Risinger et al., 1997; Tashiro
et al., 1997), including some 34–55% of all sporadic tumors
(Kong et al., 1997; Risinger et al., 1997; Tashiro et al., 1997)
and 78–86% (12/14) of those that were selected for MSI (Kong
et al., 1997; Tashiro et al., 1997). Whereas, none of the 6 serous
endometrial carcinomas tested by Tashiro et al. (1997) showed
MSI or had PTEN mutations.
Reduced PTEN protein expression has been reported in
both endometrial hyperplasias and advanced endometriosis
(Ali-Fehmi et al., 2006; Levine et al., 1998; Martini et al., 2002;
Maxwell et al., 1998; Mutter et al., 2000; Sato et al., 2000). During
their studies of PTEN mutations in endometrioid endometrial
carcinomas, Mutter et al. (2000) also tested several ‘‘endometrial intraepithelial neoplasias’’ (EIN) or ‘‘precancers,’’ which
others often describe as endometrial hyperplasia and found
that 55% (16/29) of these lesions had PTEN mutations. Although PTEN mutations have been reported in 20–24% of endometrial hyperplasias, most were somatic mutations (Levine
et al., 1998; Maxwell et al., 1998); however, Levine et al. (1998)
of Johns Hopkins University found a germline PTEN mutation
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in one of 11 complex atypical endometrial hyperplasias associated with endometrioid endometrial carcinoma.
Reduced PTEN expression was found by Martini et al. (2002)
of the Catholic University-Rome in 15% (7/46) cases of stage IV
endometriosis, and two of the cases which coexisted with
endometrioid cancer had hypermethylated MLH1, while a collaborative group headed by Ali-Fehmi (Ali-Fehmi et al., 2006)
of Wayne State University – Harper Hospital, Detroit found
LOH of chromosome 10q23.3 loci, corresponding to PTEN, in
7/23 (30%) of their cases of endometriosis, 3/12 (25%) of atypical endometriosis, 3/6 (50%) ovarian endometrioid carcinomas
and 3/5 (60%) ovarian clear cell carcinomas. Sato et al. (2000) at
the University of Tsukuba, Japan demonstrated LOH at the
chromosome 10q23.3 locus in 8/19 (42%) informative cases of
endometrioid ovarian carcinoma, 13/23 (57%) solitary benign
endometrial ovarian cysts and 6/22 (27%) of ovarian clear
cell carcinomas. Somatic PTEN mutations were identified in
4/20 (20%) endometrioid ovarian carcinomas and in 7/34
(21%) benign endometrial ovarian cysts but in just 2/24 (8%)
of the ovarian clear cell carcinomas studied by Sato et al. Common PTEN LOH in both carcinoma and endometriosis was
found by Sato et al. in 3/5 (60%) of the endometrioid ovarian
carcinomas with synchronous endometriosis and 7/12 (50%)
of the ovarian clear cell carcinomas with synchronous endometriosis. Although PTEN LOH was not found in any of 12
specimens of benign ectopic endometrium studied by Sato
et al., one of the endometrioid carcinomas and 3 of the clear
cell carcinomas associated with endometriosis had PTEN
LOH only in the ovarian cancer and not in the endometriosis,
and the other endometrioid and clear cell ovarian carcinomas
did not show PTEN LOH in either cancer or endometriosis.
From these findings, Sato et al. (2000) inferred that PTEN mutations or inactivation and allelic loss of heterozygosity are
early events that lead to the genesis of endometrioid and clear
cell carcinomas.Ali-Fehmi et al. (2006) found MSI in 19/23
(83%) of their cases of endometriosis, 9/12 (75%) cases of atypical endometriosis and 4/6 (67%) cases of atypical endometriosis adjacent to ovarian carcinomas (2 endometrioid
carcinoma, 2 clear cell carcinoma and 1 serous carcinoma).
The foregoing observations and data suggest that endometrioid carcinoma may arise from malignant transformation
through the loss of MMR in benign or estrogen stimulated endometrium, endometrial hyperplasia or even endometriosis.
Thus, unfolding molecular science investigations are beginning to shed light on the genesis of endometrioid and perhaps
mixed and clear cell ovarian carcinomas, which may apply to
patients who inherit cancer-associated mutations in MMR
genes. It is, therefore, interesting to speculate that inheritance
of defective mutations in one or more of the major MMR genes
implicated in Lynch syndrome may be paired with a wild-type
allele which becomes destabilized or lost, or which mutates;
thereby down-the-line adverse somatic mutations are not rectified and continue to accumulate in other MMR genes so that
their protein products fail to bind and/or correct subsequent
somatic mutations until finally irreparable biallelic mutations
occur or there are deleterious allelic mutations along with
LOH in key tumor suppressor genes such as, possibly, PTEN,
causing loss of their protective functions.
Somatic mutations in CTNNB1 located in chromosome
3p21 which codes for b-catenin also have been implicated in
the genesis of ovarian endometrioid and clear cell carcinomas
(Catasús et al., 2004; Gamallo et al., 1999). Gamallo et al. (1999)
of the Hospital La Paz in Madrid demonstrated nuclear b-catenin expression in 9/13 (70%) of the endometrioid ovarian carcinomas and 2/16 (13%) serous ovarian carcinomas but in
none of the 18 clear cell, 13 mucinous or 9 mixed ovarian carcinomas that they studied. Gamallo et al. (1999) tested 25 ovarian carcinomas of various histologies by DNA sequencing and
found oncogenic CTNNB1 mutations in only 7/13 (54%) of their
endometrioid carcinomas. However, they noted limitations in
their analysis and also commented that genetic alterations
other than mutation might explain this discrepancy. In
a DNA analysis by Wright et al. (1999) at Queensland University and the Queensland Institute of Medical Research,
CTNNB1 mutations were found in only 10/63 (16%) endometrioid ovarian cancers. Catasús et al. (2004) at the Autonomous
University of Barcelona reported nuclear staining of b-catenin
with immunohistochemistry in 8/21 (38%) and accompanying
CTNNB1 mutations in 5/21 (24%) of the endometrioid ovarian
carcinomas and 1/8 (13%) of the mixed endometrioid–clear
clear cell ovarian carcinomas that they studied; while PTEN
mutations were found in 3/21 (14%) of the endometrioid ovarian carcinomas and in 13% (1/8) of mixed endometrioid–clear
cell ovarian carcinomas. Nuclear b-catenin expression was
found in only 1/18 (6%) of the ovarian clear cell carcinomas,
none of which showed a CTNNB1 mutation, and a PTEN mutation was found in only 1/18 (6%) of ovarian clear cell carcinomas tested in this study (Catasús et al., 2004). Eighteen per
cent (3/17) of the endometrioid ovarian carcinomas and 6%
(1/16) of the clear cell ovarian carcinomas showed MSI. All of
the 26 endometrioid and endometrioid–clear cell carcinomas
in this series still were confined to the ovary when they
were removed, and Catasús et al. noted that 24/54 (46%) of
the total ovarian cancer cases, including 9/18 (50%) of the
endometrioid carcinomas, 4/8 (50%) of the mixed endometrioid–clear cell carcinomas, and 10/18 (56%) of the pure clear
cell carcinomas, were associated with endometriosis. In a follow-up investigation, the Hospital La Paz group in Madrid
studied differential expression of b-catenin and found nuclear
staining in 9/13 (70%) of the endometrioid ovarian carcinomas
and in 2/16 (13%) serous ovarian carcinomas, but in none of 18
clear cell, 13 mucinous, or 9 mixed ovarian carcinomas (Sarrió
et al., 2006). Nuclear expression of b-catenin was demonstrated by Sarrió et al. (2006) in all of the seven endometrioid
ovarian carcinomas in which CTNNB1 mutations were found.
Herein, another avenue of investigation has been opened to
pursue to the end of ovarian carcinogenesis in tumors that
most resemble those found in the Lynch syndrome. Whether
immediately fruitful or not, it is always basic science that
lays the foundations for preventive and clinical applications
that will finally relieve the suffering and increase the longevity
of those who inherit genetic predilections to cancer and other
diseases.
3.4.
Specific MMR gene mutations carried in closed
populations
Like the findings in HBOC syndrome kindreds that carry common BRCA1 and BRCA2 mutations in relatively close-knit,
closed populations, a common specific MSH2 founder
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
mutation has been described in Ashkenazi Jews with Lynch
syndrome (Foulkes et al., 2002; Yuan et al., 1999). This mutation
is a nucleotide substitution, MSH2*190G / C, which results in
a substitution of proline for alanine in the MSH2 protein. It is
believed to have arisen in northeastern Europe during the seventeenth century and now is found in Ashkenazi Jews of at
least five countries, though it was not identified in individuals
of non-Jewish descent (Foulkes et al., 2002; Sun et al., 2005). Although the pedigree of an Ashkenazi Jewish New York family
did not fulfill the Amsterdam criteria for the HNPCC syndrome,
a tested proband, studied by Foulkes et al. (2002), was a 41year-old patient with an MSI-H ovarian cancer who carried
a germline MSH2*1906G / C mutation, and she descended directly from a maternal grandmother who was diagnosed with
ovarian cancer and died in her fifth decade.
During the early studies that led to the association of Lynch
syndrome with MLH1 mutations, a genealogical investigation
by Nyström-Lahti et al. (1994) linked at least eight Finnish
HNPCC families to a region in chromosome 3p, and traced
their common ancestry to a progenitor who lived in an isolated rural area of south-central Finland early in the sixteenth
century. Only after mass migration to Helsinki during and following World War II did it appear that this trait became more
disseminated in the population (Nyström-Lahti et al., 1994).
Further studies demonstrated that an identical heterozygous
germline deletion of 165 base pairs in codon 16 of MLH1 was
responsible for the CRC susceptibility trait in fourteen Finnish
families, and this was termed ‘‘mutation 1.’’ by Nyström-Lahti
et al. (1995). A separate MLH1 mutation carried by another 5
Finnish HNPCC kindreds that originated in or was introduced
into southern Finland during the early eighteenth century is
a 92 base pair splice site deletion in codon 6, designated as
‘‘mutation 2’’ (Nyström-Lahti et al., 1995). Together these
two germline mutations account for some 60% or more of
CRC associated with Lynch syndrome in Finland (Moisio
et al., 1996; Nyström-Lahti et al., 1995), and therefore may be
used for primary screening of these families (Aaltonen et al.,
1998; Salovaara et al., 2000).
Though seemingly less geographically or culturally constrained, a genomic deletion of exon 1–6 in MSH2 (Wagner
et al., 2002) has been identified in several Midwestern American families and initially traced to an alleged common ancestor of German stock, who was born in Alabama around 1814
(Wagner et al., 2003), although no European investigations
had yet detected this mutation (Lynch et al., 2004; Wijnen
et al., 1998). With the accumulation of further families and
pedigrees, it became recognized that this mutation was far
more widely dispersed than at first recognized, and it was postulated that it may have arisen in eastern Pennsylvania during
the early eighteenth century and then followed westward
migration to California and the Southwestern United States
and also into the Southeastern States and Florida (Lynch
et al., 2004). Based on that history, it was estimated that there
were some 19,000 (estimated from a female founder) to over
34,000 (estimated from a male founder) carriers of this American Founder Mutation (AFM) in MSH2 scattered among unbeknown related families throughout the United States (Lynch
et al., 2004, 2006b). Clendenning et al. (2008) further investigated the genomic sequence flanking the deletion and identified a common disease haplotype in all probands, which
109
provided evidence for a common ancestor between these
extended families. However, their work has estimated the
mutation’s age at approximately 500 years (95% CI, 425–625).
Collectively, their results would place the founding event at
a much earlier time than first thought, likely occurring in a European or Native American population. The consequence of
this finding would be to increase the estimated number of
AFM carriers in the United States significantly over those previously predicted (Clendenning et al., 2008).
Up to 20% of all deleterious mutations within this MMR
gene, including the AFM, are large germline deletions which
would not have been detectable prior to the methodology
developed by Wagner et al. (2002) and used to identify the
AFM. Now, because of the prevalence of this mutation, a specific assay can be utilized in routine DNA analysis to screen
American Lynch syndrome families without already determined cancer-associated mutations (Clendenning et al.,
2008; Lynch et al., 2004, 2006b; Wagner et al., 2003).
A fascinating discovery made in Canada was that a specific
A / T at nt942 þ 3 mutation in MSH2, though previously demonstrated worldwide, is found in 27% of Lynch syndrome families of the relatively isolated Province of Newfoundland.
Although specific, this mutation was not traceable by haplotype analysis to Lynch syndrome families from England, Italy,
Hong Kong, and Japan who carry it, leading Desai et al. (2000)
to conclude that spontaneous A / T change at 942 þ 3 may be
a relatively common de novo mutational event.
4.
Survival of ovarian cancer in HBOC and Lynch
syndrome
For several years improved prognosis and response to standard antineoplastic chemotherapy of epithelial ovarian cancers diagnosed in carriers of BRCA1 and BRCA2 mutations
from HBOC syndrome families has been noted by the majority
of investigators (Aida et al., 1998; Ben David et al., 2002; Boyd
et al., 2000; Cass et al., 2003; Chetrit et al., 2008; Pal et al.,
2007; Rubin et al., 1996; Tan et al., 2008). However, the earliest
report from the University of Pennsylvania by Rubin et al.
(1996) claiming a survival advantage for patients with ovarian
cancer associated with BRCA1 and BRCA2 mutations was
severely challenged by other authors citing the Pennsylvania
group’s failure to secure detailed information concerning surgical resection and residual disease, to histologically review
and classify a majority of the cases, to meticulously ascertain
survival status, to confirm chemotherapy drugs and regimens
and to consider lead-time bias, etc. (Canistra, 1997; Whitmore,
1997). Then studies soon followed by Jóhannsson et al. (1998)
from the University Hospital, Lund, and by Pharoah et al.
(1999) at the University of Cambridge which failed to confirm
improved survival of ovarian cancer patients from HBOC syndrome families associated with BRCA1 or BRCA1 and BRCA2
mutations. All the same, it bears noting that a subsequent
study by the Cambridge group, which selected carriers confined to the Ashkenazi Jewish mutations 185delAG and
5382insC in BRCA1 and 6174delT in BRCA2, found that ovarian
cancer patients who carried one or another of these mutations
had a survival advantage over noncarriers, though the difference did not reach significance (Ramus et al., 2001). On the
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M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
other hand, 3 relatively small studies of ovarian cancer
patients, selected because their families had strong family
histories for breast and/or ovarian cancer or they were presumed carriers of either germline or sporadic BRCA1 mutations or they were carriers of 1675delA or 1135insA founder
mutations in BRCA1 without regard to ethnicity, found no significant differences in the survival of these patients compared
with ovarian cancer patients who were not considered to bear
increased hereditary risk (Buller et al., 2002; Kringen et al.,
2005; Zweemer et al., 2001). Pursuant to those observations,
4 further studies in which ovarian cancer patients were selected because they carried an Ashkenazi mutation found significant survival advantages among carriers compared with
ovarian cancer patients who were not mutation carriers. These
larger series, which included 88 mutation carriers reported by
Boyd et al. (2000), 229 carriers reported by Ben David et al.
(2002), 34 carriers reported by Cass et al. (2003), and 213 carriers reported by Chetrit et al. (2008), found significantly improved 3–5-year survival rates in mutation carriers
compared with noncarriers. Studies reported from Tel Aviv
University by Ben David et al. (2002) and later by Chetrit
et al. (2008), demonstrated significantly higher survival rates
at 3 years of 65.8% and at 5 years of 38.1% in carriers of Ashkenazi mutations compared with 51.9% at 3 years and 24.5% at 5
years in noncarriers ( p ¼ 0.001). In an extended follow-up of
this series, the median survival of 53.7 months in mutation
carriers, compared with a medium survival of just 37.9
months in noncarriers, also was significantly longer in mutation carriers ( p ¼ 0.002) (Chetrit et al., 2008). The greatest differences found in 5-year survival rates by the Tel Aviv
investigators were in carriers compared with noncarriers
who had advanced stages and poor grade ovarian cancers
( p < 0.001) (Chetrit et al., 2008). Boyd et al. (2000) at the Memorial Sloan-Kettering Cancer Center (MSKCC) in New York
found not only improved survival after the diagnosis of ovarian cancer in their group of BRCA1 and BRCA2 Ashkenazi mutation carriers compared to noncarriers ( p ¼ 0.004), but
mutation carriers in their series also demonstrated a significantly longer median time to recurrence ( p < 0.001) with positive mutation carrier status being an independent predictor
of survival even in cases having advanced cancers ( p ¼ 0.03).
Histology, cancer grade and stage and the results of cytoreductive surgery were similar between the hereditary and sporadic cases in the MSKCC series, leading these authors to
speculate that the observed improved median survival and
longer recurrence-free intervals after treatment of BRCA-mutation associated ovarian cancers may be due to a slower rate
of cell division with more indolent behavior and/or more susceptibility to primary antineoplastic chemotherapy. Boyd’s
group did, however, note that the observed improvement in
survival was greater among BRCA1 mutation carriers
( p ¼ 0.008) than it was for BRCA2 mutation carriers
( p ¼ 0.08), though their numbers of BRCA2 mutation carriers
were smaller, compared with noncarriers (Boyd et al., 2000).
Using the Kaplan–Meier method, Pal et al. (2007) from the
H. Lee Moffitt Cancer Center of the University of South Florida
actually estimated a higher expected 4-year survival of 83%
among their 12 BRCA2 mutation carriers with ovarian cancer
than the expected survival of 37% among their 20 BRCA1
mutation carriers with ovarian cancer. This survival rate in
BRCA2 mutation carriers was significantly higher than the
expected 4-year survival rate of 12% in 200 sporadic ovarian
cancer control cases ( p ¼ 0.013), but the difference between
expected 4-year survival rates between BRCA2 and BRCA1 carriers was not significant. Byrd et al. (2008) in a collaborative
British study looked at the contribution of BRCA2 carrier status
compared with BRCA1 carrier status to life expectancy. They
found a significantly increased death rate in BRCA1 mutation
carriers compared with BRCA2 mutation carriers ( p ¼ 0.04),
and this was attributable to increased deaths from ovarian
cancer in BRCA1 carriers rather than breast cancer death rates,
which were slightly higher in BRCA2 carriers. Kaplan–Meier
analysis by Byrd et al. showed that the improvement in survival at 5 years, 10 years and 20 years in BRCA2 mutation carriers was due largely to improved prognosis for early stage
disease; because both BRCA1 and BRCA2 mutation carriers
with ovarian cancers were diagnosed with similar proportions
of advanced disease and the difference in survival with
advanced ovarian cancers was not significant.
Cass et al. (2003) at Cedars-Sinai Medical Center and the
University of California – Los Angeles found not only an
improved median survival of 91 months among a combined
group of carriers of Ashkenazi mutations in BRCA1 (n ¼ 22)
and BRCA2 (n ¼ 12) with advanced ovarian carcinoma compared with 54 months median survival among patients
who had advanced sporadic ovarian carcinoma ( p ¼ 0.046);
but also the group with BRCA1 and BRCA2 mutations had
a significantly higher 72% (21/29) response rate to primary
antineoplastic chemotherapy than the 36% (9/25) response
rate in patients with sporadic disease ( p ¼ 0.01). Ninety-one
per cent (31/34) of the ovarian carcinomas in BRCA-mutation
carriers and 78% (29/37) in noncarriers were serous type. In
spite of similar 83% (15/18) optimal results from cytoreductive surgery in mutation carriers and 100% (11/11) optimal
cytoreduction in noncarriers, 62% (18/29) of mutation carriers had negative second look operations compared with
28% (7/25) negative second look operations in noncarriers
( p ¼ 0.01). Cass et al. discovered that in vitro chemoresistance
tests to platinum chemotherapy were highly predictive of
BRCA-mutation carrier status. Following this lead, Tan
et al. (2008) in the United Kingdom matched 22 patients
with ovarian carcinoma who carried germline mutations in
BRCA1 or BRAC2 with 44 nonhereditary ovarian carcinoma
patients. Ninety-six per cent of the patients in both groups
had serous or unspecified adenocarcinomas. Patients were
matched for age, year of diagnosis, stage and histopathology,
and the authors found significantly increased response rates
in the mutation carriers to first, second and even third line
platinum based chemotherapy in the BRCA-mutation carrier
group compared with the sporadic ovarian cancer control
group. Tan et al. reported response rates of 95.5% (21/22) to
first line treatment, 91.7% (11/12) to second line treatment
and an amazing 100% (7/7) to third line treatment, compared
with 59.1%, 40.9% and 14.3%, respectively, in the control
group. The complete response rate to first line platinum
based chemotherapy was 81.8% in the BRCA-mutation carriers but just 43.2% in the control patients ( p ¼ 0.004), and
the time to relapse following first line chemotherapy was 5
years in mutation carriers compared with 1.6 years to relapse in noncarriers ( p < 0.001). In contrast with the series
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
111
Figure 6 – Schematic representation of a dualistic model depicting the development of ovarian cancer. Low-grade carcinomas are thought to
develop in a stepwise manner from an atypical proliferative tumor through a noninvasive stage (LMP) before becoming invasive. These tumors are
frequently associated with K-RAS or BRAF mutations and loss of PTEN. Somatic high-grade carcinomas (most commonly serous) develop from
the ovarian surface epithelium and/or inclusion cysts without morphologically recognizable intermediate stages. K-RAS and BRAF mutations are
less common in these tumors, whereas TP53 is frequently mutated as well as members of the PI3K/AKT pathway. In hereditary forms of this
disease (far left), the initial step in BRCA1 or BRCA2 mutation carriers is thought to consist of a TP53 mutation followed by genotoxic injury (p53
signature). In the fimbria, a tubal intraepithelial carcinoma (TIC) develops in some instances and may invade locally or spread to other peritoneal
surfaces, such as the ovary and pelvis. Depending on the location and rate of tumor growth, the tumor might be diagnosed as a primary tubal,
ovarian, or peritoneal carcinoma. Whether somatic ovarian cancers arise via the fimbria route remains to be demonstrated.
reported by Cass et al. (2003) in which all test subjects carried Ashkenazi mutations in BRCA1 or BRCA2, only 6/22
(27%) of the test subjects in the case–control study reported
of Tan et al. (2008) carried Ashkenazi mutations.
Cass et al. (2005) also examined the outcomes of 12 women
with primary fallopian tube carcinomas who carried mutations in BRCA1 (n ¼ 11) or BRCA2 (n ¼ 1) and compared these
with 16 cases of sporadic fallopian tube carcinoma. Eightythree per cent (10/12) of BRCA-mutation associated fallopian
tube carcinomas and 94% (15/16) of the sporadic fallopian
tube carcinomas were serous, and all others were endometrioid. When the site of primary cancer could be determined,
9/12 (81%) of those in BRCA1 and BRCA2 mutation carriers
and 6/16 (67%) of those in noncarriers arose in the distal or
middle fallopian tubes, and overexpression of p53 was demonstrated in 71% (5/7) of the BRCA-mutation associated cases and
72% (8/11) of the sporadic cases that were tested. There were
no significant differences in the proportions of associated dysplastic epithelium, bilateral carcinomas, immunohistochemical staining for Ki67, ER or PR in benign, dysplastic and
cancerous epithelium in the fallopian tubes of mutation carriers and noncarriers. However, the median 2-year survival
rate of 100% and 4-year survival rate of 75% in carriers
exceeded the median 2-year survival rate of 74% and 4-year
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M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
survival. Findings showed that the mean age at diagnosis of
Lynch syndrome-associated ovarian cancer was significantly
lower than that of sporadic ovarian cancer (49.5 versus 60.9
years). While ovarian cancer in Lynch syndrome was diagnosed at an earlier stage, nevertheless, the survival rate for
ovarian cancer was not significantly different between patients with ovarian cancer in Lynch syndrome and controls
with sporadic ovarian cancer. Specifically, the cumulative 5year survival rates were 64.2% and 58.1%, respectively. They
concluded that ovarian cancer in Lynch syndrome should be
treated similarly to sporadic ovarian cancer. A limitation of
this study is its relatively small numbers, thereby meriting
caution in its interpretation.
Figure 7 – Serous papillary carcinoma, 2003, H&E. Arrow shows
cross-section of a papilla.
survival rate of 50% in noncarriers; although these differences
did not reach significance in such a small series. While the
median survival of 68 months in mutation carriers with fallopian tube cancers exceeded the 37 months median survival in
noncarriers ( p ¼ 0.14).
Finally, the groups of Boyd et al. (2000), Cass et al. (2005),
and Pharoah et al. (1999) each found that the mean or median
ages of ovarian carcinoma diagnosis among BRCA1 mutation
carriers were significantly younger than the ages at which
ovarian carcinomas were diagnosed in those who carried
BRCA2 mutations.
These observations and data raise the hope of proving
more favorable prognosis and higher expectations from platinum based chemotherapy for ovarian carcinoma arising in
BRCA1 and BRCA2 mutation carriers. But much meticulous
work remains to be done. Determining whether median age
of onset, survival rates and disease-free interval results may
be skewed by inclusion of certain mutations, such as those
found in Ashkenazi Jewish populations, will require further
and larger investigations stratified as to specific BRCA1 and
BRCA2 mutations. The investigations already completed
have implications for the design of case-matched control
studies and prospective management trials. Besides the traditional variables, designation of control groups and randomized studies of prophylactic and antineoplastic agents
should consider and take care to include appropriate numbers
of carriers with specific mutations in future clinical investigations, which in turn may influence the direction of molecular
research, and vice versa, toward the goal of discovering genetic
mechanisms that might influence differential tumor growth
and response treatment.
Crijnen et al. (2005) discussed whether patients with ovarian cancer from Lynch syndrome families have improved survival comparable to that which has been shown for CRC in
Lynch syndrome (Watson et al., 1998). Twenty-six patients
with ovarian cancer, who were identified from the Dutch
Lynch syndrome registry, were compared with a control group
(52 sporadic ovarian cancer cases) which were matched for
age, stage, and year of diagnosis, all of which were derived
from the population-based Eindhoven Cancer Registry.
Kaplan–Meier analysis was used to calculate their crude
5.
Pathology of hereditary ovarian carcinomas
Ovarian tumors can be classified according to their cells of origin into three main categories: surface epithelial tumors,
germ cell tumors, and sex cord–stromal tumors. Ovarian surface epithelial (OSE) cancers are the most common type of
malignant ovarian tumor and the predominant type in the
context of hereditary ovarian cancer (Bewtra et al., 1992;
Seidman et al., 2002). Traditionally, the OSE tumors have
been histologically classified according to their cellular
appearances into (i) serous (ciliated columnar cells of tubal
type), (ii) mucinous (goblet, mucinous cells), (iii) endometrioid
(pseudostratified columnar, endometrial type), (iv) clear cell
(vacuolated cytoplasm), and (v) Brenner type (grooved nuclei)
(Seidman et al., 2002). Out of these, the first four types are
most pertinent in the context of hereditary ovarian cancers.
5.1.
Histology of ovarian carcinomas associated with
BRCA1 and BRCA2 mutations
The predominant cell type of ovarian cancers associated with
the HBOC syndrome and BRCA1 and BRCA2 mutations is serous
carcinoma (Bewtra et al., 1992; Lakhani et al., 2004; Mæhle et al.,
2008; Pal et al., 2005; Piver et al., 1996; Rubin et al., 1996), which
also is the histology of most primary fallopian tube and peritoneal carcinomas as well as intra-abdominal carcinomatosis
Figure 8 – Mucinous carcinoma, 2003, H&E. Arrow shows tall
columnar cells with intracytoplasmic mucin.
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113
BRCA1 mutation carriers and 39% of ovarian cancers in BRCA2
mutation carriers were serous carcinomas, compared with
29% serous ovarian carcinomas in noncarriers. Only 14% (5/35)
of the primary ovarian cancers in our BRCA1 and BRCA2 mutation carriers were endometrioid carcinomas, and evidently
none of these arose from areas of endometriosis (MJC, unpublished data).
5.2.
Histology of ovarian carcinomas associated with the
Lynch syndrome
Figure 9 – Endometrioid carcinoma, 2003, H&E. Arrow shows
columnar cells with complex gland formation.
diagnosed in patients who have had previous salpingo-oophor
ectomies (Casey et al., 2005; Casey and Bewtra, 2004; Piek et al.,
2003a). Review of our own Creighton University Hereditary Cancer Center database showed that 84% (37/44) of the ‘‘ovarian’’
cancers in BRCA1 and BRCA2 mutation carriers were serous carcinomas (MJC, unpublished data). Actually, 24% (9/37) of the serous carcinomas in BRCA1 and BRCA2 mutation carriers
registered as ovarian carcinomas, appear possibly to have arisen
from the fallopian tube (MJC, unpublished data). This proportion
of serous carcinomas is consistent with the collaborative study
reported by Rubin et al. (1996) to which we contributed, that
found 81% (43/53) of ovarian cancers in BRCA1 germline mutation carriers were serous carcinomas. Our own data and those
reported by Rubin et al. contrast on one hand with Shaw et al.
(2002), who found on blinded histopathology review that all 32
(100%) ovarian carcinomas from BRCA1 and BRCA2 mutation
carriers were serous carcinomas compared with 70% (28/40) serous carcinomas in noncarriers; on the other hand, these three
studies contrast with Lakhani et al. (2004), who found that although ovarian cancers in BRCA1 mutation carriers were significantly more likely than noncarriers to be serous carcinomas
(OR ¼ 1.84, 95% CI ¼ 1.21–2.79), only 40% of ovarian cancers in
A Finnish study of malignancies in 50 Lynch syndrome families that carried cancer-associated MSH2 or MLH1 mutations
recovered 13 cases of ovarian cancer. Eight of these ovarian
cancers were in women who were proven (n ¼ 6) or obligate
(n ¼ 2) MLH1 mutation carriers. No ovarian cancers were registered in the 3 families that carried MSH2 mutations. Serous
carcinomas made up just half (4/8) of the ovarian malignancies in these MLH1 mutation carriers; whereas, two of the
ovarian tumors were clear cell carcinomas and two ovarian
tumors were mucinous carcinomas (Aarnio et al., 1999). These
findings are comparable to the histological characteristics of
ovarian cancers associated with the Lynch syndrome in the
Creighton registry (MJC, unpublished data), and a marked
deviation from the accumulated literature on the histological
diagnoses of ovarian cancers occurring sporadically in the
general population (Ozols et al., 2005), as well as from the
ovarian malignancies reported in HBOC syndrome families
and the ovarian cancers that we have found in BRCA1 and
BRCA2 mutation carriers (MJC, unpublished data; Piek et al.,
2003a; Rubin et al., 1996).
Of 57 cases registered as ovarian carcinomas from mutation carriers of BRCA1, BRCA2, MLH1 or MSH2 in our Creighton
registry, we found only 25% serous carcinomas in those who
carried MMR gene mutations compared with serous carcinomas in 84% of women who carried BRCA1 and BRCA2 mutations (MJC, unpublished data). The remaining 75% of ovarian
carcinomas from MLH1 and MSH2 mutation carriers were
endometrioid, mixed endometrioid–clear cell–serous, or
mixed mucinous–serous (MJC, unpublished data). And 3/8 of
these cancers were associated with adjacent endometriosis
(MJC, unpublished data). Whereas, excluding possible primary
fallopian tube carcinomas, 8 of 9 of which were papillary
serous, just 20% of primary ‘‘ovarian’’ cancers in the Creighton
registry’s BRCA1 and BRCA2 mutation carriers were endometrioid, clear cell, or mixed endometrioid–clear cell carcinomas
(MJC, unpublished data). Currently we are definitively re-evalu
ating all gynecological pathological specimens, blinded as to
genetic mutation status.
6.
Figure 10 – Clear cell carcinoma, 2003, H&E. Numerous vacuolated
cells are seen.
Pathogenesis of ovarian cancer
Based on extensive clinical–pathologic and molecular genetic
studies, a dualistic model of ovarian tumorigenesis has been
proposed in which ovarian cancers can be divided into 2
sub-groups: Type I (also referred to as the low-grade pathway)
and Type II (high-grade pathway; see Figure 6) (Kurman and
Shih le, 2008; Shih le and Kurman, 2004). Type I tumors
include low-grade micropapillary serous carcinoma,
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Figure 11 – Immunohistochemical analysis of a tubal intraepithelial carcinoma (TIC) and a concurrent ovarian serous carcinoma diagnosed in a 59
year old. The tumor and TIC both stained strongly for p53 and MIB1 (the proliferative marker Ki-67). Images were taken under 403 and 4003
magnification, respectively (Q. Cai and Godwin, unpublished data).
mucinous, endometrioid, and clear cell carcinomas, and malignant Brenner tumors. This pathway typically involves
a multi-step process, such that these tumors may exhibit
a spectrum from benign to malignant. Examples include endometriosis and endometrioid carcinoma, or a combination of
benign, borderline, and malignant serous or mucinous ovarian tumors (Singer et al., 2005). Type II tumors are rapidly
growing and highly aggressive neoplasms. They include
high-grade serous carcinomas, malignant mixed mesodermal
tumors (carcinosarcomas), and undifferentiated carcinomas;
epidemiologically, Type II disease represents most of the current public health burden for epithelial ovarian cancer, and
a putative precursor lesion for this type of cancer remains
unidentified.
Benign serous cysts, cystadenomas, and serous carcinomas (Figure 7), are the most common types of ovarian tumors.
Serous ovarian cysts and low-malignant potential borderline
tumors occur in younger women (Seidman et al., 2002), are often bilateral and multifocal, and are typically less responsive
to chemotherapy. Pathological studies of ovarian tumors
have found that approximately 60% of low-grade serous carcinomas contain areas of serous borderline tumors (Malpica
et al., 2004), supporting the idea that low-grade serous carcinomas may arise from the micropapillary type borderline
lesions through the adenoma–carcinoma Type 1 (Bell, 2005).
In contrast, the common high-grade serous carcinomas,
which comprise approximately 60–80% of all ovarian cancers,
as well as those most ovarian carcinomas in the HBOC syndrome, are considered to arise de novo, from the OSE and/or
the lining cells of the tubal fimbria (Powell, 2006). These malignancies are rapidly growing, relatively chemosensitive, and
seem to occur without a definitive histological precursor
lesion. Several hypotheses concerning the pathological processes that may increase the risk of malignant transformation
of the ovarian epithelium have been proposed (Fathalla, 1971)
and reviewed (Landen et al., 2008).
Molecular analyses of these different ovarian epithelial
tumor subtypes are beginning to shed light on their genetic
pathogenesis. Mutations in the K-RAS and BRAF genes, rarely
detected in high-grade invasive carcinomas, are present in
30–50% of borderline ovarian tumors, low-grade adenocarcinomas, and often in adjacent benign epithelium (Mok et al.,
1993; Shih le and Kurman, 2004; Singer et al., 2003a,b; Teneriello
et al., 1993). In contrast, the TP53 gene is mutated in 50–80% of
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115
Figure 12 – Immunohistochemical analysis showing examples of a p53 signature (brown staining cells) found in benign-appearing distal fallopian
tube mucosa from two individuals. Images were taken under 2003 magnification.
high-grade invasive ovarian carcinomas, but rarely in other
ovarian cancer subtypes or borderline serous tumors (Kohler
et al., 1993; Kupryjanczyk et al., 1993; Skilling et al., 1996). Epidermal growth factor receptor (EGFR) (also referred to as ERBB1/
HER1) is overexpressed in 30–70% of high-grade serous ovarian
carcinomas, with the varying frequency estimation reflecting
the assessment technique used, e.g., immunohistochemistry,
Northern blot, or radioreceptor assay. The relationship between
EGFR overexpression and clinical prognosis is not clear, with
some reports suggesting a clear prognostic importance (Maihle
et al., 2002), and others refuting that association (Elie et al.,
2004). Increased EGFR signaling is detected more often in metastases than in primary epithelial ovarian cancer tumor samples
(Scambia et al., 1992). EGFR homodimerizes or heterodimerizes
with other members of the ERBB family upon ligand binding;
this is potentially significant, given that ERBB2 (also known as
HER2/neu) is overexpressed in 20–30% of serous ovarian highgrade carcinomas, but rarely in low-grade and borderline
tumors (Lafky et al., 2008). The significance of the PI3K/AKT
(including PIK3CA, PIK3CB, PIK3R1, AKT1 and AKT2) pathway in
ovarian cancer is clear (Vivanco and Sawyers, 2002); evidence
of deregulation of the PI3K/AKT signaling pathway in ovarian
cancer includes gain-of-function mutations and amplifications
of PI3-kinase genes; amplification of AKT2; and allelic imbalance
and mutations of PTEN (Nakayama et al., 2006). Previous studies
have reported that patients with alterations of AKT2 have a poor
prognosis, with amplification of AKT2 being especially frequent
in undifferentiated tumors, suggesting that AKT2 alterations
may be associated with tumor aggressiveness (Bellacosa et al.,
1995). The finding of copy number gains of AKT2 (Cheng et al.,
1992), but not the related genes AKT1 or AKT3, suggests a particular significance of AKT2 overexpression in serous ovarian tumorigenesis. Germane to this, overexpression of AKT2, but not
other AKT family members, has been shown to lead to up-regulation of b1 integrins, increased invasion, and metastasis of
ovarian cancer cells (Arboleda et al., 2003).
Although BRCA1 and BRCA2 genes are rarely mutated in
sporadic ovarian cancer (Merajver et al., 1995), epigenetic
changes, alternative splicing, and other genetic factors may
influence BRCA function in a significant fraction of sporadic
occurrences, and molecular pathology studies, such as these,
may be the linchpin between heritable ovarian cancers and
those which occur in the general population (Baldwin et al.,
2000; Chen et al., 2006, 2008; Esteller et al., 2000; Hilton
et al., 2002). Clinically, patients with BRCA1 or BRCA2 mutations tend to develop Type II epithelial ovarian cancer, though
these patients may have independently more favorable outcomes than those with sporadic disease (Cass et al., 2003). Recently, Levanon et al. (2008) have proposed that serous
columnar glandular epithelial cells of the fallopian tube fimbrial mucosa may be the putative precursor cells for these tumors in BRCA1 and BRCA2 germline mutation carriers (see
below). Borderline tumors have much less frequent incidence
of BRCA mutations which also suggests a different molecular
origin (Gotlieb et al., 2005).
Mucinous tumors (Figure 8) are the next most common
type of sporadic ovarian carcinoma, are less common than serous and endometrioid carcinomas in HBOC syndrome, and
mucinous carcinomas are the least common histologic type
we found in ovarian carcinoma in MMR gene mutation carriers (MJC, unpublished data). These are often slow-growing
carcinomas which may be associated with the benign and borderline foci, suggesting an adenoma–carcinoma Type 1 sequence, perhaps involving K-RAS and BRAF mutation
pathways, among others (Bell, 2005). Non-genetic exogenous
risk factors, such as cigarette smoking and excess alcohol consumption, may also be involved (Pal et al., 2008b). These tumors as well as low-grade and borderline serous tumors
may arise in the cortical inclusion cysts which often undergo
Müllerian metaplasia into tubal or endocervical type epithelia
(Levanon et al., 2008).
The next most common epithelial cancer overall is the
endometrioid type (Figure 9). Endometrioid and clear cell carcinomas (Figure 10) are sometimes seen associated with endometriotic foci with atypical hyperplasia, similar to that seen in
the endometrium. Synchronous endometrial carcinomas are
also described and perhaps involve similar molecular pathways with PTEN and b-catenin mutations (Bell, 2005; Obata
et al., 1998; Wu et al., 2001). High-grade tumors, however,
may involve the p53 pathway similar to their serous counterparts. Endometrioid carcinomas, frequently mixed with clear
cell, serous, and mucinous elements, predominate among
the Lynch syndrome-related ovarian cancers (MJC unpublished data; Pal et al., 2008b).
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7.
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Carcinoma precursor lesions
Numerous studies have compared the macroscopically normal ovaries and fallopian tubes from women with elevated
genetic risk who have undergone prophylactic salpingo-oophorectomy with general population controls in terms of atypia of OSE cells, papillary proliferation, and number of
inclusion cysts and atypia of the lining cells (Cai et al., 2006;
Casey et al., 2000; Salazar et al., 1996). Some of these studies
have shown increased atypical cells, micropapillae, etc., and
others have not (Casey et al., 2000).
7.1.
Fallopian tube lesions
Recent pathological and molecular studies (Levanon et al.,
2008; Medeiros et al., 2006) suggest that the secretory epithelium cells of the fallopian tube may be the site of origin for
the high-grade serous ovarian tumors in the hereditary ovarian cancer setting.
Piek et al. (2004) demonstrated increased Ki-67 (cell proliferation marker), CA-125, and p53 immunostaining of OSE cells
in specimens from prophylactic salpingo-oophorectomies.
Their data suggest that ectopic dysplastic glandular epithelial
cells originating in the fimbria of the fallopian tube are the initial culprit for the development of epithelial ovarian cancer, by
shedding onto the ovarian surface during ovulation and subsequently incorporating into cortical ovarian cysts. Compared
with the fallopian tube and peritoneal surface, ovarian cortical
inclusion cysts may be a preferential site for overt disease
development, as indicated by epidemiologic data on primary
site distribution. Crum et al. (2007a,b) have recently extended
these initial observations to ovarian and fallopian tube specimens from BRCA1 and BRCA2 mutation carriers and described
an entity in the fimbria that shares many attributes with
serous carcinomas. These include: p53 positivity, fimbrial
location, secretory cell phenotype, evidence of DNA damage
by localization of g-H2AX, and p53 mutations (Callahan
et al., 2007; Crum et al., 2007a,b; Jarboe et al., 2008a,b; Kindelberger et al., 2007; Lee et al., 2006, 2007; Medeiros et al., 2006).
This entity has been designated the ‘‘p53 signature.’’ As
shown in Figure 11, both areas of tubal intraepithelial carcinoma (TIC) and the corresponding ovarian carcinoma stained
strongly for p53 and MIB1 (Ki-67).
Folkins et al. (2008) compared the prevalence of p53 signature in Müllerian epithelium of the fallopian tube with overtly
normal ovaries from the same patient population. Although
p53 expression signature coupled with g-H2AX expression
was observed in benign-appearing salpingeal epithelium, frequently at the fimbriated end, no such abnormalities were
identified in the cortical inclusion cysts of the corresponding
ovaries. While interesting, these results do not yet confirm
p53 signature as a likely precursor for Type II epithelial ovarian cancer. If morphologic evidence of TIC in the distal fallopian tube serous glandular epithelium represents the
primary anatomic origin of disease in the majority of hereditary Type II ovarian carcinomas, then the identification of
TIC through relatively non-invasive approaches such as in
situ molecular imaging could lead to improvement in primary
and secondary prevention of disease.
7.2.
Peritoneal carcinoma
The extra-ovarian peritoneal serous carcinomas identified in
families with BRCA1 and BRCA2 mutations appear morphologically similar to the high-grade ovarian serous cancers but
often show no significant lesions in the ovaries. In times
past, the fallopian tubes in many such cases were examined
minimally, with one routine section from the middle portion
of the tube that showed no obvious pathology. However, thorough sectioning of the fallopian tube, particularly the fimbria,
with immunostaining for p53 and cell proliferation marker ki67, shows positive stains and preneoplastic features in the
mucosal cells when compared with normal fimbria. Approximately 50% of peritoneal serous carcinomas cases with
unknown BRCA mutation status showed these microscopic
changes (Crum et al., 2007a,b).
As discussed above, Piek et al. (2003b) have shown tubal
dysplasia and increased cell proliferation in the tubes
removed prophylactically in HBOC patients with high risk of
ovarian cancer. Crum et al. (2007b) have serially sectioned
the tubes from prophylactic salpingo-oophorectomy cases
and by increased (>75%) positive immunostaining of Ki-67
and p53, have shown occult micro carcinomas (TICs), most
commonly in the tubal fimbria (Medeiros et al., 2006; Powell,
2006). Levanon et al. (2008) have postulated that fimbrial
mucosal dysplasias may be the precursor lesions of the
high-grade serous ovarian cancers, BRCA1 and BRCA2 related
ovarian cancers, and potentially all extra-ovarian serous peritoneal cancers; however, this claim is far from proven. These
lesions may often go undiagnosed in the routine examination
of the tube and their identification may require thorough examination of the fimbria with p53 and Ki-67 immunostains
(Figure 11). Powell (2006) has shown 4.4% of adnexa from prophylactic salpingo-oophorectomies to harbor occult carcinomas. Eighty per cent of these extra-ovarian tumors appear to
be of tubal origin and relatively few are from ovarian or peritoneal surface. In addition, Powell found increased incidence
of these lesions with the BRCA1 gene and increased age,
with very few lesions identified before age 40. This may be
a factor in the prophylactic surgical management of these
cases. Nevertheless, an important question remains regarding
the association of premalignant lesions in the fallopian tubes
and the subsequent risk of developing ovarian cancer. Studies
at Fox Chase Cancer Center in Philadelphia, Pennsylvania,
using overtly normal ovarian and fallopian tube specimens
from women undergoing total abdominal hysterectomy and
bilateral salpingo-oophorectomy examined p53 expression.
Fallopian tubes were analyzed using a procedure for sectioning and extensively examining the fimbriated end (SEE-FIM)
protocol (Medeiros et al., 2006). All ovaries and fimbriated
tubes were sectioned and stained with H&E, subjected to immunohistochemical staining for p53 and MIB1 and evaluated
by conventional microscopy. The prevalence of the p53 signature, defined as 12 or more consecutive p53 positive cell nuclei
(for example, Figure 12), in fallopian tubes (mostly within the
fimbriated end) was approximately 32% (13/41) (AKG, unpublished data). The number of cortical inclusion cysts (CICs) in
the ovaries was also recorded. As recently reported by Folkins
et al. (2008), there was no correlation between the presence of
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a p53 signature and the number of CICs in ovaries. Importantly, the occurrence of TP53 mutated cells in the fimbria of
these women was much more frequent than the average
risk predicted for sporadic ovarian cancer in unselected populations (approximately 1% by age 70 years), and this suggests
that either there is a long latency period for preneoplastic cells
in the tubes before they acquire additional mutations that
lead to rapid tumor development, or these lesions regress
over time and are not the precursor of epithelial ovarian tumors. Similarly, Folkins et al. (2008) have reported that the
prevalence of p53 tubal signatures in BRCA-mutation carriers
is similar to women with unknown BRCA status (38 versus
33%). However, as the 11–66% lifetime risk of developing ovarian cancer in BRCA1-mutation carriers and 10–20% lifetime
risk for ovarian cancer in BRCA2 mutation carriers are sufficiently higher, these results suggest that a p53 mutation in
the background of a BRCA mutation may be an important early
event in the pathogenesis of hereditary forms of the disease
(Figure 6).
7.3.
Endometriosis
Endometriosis is a common disorder, occurring in some 7–
20% of women of reproductive age. In the general population, endometriotic foci are seen in association with up to
21% of endometrioid and clear cell ovarian cancers and
the preneoplastic atypical hyperplasia–carcinoma has
been described in the ectopic endometrium, similar to
that seen in the uterus (Bell, 2005; Seidman et al., 2002).
In the Creighton registry, we found that 3/8 endometrioid
and mixed endometrioid carcinomas in Lynch syndrome
MMR gene mutation carriers were associated with endometriosis (MJC, unpublished data).
8.
Genes commonly associated with hereditary
ovarian cancer
8.1.
Proto-oncogenes (Bell, 2005; Seidman et al., 2002)
c-ERBB-1 (EGFR) is a member of the type I tyrosine kinase
receptor family HER (i.e., ERBB) that is expressed in normal
ovarian surface epithelium and overexpressed in 35–70% of
ovarian cancers. However, the gene is rarely amplified or
mutated in ovarian cancer.
c-ERBB2 (HER2-neu) is a member of the type I tyrosine
kinase receptor family HER (i.e., ERBB). HER2 expression in
ovarian cancer varies widely; overexpression is found in
20–30% of cases. It has been reported that approximately
40% of HBOC cases overexpress HER2 (Seidman et al., 2002).
c-Myc is a transcription factor that regulates expression of
many genes. The c-Myc gene is amplified in both hematopoietic and solid neoplasms, including more than 30% and 40%
of endometrioid and clear cell carcinomas, respectively. Overexpression of c-Myc has been reported in 30% of all ovarian
tumors, but most frequently in serous adenocarcinomas.
K-RAS is a G-protein that promotes growth through MAP
kinase pathway. Mutations in the K-RAS gene have been
reported in approximately 60% of borderline tumors, in nearly
117
70% of low-grade tumors, and in 50% of mucinous
adenocarcinomas.
b-Catenin (CTNNB1) is a regulator of the Wnt signaling
pathway and is often mutated and deregulated in human
malignancies. b-Catenin is a subunit of the cadherin protein
complex, and in the absence of Wnt signal it becomes phosphorylated by GSK-3 and targeted for degradation by the ubiquitin–proteasome system. It is positively expressed in up to
16% of endometrioid carcinomas of the ovary, and nuclear
b-catenin expression is strongly associated with endometrioid
histological subtype. Similar positivity has also been noted in
endometrial carcinomas.
8.2.
2004)
Tumor suppressor genes (Bell, 2005; Piek et al.,
TP53 is an example of a prototype tumor suppressor gene that
promotes cell cycle arrest/apoptosis in cells with DNA damage. Mutation of this gene is seen in many human malignancies including 50–60% of ovarian serous carcinomas. TP53
mutations have also been detected in ovarian inclusion cysts
adjacent to cystadenocarcinomas, in microscopic ovarian
cancer, and in tubular intraepithelial carcinomas removed
prophylactically from patients with BRCA1 mutations, suggesting that the p53 inactivation may be a relatively early
event in ovarian cancer pathogenesis. Serous endometrial
carcinomas are also p53 mutation positive as are the ‘‘dysplastic’’ ovarian surface cells from prophylactic salpingooophorectomies.
PTEN is one of the most frequently mutated genes in
human cancer and acts as a tumor suppressor by dephosphorylating the plasma membrane lipid second messenger phosphoinositide-3,4,5-trisphosphate (PIP3) generated by the
action of PI3Kinases back into PIP2. Mutations are seen in
the endometrioid type of ovarian and uterine carcinomas.
BRCA1 (breast cancer susceptibility gene 1) is one of the
most intensively studied susceptibility genes and has a profound role in breast and ovarian cancer etiology owing to
its involvement in several important cellular processes.
Deleterious mutations in BRCA1 are found in 5–6% of ovarian cancers, but up to 80–90% in HBOC cancer cases. Among
its many biological functions, the BRCA1 protein is involved in DNA repair.
BRCA2 (breast cancer susceptibility gene 2) is a tumor suppressor that shows similar but less common associations with
HBOC as compared with BRCA1. Extensive genetic and biochemical characterization has shown that BRCA2 is involved
in the maintenance of chromosomal stability and that it has
an important role in recombination-mediated double-strand
DNA break repair.
8.3.
Epigenetic changes (hypermethylations)
Up to seven mismatch repair (MMR) gene mutations and epigenetic hypermethylations are seen in ovarian cancers associated with the Lynch syndrome, most of which are non-serous
epithelial carcinomas (Pal et al., 2008a). MSI is detected in 50%
of low-grade endometrioid tumors.
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9.
Diagnosis and management
9.1.
Ovarian cancer associated with the HBOC syndrome
The foundation for detection and diagnosis of the HBOC syndrome and Lynch syndrome is the extended family history
with all possible pathology verification. Since kindreds often
are small, if possible at least three extended generations
should be included to correctly diagnose hereditary cancer
syndromes (Lynch et al., 1992). In the case of HBOC, even a single first-degree relative and two or more second-degree relatives with ovarian cancer and/or breast cancer will indicate
an increased long-term ovarian cancer risk. These women
and those from populations known to bear a high prevalence
of cancer-associated BRCA1 and BRCA2 mutations should be
offered cancer genetics counseling and considered for DNA
testing. In the case of the Lynch syndrome, similar strategies
should be employed, given knowledge of its genotypic (MMR
mutations) and phenotypic features.
Women determined by pedigree to be obligate carriers of
an HBOC susceptibility trait and those found to harbor germline cancer-associated BRCA1 or BRCA2 mutations are known
to bear 10–66% cumulative lifetime risk for ovarian carcinomas, which might be more precisely defined in some families
by specific gene and location determination of the aberrant
mutation through DNA testing (Brose et al., 2002; Easton
et al., 1993, 1995; Ford et al., 1994, 1998; King et al., 2003; Satagopan et al., 2002; Struewing et al., 1997; The Anglian Breast
Cancer Study Group, 2000). From accumulating data in the literature, it appears that the penetrance of adverse BRCA1
mutations in predisposing to ovarian carcinoma slightly exceeds that of BRCA2 mutations (Antoniou et al., 2000; Brose
et al., 2002; Easton et al., 1997; Ford et al., 1995, 1998; King
et al., 2003; Satagopan et al., 2002). Using pooled data, Antoniou et al. (2003) estimated from 22 studies an average of
39% cumulative lifetime risk for ovarian cancer in carriers of
BRCA1 mutations and an average of 11% cumulative lifetime
risk for ovarian cancer in carriers of BRCA2 mutations. Struewing et al. (1997) studied carriers of three Ashkenazi mutations,
namely 185delAG and 5382insC in BRCA1 and 6174delT in
BRCA2, and estimated accumulated risks for ovarian cancer
by age 70 years of 22% in carriers of the 5382insC mutation,
12% in carriers of the 185delAG mutation, and 18% for carriers
of the 6174delT mutation. In another study of ovarian cancer
penetrance in carriers of the Ashkenazi mutations, Satagopan
et al. (2002) showed greater risks for ovarian cancer in carriers
of mutations in BRCA1 than in carriers of BRCA2 mutations. In
their penetrance studies of these same three Ashkenazi mutations, Satagopan et al. (2002) estimated a 37% risk for ovarian
cancer by 70 years age for carriers of the 185delAG and
5382insC mutations in BRCA1 and a 21% risk for ovarian cancer by 70 years age for carriers of the 6174delT mutation in
BRCA2.
9.2.
Prophylactic bilateral salpingo-oophorectomy
Prophylactic oophorectomy with and without salpingectomy
and hysterectomy has removed previously undiagnosed
occult ovarian carcinomas and lowers the risk of subsequent
ovarian cancer and disseminated intra-abdominal carcinomatosis in women who are likely or proven carriers of cancer-associated BRCA1 or BRCA2 mutations (Casey et al., 2005; Kauff
et al., 2002; Rebbeck et al., 2002; Rutter et al., 2003). The groups
of Rebbeck et al. (2002) and of Kauff et al. (2002) reported historical series of women deemed to be at increased risk for
ovarian cancer because of their family histories (Rebbeck
et al., 2002) or because they carried BRCA1 or BRCA2 mutation
(Kauff et al., 2002), showing decreased risk for this disease in
family members who had undergone oophorectomy. In our
own material, only 5 cases of intra-abdominal carcinomatosis
were diagnosed among 238 carriers of cancer-associated
BRCA1 and BRCA2 mutations from which a 3.5% cumulative
risk was calculated through 20 years of follow-up after prophylactic oophorectomy (Casey et al., 2005). Four of these 5
patients also had hysterectomy, and retrospective review of
the surgical specimens showed a borderline serous papillary
tumor on an ovary in 2 patients, one with possible early stromal invasion (Casey et al., 2005).
The results of a large collaborative study, involving 11 separate institutions, of 498 BRCA1 mutation carriers recently
reported by Kauff et al. (2008) showed an 85% reduction in
gynecological cancers among subjects who elected prophylactic salpingo-oophorectomy compared with subjects who
chose surveillance. Fewer than 1% of the BRCA1 mutation carriers who underwent prophylactic surgery were diagnosed
with intra-abdominal carcinoma during a mean follow-up of
41 months in this study; whereas gynecologic cancers, including invasive carcinomas of the ovary, fallopian tube, or peritoneum, were diagnosed in 6% of the BRCA1 mutation carriers
who chose surveillance (p ¼ 0.001). Likewise, there was an
observed reduction in risk for gynecologic cancers in BRCA2
mutation carriers who elected prophylactic salpingo-oophor
ectomy compared with those BRCA2 mutation carriers who
chose surveillance during 39 months’ mean follow-up,
although the difference did not reach significance. This study
also indicated a 72% reduction in breast cancers among BRCA2
mutation carriers and suggested a reduction in breast cancers
among BRCA1 mutation carriers who underwent prophylactic
salpingo-oophorectomy (Kauff et al., 2008).
Since the report of fallopian tube carcinoma in the 48-yearold proband of one of the first two families in which pedigree
analysis was used by Lynch et al. (1974) to establish the familial association of breast and ovarian cancers, as well as the
confirming report of fallopian tube cancer by history in a 42year-old member of a breast–ovarian cancer family by Fraumeni et al. (1975) just one year later, it has become increasingly evident that primary fallopian tube carcinoma is an
integral cancer in the HBOC syndrome and these cancers are
associated with germline mutations in BRCA1 and BRCA2
(Agoff et al., 2002; Aziz et al., 2001; Casarsa et al., 2004; Cass
et al., 2005; Colgan et al., 2001; Friedman et al., 1995; Hartley
et al., 2000; Hébert-Blouin et al., 2002; Jongsma et al., 2002;
Lamb et al., 2006; Leeper et al., 2002; Levine et al., 2003; Mæhle
et al., 2008; Medeiros et al., 2006; Meeuwissen et al., 2005; Olivier et al., 2004; Paley et al., 2001; Peyton-Jones et al., 2002; Piek
et al., 2003a; Powell et al., 2005; Rose et al., 2000; Scheuer et al.,
2002; Schubert et al., 1997; Simard et al., 1994; The Breast Cancer Linkage Consortium, 1999; Tong et al., 1999; Tonin et al.,
1995; Zweemer et al., 2000). Brose et al. (2002) estimated that
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
there is a 120-fold increased lifetime risk for fallopian tube
cancer in BRCA1 mutation carriers.
Although Brose et al. noted no increased risk for uterine
cancer in their study of 483 BRCA1 mutation carriers, the
Breast Cancer Linkage Consortium (Thompson et al., 2002b)
reported significantly increased relative risks of 2.65 (95% CI
1.26–4.06, p ¼ 0.004) for uterine corpus cancer and 3.72 (95%
CI 2.26–6.10, p 0.001) for cancer of the uterine cervix among
11,847 individuals from cancer families associated with
BRCA1 mutations. Finding germline Ashkenazi BRCA1 and
BRCA2 mutations in only three of 199 consecutive Jewish
endometrial carcinoma patients, a frequency of 1.5 compared
with the expected frequency of 2.0 in the general population,
Levine et al. (2001) concluded that the lifetime risk for endometrial carcinoma is not increased in BRCA1 and BRCA2 mutation carriers.
On the other hand, Beiner et al. (2007) reported the diagnosis of 6 endometrial cancers in a collaborative study of 857
BRCA1 and BRCA2 mutation carriers during an average follow-up time of 3.3 years compared with just 1.13 endometrial
cancers expected in the general population. This is a significantly increased standardized incidence ratio (SIR ¼ 5.3,
p ¼ 0.001) for endometrial cancer in the mutation carriers
reported by Beiner et al. However, in this study, 4 of the 6 mutation carriers diagnosed with endometrial carcinoma had
been treated with tamoxifen. Excluding these 4 cases, Beiner
et al. calculated a 2.7 SIR for endometrial cancer among mutation carriers never exposed to tamoxifen, a difference from
the general population which did not reach significance
( p ¼ 0.17); however, the 11.6 relative risk for endometrial cancer among 226 participants who used tamoxifen was highly
significant ( p ¼ 0.0004), leading these authors to conclude
that tamoxifen treatment was the main contributor to the increased diagnosis of endometrial cancer among BRCA1 and
BRCA2 mutation carriers in their study (Beiner et al., 2007).
All of the 5 BRCA1 and 4 BRCA2 mutation carriers who were
diagnosed with endometrial cancers in the series reported by
Levine et al. (2001) and by Beiner et al. (2007) were endometrioid type. Our preliminary review of gynecological cancers
in BRCA1 and BRCA2 mutation carriers from the Creighton registry, found that 2/6 (33.3%) of the primary endometrial carcinomas, 8/9 (89%) of the fallopian tube cancers, and all 5 of the
peritoneal carcinomas were serous type, an extraordinary
proportion of serous endometrial carcinomas compared
with 30/35 (86%) endometrioid endometrial carcinomas with
only 3/35 (14%) showing clear cell or papillary forms but not
serous elements in hMLH1 and hMSH2 mutation carriers
(MJC, unpublished data). So not only does the finding of
asymptomatic occult endometrioid endometrial carcinomas,
particularly in patients who have received tamoxifen, have
implications in managing women at hereditary risk for
HBOC, but even more significant may be the possibility that
endometrium, as well as ovarian fallopian tube epithelium,
might be a site of primary transformation to serous carcinoma
in carriers of cancer-associated BRCA1 and BRCA2 mutations
(Casey and Bewtra, 2004).
Apropos our observations, Hornreich et al. (1999) reported
a case of uterine serous papillary carcinoma in an Israeli
woman who carried the same Ashkenazi germline BRCA1
mutation as her sister who also was diagnosed with ovarian
119
papillary serous carcinoma, and subsequently this group
found that BRCA1 mutations were carried by 4 of their 20 patients (20%) with papillary serous uterine carcinoma (Lavie
et al., 2004). Ashkenazi BRCA1 or BRCA2 founder mutations
were found in 7/22 (32%) consecutive cases of papillary serous
uterine carcinoma in Jewish women studied by Biron-Shental
et al. (2006). Three of the BRCA1 and BRCA2 mutation carriers
with uterine serous carcinoma in the series of Biron-Shental
et al. had past histories of breast cancer and 4 of these patients had first-degree relatives with breast or ovarian cancers. For the purpose of retrospectively assessing the
effectiveness of antineoplastic chemotherapy, particularly
platinum compounds for treating endometrial cancer in
BRCA1 and BRCA2 mutation carriers, Kwon et al. (2008a) recently searched the London Health Sciences Centre database
in Ontario. They identified only 8 patients with a diagnosis of
endometrial cancer among 587 mutation carriers. Four of
these women had endometrioid carcinomas and their tumors
were confined to the corpus, one endometrial cancer patient
had a mixed endometrioid–clear cell carcinoma with extension to the uterine cervix and 3 of the 8 women (38%) had
cancer beyond the pelvis. Two of the advanced endometrial
cancers were papillary serous type and one was a sarcomatoid
carcinoma. The discovery by Kwon et al. (2008a) that 2/8 (25%)
endometrial cancers were papillary serous type in this database of BRCA1 and BRCA2 mutation carriers is most curious,
especially since these women were relatively young for this
histological type at 59 years and 64 years, respectively. In
comparison, only 3.9% of 7496 uterine corpus cancer patients
reported in the International Federation of Gynecology and
Obstetrics 25th Annual Report on the Results of Treatment
of Gynecological Cancer were papillary serous carcinomas
(Creasman et al., 2003).
Finally, it should be kept in mind that though rare, families
and individuals may harbor more than a single dangerously
mutated gene. This is of special risk in culturally and geographically restricted populations. For instance, germline mutations in the genes associated with both HBOC syndrome and
the Lynch syndrome have been reported in a single kindred
(Borg et al., 2000). Therefore, whenever suspicion arises from
family history, an extended pedigree over at least three generations should be developed, and when cancer patterns are not
confined to those that characterize the two major hereditary
syndromes associated with increased susceptibility to ovarian
cancer, the most diligent accumulation of records, pathology
review and DNA testing may be needed to sort out and isolate
the culprit gene(s) and mutation(s).
With these considerations, we believe it is prudent to advise proven female carriers of cancer-associated BRCA1 or
BRCA2 mutations and other women at highest risk for HBOC
syndrome, who have chosen prophylactic surgery, that bilateral salpingo-oophorectomy and complete hysterectomy are
the surest means to reduce the risk of genetically determined
cancers and disseminated intra-abdominal carcinomatosis
that may arise from the ovary, fallopian tube, and perhaps
from endometrial epithelium.
Although the risk for ovarian cancer in BRCA1 and BRCA2
mutation carriers exceeds population risk for this disease
even at ages of 39 years and younger, data from the literature
indicates that the cumulative incidence for ovarian cancer in
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BRCA1 and BRCA2 mutation carriers is quite low before the age
of 40 years (King et al., 2003; Milne et al., 2008; Satagopan et al.,
2002). Satagopan et al. (2002) calculated an ovarian cancer
penetrance of only 3% (95% CI ¼ 1–7%) before age 40 years in
BRCA1 mutation carriers and just 0.7% (95% CI ¼ 0–1%) before
age 40 years in BRCA2 mutation carriers. In the Creighton database, 51 years was the median age at which ovarian cancer
was diagnosed in both BRCA1 (age range, 33–73 years) and
BRCA2 (age range, 30–73 years) mutation carriers. Eight per
cent of the ovarian cancers in BRCA1 and BRCA2 mutation carriers in our registry were diagnosed before age 40 years, but
w18% were diagnosed before their 45th birthday (CLS, unpublished data). So, although the risk for ovarian carcinoma in
carriers of cancer-associated mutations in BRCA1 and BRCA2
before age 40 years may be relatively small, this risk is not insignificant, and patients should be counseled accordingly. If
women, well informed of their genetic risk for ovarian cancer,
are willing to accept these risks to complete their plans for
childbearing, they should be offered the best available surveillance until they may elect to proceed with prophylactic surgery, preferably, if they choose, before age 40 years.
The Prevention and Observation of Surgical Endpoints
(‘‘PROSE’’) Study group found that the observed favorable
reduction of breast cancer risk by some 56% in BRCA1 mutation carriers and 46% in BRCA2 mutation carriers who have
undergone oophorectomy was not obviated at least by the
short-term use up to 3.6 years of estrogen replacement therapy (Eisen et al., 2005; Rebbeck et al., 2005). Because the fourth
and fifth decades of life are still relatively early for women to
lose the favorable effects of endogenous estrogen, well earlier
than the expected age of natural menopause, many who elect
prophylactic salpingo-oophorectomy will choose transient
estrogen hormone replacement therapy for relief of postmenopausal symptoms and protection against premature osteoporosis.
However,
unopposed
exogenous
estrogen
replacement therapy is by now an established risk factor for
endometrial carcinoma (Casey, 1977; Feeley and Wells, 2001;
Gambrell, 1977; Gambrell et al., 1983; Jick et al., 1993).
Although it has been expected that sufficiently protracted
treatment with progestins along with continuous estrogen
replacement may be protective against endometrial hyperplasia and thence carcinoma (Feeley and Wells, 2001; Gambrell
et al., 1983; Jick et al., 1993; Newcomb and Trentham-Dietz,
2003), a recent analysis of data from the National Cancer Institute’s Breast Cancer Detection Demonstration Project calls
into question the protective effect of progestins against endometrial cancer in women receiving estrogen replacement, and
protracted use may increase the risk for breast cancer (Lacey
et al., 2005). Lacey et al. (2005) of the National Cancer Institute
Division of Epidemiology analyzed the records of 541 endometrial carcinoma patients enrolled in the study and determined
an increased relative risk (RR) for this disease of 3.0 (95%
CI ¼ 2.0–4.6) in women receiving estrogen replacement with
<15 days/month of sequential progestin and an RR of 2.3
(95% CI ¼ 1.3–4.0) in women on continuous >15 days/month
regimens compared with those who received no hormone
therapy at all (Lacey et al., 2005). Other women at increased
hereditary risk for both breast and ovarian cancers will be prescribed selective estrogen receptor modulators (SERMs) for
chemoprophylaxis or treatment of breast cancer (Cuzick
et al., 2003; Fisher et al., 1998; King et al., 2001; Narod et al.,
2000; Vogel et al., 2006) and skeletal support (Chang et al.,
1996) after surgical removal of their ovaries. While tamoxifen
may decrease the risk of breast cancer in both BRCA1 (Narod
et al., 2000) and BRCA2 (King et al., 2001) mutation carriers,
use of this SERM has been associated with increased risk for
endometrial carcinoma (Bergman et al., 2000; Bernstein
et al., 1999; Fisher et al., 1998; Matsuyama et al., 2000; Mignotte
et al., 1998; Peters-Engl et al., 1999; Pukkla et al., 2002; UrsicVrscaj et al., 2001). Although later generation SERMs, such as
raloxifene, as yet have not been associated with the significantly increased risks for endometrial cancer that were found
in patients treated with tamoxifen (Cauley et al., 2001; Martino
et al., 2004; Vogel et al., 2006), the effectiveness of later SERMs
for protecting against breast cancer in genetically susceptible
women has not been established (Shelly et al., 2008). With
these considerations, we believe that hysterectomy at the
time of salpingo-oophorectomy in members of HBOC syndrome families further simplifies decisions regarding hormone replacement, chemoprophylaxis and treatment in
women so highly at risk for breast, ovarian, fallopian tube
and, perhaps, endometrial carcinomas with poor prognosis.
Currently available techniques for ovarian cancer screening are far from satisfactory. Nonetheless, for BRCA1 and
BRCA2 mutation carriers and others at high risk for ovarian
carcinomas who delay prophylactic or indicated salpingooophorectomy and hysterectomy, we offer surveillance using
currently available screening methods. Albeit, the potential
for early detection of invasive ovarian carcinomas in highrisk patients through transvaginal ultrasound screening is
problematic. van Nagell et al. (2000) published the 12-year results from their University of Kentucky annual screening program that involved transvaginal ultrasound scans on 14,469
women over age 50 years or over age 25 years with at least
one first- or second-degree relative who had ovarian cancer.
They reported that all 11 patients whose ovarian tumors
were detected while confined to the ovary and 3 patients
with ovarian tumors detected while limited to the pelvis
were alive without evidence of ovarian cancer 1.8–9.8 years
(median, 4.5 years) after their diagnoses. However, inspection
of this series reveals that 2 of the 11 tumors detected while
still confined to the ovary were borderline (18%) and 2 of the
other early ovarian tumors were granulosa cell tumors (18%);
on the other hand, 3 of the ovarian carcinomas that were
detected by screening, 4 interval ovarian carcinomas that
were diagnosed <12 months after falsely negative transvaginal ultrasound scans and multiple screenings and 4 symptomatic ovarian carcinomas, diagnosed at 14, 15, 20 and 62
months respectively following their last screening tests,
already were disseminated to the upper abdomen. Only one
invasive ovarian carcinoma was diagnosed in a women younger than 40 years in van Nagell’s series. Even in the screening
of postmenopausal women, Kobayashi et al. (2008) found no
significant difference in the overall detection and proportion
of primary carcinomas diagnosed by histological types and/
or while still confined to the ovary between subjects prospectively randomized to a program of physical examination,
ultrasound scanning and serum CA-125 determinations and
control subjects randomized to routine follow-up over 3–14
years (mean, 5.4 years). Kobayashi et al. reported that 63% of
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
the ovarian cancers detected among 41,688 postmenopausal
Japanese women assigned to annual screening were still confined to the ovary compared with the diagnosis of 38% primary
carcinomas while still confined to the ovary in 40,779 control
subjects, but this difference was not significant ( p ¼ 0.23).
So, although these techniques are capable of detecting tumors
while still confined to the ovary, their benefit in population
screening is yet to be established.
Several other large screening series, including not only
ultrasound scanning but also serum tumor marker determinations, in women deemed to be at increased familial or
hereditary risk for ovarian cancer confirm the disappointing
results that can be extracted from the data reported by van
Nagell et al. (Bosse et al., 2006; Dorum et al., 1999; Fishman
et al., 2005; Gaarenstroom et al., 2006; Laframboise et al.,
2002; Oei et al., 2006; Olivier et al., 2006; Tailor et al., 2003;
van Nagell et al., 2000; Vasen et al., 2005; Woodward et al.,
2007). Oei et al. (2006) summarized then-available literature
that indicated the detection of an early primary cancer confined to the ovary in only one of over 500 BRCA1 and/or
BRCA2 mutation carriers entered into screening programs
(Laframboise et al., 2002; Meeuwissen et al., 2005; Oei et al.,
2006; Vasen et al., 2005). They concluded that surveillance,
using available methods, is very inefficient even in proven
mutation carriers. They lamented the yield of only one early
ovarian cancer from the total 89 diagnostic surgeries that
were done in these programs (Oei et al., 2006).
Clinics focused on the prevention and/or early detection of
ovarian cancer in genetically susceptible individuals have
offered prophylactic surgery or surveillance as an alternative.
Olivier et al. (2006) at the Antoni van Leeuwenhoek Hospital in
The Netherlands found 3 occult localized ovarian or fallopian
tube carcinomas and 2 advanced carcinomas in 91 proven
BRCA1 mutation carriers through prophylactic salpingooophorectomy. No gynecologic cancers were found in 10
BRCA2 mutation carriers who underwent salpingo-oophorectomy. In this program, 41/132 (31%) known BRCA1 mutation
carriers, 10/20 (50%) of the BRCA2 mutation carriers, 45/72
(63%) members of HBOC syndrome families and 64/88 (73%)
members of hereditary breast cancer families chose screening
at yearly intervals by physical pelvic examinations, transvaginal ultrasound scans and serum CA-125 determinations.
Among the 160 women who chose surveillance, 2 disseminated ovarian carcinomas but only one primary carcinoma
confined to the ovary were detected over 7 years; while one interval disseminated ovarian carcinoma was diagnosed in a patient who presented with abdominal pain only 2 months after
a normal transvaginal ovarian ultrasound and a serum CA-125
titer of 33 units/ml. A series of 269 carriers of known BRCA1 or
BRCA2 mutations and women estimated to have at least a 50%
risk of being mutation carriers because of their family histories of breast and/or ovarian cancer were offered DNA mutation analysis, followed by either prophylactic salpingooophorectomy or continued screening with transvaginal
ultrasound scanning and serum CA-125 determinations in
a project reported by Gaarenstroom et al. (2006) in The Netherlands. BRCA1 or BRCA2 mutations were found in 42% (113/269)
of the women. No occult ovarian or other cancers were discovered in the 127 subjects (47%) who elected prophylactic surgery, and none of these women were diagnosed with
121
ovarian cancer during 16 months mean follow-up. The first
and second screenings of the remaining women detected
just one primary carcinoma still confined to the ovary and
one borderline ovarian tumor, but 2 disseminated intra-abdominal carcinomas were detected during the first screening
and 4 more patients were diagnosed with disseminated carcinomas during the next 12 months (Gaarenstroom et al., 2006).
In another Dutch study, Oei et al. (2006) similarly offered DNA
mutation analysis followed by either prophylactic salpingooophorectomy or annual surveillance with physical examinations, transvaginal ultrasound screening, and serum CA-125
testing to 512 women at high risk for ovarian cancer by family
histories. Of those who had DNA testing, 265 were found to be
actual carriers of BRCA1 and/or BRCA2 mutations. Surveillance
was chosen by 343 of all subjects in this study with their
screening beginning between ages 20 and 75 years (median
42 years). Seventy-three per cent of those choosing surveillance were premenopausal. A third of the subjects (169/
512 ¼ 33%) elected prophylactic salpingo-oophorectomy, and
their median age was 45 years (range, 29–70 years). One ovarian cancer was found among those electing surgery, and this
was in a 60-year-old BRCA2 mutation carrier with prior breast
cancer who had a primary carcinoma extended beyond the
ovary but still limited to the pelvis. During the median follow-up time of 2.07 years (range, 0–9.4 years), Oei et al. found
persisting abnormalities on screening tests which led to 24
diagnostic operations with the discovery of one disseminated
ovarian carcinoma in a 52-year-old BRCA1 mutation carrier
with history of a previous breast cancer (Oei et al., 2006).
Both van Nagell et al. (2000) at the University of Kentucky
and Bosse et al. (2006) at the University of Cologne commented
on the low positive predictive values (PPV) of 9.4% and 10%
from their respective screening studies. Olivier et al. (2006),
whose cases were composed of 49% known BRCA1 and
BRCA2 mutation carriers, determined that the PPV from their
combined screening methods, using physical examination,
transvaginal ultrasound scanning, and serum CA-125 determinations, was only 40%. While PPV and specificity are important when considering all screening modalities, even the
demonstration of nonfunctional ovarian cysts and tumors
that have led to reported low PPV and low specificity values
with transvaginal ultrasound scanning and tumor marker
determinations that would not be efficacious in populations
with relatively low prevalence of ovarian cancer, the use of
these methods is not precluded for surveillance of premenopausal women at high genetic risk for gynecological tumors.
We believe that the reported low yields of early ovarian carcinoma from surgical exploration prompted by the results of
transvaginal ultrasound scans and tumor marker determinations ought not proscribe offering these methods in the periodic surveillance of women at risk for carcinomas of the
HBOC syndrome proven through extended pedigree analysis
and/or by DNA testing for cancer-associated BRCA1 or BRCA2
germline mutations.
A further problem arises in the care of women whose personal and/or family histories suggest that they may be at risk
for gynecologic cancers, but who decline mutation tests or
whose results have not demonstrated deleterious mutations
in BRCA1 or BRCA2 (see Figure 13). For, as noted (vide supra),
data from the Breast Cancer Linkage Consortium (Ford et al.,
122
Figure 13 – This remarkable family contains an excess of ovarian carcinoma in association with carcinoma of the breast. It appears from the clinical standpoint to be a classical HBOC kindred. However,
BRCA1, BRCA2, p53, and PTEN have all been evaluated only to find a complete absence of any cancer-causing mutations. This pedigree clearly shows the diagnostic dilemma that may take place in
assessing pedigrees with the advantage of a molecular genetic search for cancer-causing germline mutations while turning up an absence of any diagnostic certainty.
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
= Ovarian Cancer
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
1998) indicate that families afflicted with four or more breast
cancers and even one ovarian cancer in their lineage are likely
linked to either BRCA1 or BRCA2 mutations. Kauff et al. (2005)
at the Memorial Sloan-Kettering Cancer Center in New York
City addressed this matter by enrolling 184 such women,
whom they considered to be at ‘‘intermediate risk’’ for ovarian
cancer, into a screening program of semi-annual physical
examinations, transvaginal ultrasound scans, and serum
CA-125 determinations. All subjects were age 30 years or
older, and the mean age was 50 years; 50% were post-menopause, 61% had a personal history of previous breast cancer,
and 50% were of Ashkenazi Jewish descent. As may be
expected, no gynecological cancers were detected in this
small group of intermediate risk women, all followed fewer
than 4 years (mean follow-up, 19.9 months; range, 4.4–41.7
months), but abnormal ultrasound findings led to endometrial
sampling in 13 asymptomatic women of unreported age and
menopausal status. Short-term follow-up was necessary
because of findings in 19.4% of ultrasound scans, and 4.7% of
serum CA-125 results were abnormal in premenopausal
patients; while during the study there was a mean progressive
decline in self-assessed Quality of Life among those who participated (Kauff et al., 2005). These issues therefore must be
completely reviewed and discussed with women of both
high and intermediate genetic risks for gynecologic cancers,
when they are considering their options and timing for surveillance and surgical prophylaxis.
A comprehensive approach based on these principles, such
as that detailed in a report by the Clinical Genetics Group at
Memorial Sloan-Kettering Cancer Center, seems at present
to be promising (Scheuer et al., 2002). Scheuer et al. (2002)
counseled and offered DNA testing for cancer-associated mutations in BRCA1 and BRCA2 to 1865 women from whom 267
subjects were found to be mutation carriers. Two hundred
and thirty-three female mutation carriers, two-thirds in
BRCA1 and one-third in BRCA2, were involved in protocols
which offered prophylactic risk-reducing surgery or surveillance for breast and ovarian cancers. Twenty-one of these
women had a personal history of ovarian cancer, and 29
women already had undergone bilateral oophorectomy. Of
the remaining 179 women, 90 (50%) chose to have prophylactic
bilateral salpingo-oophorectomy, and 20% of these were done
with concomitant hysterectomy (Scheuer et al., 2002). At the
time of this surgery, one 51-year-old woman was found to
have a primary cancer confined to her ovary and another
woman, age 46 years, had an in situ carcinoma in her fallopian
tube. Both of these unsuspected gynecological cancers were in
subjects with normal transvaginal ultrasound scans less than
a month before surgery, and the latter patient had a normal
serum CA-125 titer shortly before surgery. Overall, 78% of mutation carriers younger than 40 years opted for surveillance
with physical examinations, transvaginal ultrasound scanning, and serum CA-125 determinations, whereas only 36%
of the mutation carriers age 40 years and older chose surveillance. In 84 of these patients for whom ovarian screening data
were available, abnormal transvaginal ultrasound scans or
elevated serum CA-125 titers were found in 22 subjects (36%)
of whom 10 were subjected to surgical intervention with the
detection of 4 ovarian and one peritoneal carcinoma involving
the ovary. Three of the 4 ovarian cancer patients and the
123
patient with peritoneal carcinoma had elevated serum CA125 titers. All 4 ovarian cancer patients had persistent
complex pelvic masses, and 3 of the 4 (75%) had cancers still
confined to the ovary. Six of the 7 gynecological cancers in
this series were in BRCA1 mutation carriers, and only one
was in a BRCA2 mutation carrier. No interval gynecological
or peritoneal cancers were diagnosed during intervals
between semi-annual screening (Scheuer et al., 2002). This raises the serious question, when caring for female members of
HBOC syndrome families, of who should be offered the option
of prophylactic surgery? Mæhle et al. (2008) in Norway identified 1582 women deemed to be at very high risk for ovarian
cancer because of their family histories, including known carriers of cancer-associated BRCA1 and BRCA2 mutations. These
women were offered prophylactic salpingo-oophorectomy or
screening with annual transvaginal ultrasound screening
and serum CA-125 determinations. Eleven gynecologic tumors
were diagnosed during the initial screening, and 7 further gynecologic tumors were found during follow-up. A total of 781
subjects chose prophylactic surgery either initially or during
follow-up, and 27 cancers were found or later reported in
this group. What is most remarkable in this series of Mæhle
et al. is that all but one of 47 invasive carcinomas of the ovary
(40), fallopian tube (1), and peritoneum (6) were in BRCA1 (45/
47 ¼ 96%) or BRCA2 (1.47 ¼ 2%) mutation carriers (Mæhle et al.,
2008).
In the case of known and likely mutation carriers from
HBOC syndrome kindreds, we consider surveillance programs
employing thorough history and physical examinations, ultrasound scans and serum tumor marker determination at
best to be temporizing until better methods become available
for the detection of early ovarian carcinoma or until such
high-risk patients ultimately undergo prophylactic surgery.
When persisting abnormalities suspicious for nonfunctional
ovarian tumors are found on ultrasound scans and/or suspicious serum tumor marker elevations are determined,
whether predicting benign or malignant lesions, we advocate
counseling not only for invasive operative procedures but also
for possible prophylactic surgery, whatever may be the intraoperative findings, as well as explanation of the procedures,
their purpose and possible untoward effects, along with consent and preparation for major cancer debulking procedures.
Our first step in the operating protocol, unless technically contraindicated, is thorough exploratory laparoscopy, collection
of cytological and histological specimens for diagnosis, then
either termination or, depending on our patient’s desire for
further childbearing and her age, proceeding with prophylactic adnexectomy and hysterectomy. Although others subsequently have reported successful use of laparoscopy for
prophylactic removal of the ovaries in women at hereditary
risk for ovarian cancer (Eltabbakh et al., 1999; Morice et al.,
1999), long before this we advocated laparoscopic examination and assisted transvaginal bilateral salpingo-oophorect
omy with hysterectomy in women at genetic risk for gynecologic cancers (Casey et al., 1995). Unless technically contraindicated, we believe that videolaparoscopy provides excellent
exploration, retrieval of peritoneal fluid and washings for
cytology and biopsies as may be indicated, to be safely followed by assisted wide adnexectomy incorporating the entire
fallopian tubes and ovaries removed en bloc with vaginal
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hysterectomy (Casey et al., 1994, 1995). If gross cancer is discovered at laparoscopy the patient will have been counseled,
consented, and prepared for appropriate tumor extirpation.
9.3.
Follow-up after Prophylactic Salpingooophorectomy
Although prophylactic salpingo-oophorectomy reduces the
likelihood of disseminated gynecological and peritoneal cancers in women from HBOC syndrome families, these women
remain at lifetime risk for intra-abdominal carcinomatosis
(Casey et al., 2005; Casey and Bewtra, 2004; Kauff et al., 2008;
Rebbeck et al., 2002; Struewing et al., 1995). From among
1291 women who were screened and followed at the Gilda
Radner Ovarian Cancer Detection Program in Los Angeles,
Liede et al. (2002) selected a series of 290 Ashkenazi Jewish
women with family histories of ovarian cancer at any age or
breast cancer younger than 50 years in a first- or second-deg
ree relative. Subjects were counseled, offered testing for the
BRCA1 185delAG and 5382insC mutations and the BRCA2
6174delT mutation often found in this population, and they
were screened and followed with transvaginal ultrasound
scans and serum CA-125 determinations. The mean age at
which these subjects entered their program was 44.8 years,
and 15% ultimately elected prophylactic salpingo-oophorect
omy between 1 year and 9 years after they entered. During
a mean follow-up time of 5.3 2.2 years in all participants
and 7.2 1.7 years in 33 participants who tested positive for
the Ashkenazi BRCA1 or BRCA2 mutations, 9 women were
diagnosed with pelvic–abdominal malignancies, including
one patient with uterine cervix cancer, 2 ovarian carcinomas,
5 peritoneal carcinomas, and one fallopian tube carcinoma.
All of the ovarian, peritoneal and fallopian tube cancers
were papillary serous carcinomas and 7 of these 8 cancers
were in carriers of the BRCA1 185delAG mutation. One of the
ovarian cancer patients and the patient who was diagnosed
with cervical cancer were not mutation carriers. Only one of
the 8 ovarian, peritoneal, and fallopian tube cancers was
detected by transvaginal ultrasound scan while still confined.
Serum CA-125 titers were elevated in 3 of these cancer patients, and each had disseminated intra-abdominal carcinoma when diagnosed. All 5 of the peritoneal carcinoma
patients had normal ovaries on ultrasound scans in the authors’ program or an affiliate 1–17 months (mean, 8 months)
prior to the diagnosis (Liede et al., 2002). These results hold
disappointing implications not only for the early diagnosis
of gynecological cancers in women from HBOC syndrome
families but also for the ability to offer early diagnosis of intra-abdominal carcinomatosis in women remaining at risk
for peritoneal carcinoma following prophylactic surgery
(Casey et al., 2005; Casey and Bewtra, 2004; Liede et al., 2002).
Currently, after prophylactic salpingo-oophorectomy with
or without hysterectomy, we offer to follow patients because
of their small but continued genetic risk for peritoneal carcinomatosis with at least yearly or at more frequent semi-ann
ual intervals when proven and likely carriers of cancer-associated mutations so choose. Members of HBOC syndrome families are, of course, at high risk for breast cancer, which
already may have been treated or for which they may remain
at risk, and so they are counseled regarding prophylactic
chemotherapy, mastectomy, and breast cancer screening.
Patients whom we continue to follow are counseled to be alert
to symptoms and signs that may be related to abdominal–pelv
ic cancer, while making every effort to allay anxiety and
alarm. During visits, the physician examiner carefully dissects
all of the patient’s complaints and performs a complete
review of systems and physical examination, addressing the
patient’s concerns and obtaining appropriate consultation,
laboratory, and scanning studies as may be indicated.
Although we cannot express confidence that improved outcomes will be achieved through pre-symptomatic detection
of peritoneal carcinoma by abdominal–pelvic ultrasound
scans and/or tumor marker tests, specifically serum CA-125
titer determinations for which we evaluate any persisting
upward deviation, these screening methods usually are chosen by objectively-informed individuals, who are relieved by
negative periodic examinations, that, confessedly, also are
somewhat reassuring to us.
Clearly, much work needs to be done to expand and improve surveillance protocols for the early detection of ovarian,
fallopian tube, and peritoneal carcinoma through the development of additional techniques and refinement in the use of
those which are available, with critical analysis of the results
of management if cancers are diagnosed.
9.4.
Ovarian cancer associated with the Lynch syndrome
When analysis of family pedigrees implicates an individual to
be at 50% risk of inheriting the autosomal dominant cancersusceptibility traits of Lynch syndrome, and in those
individuals in whom the personal and family risk assessment
determines a high likelihood of inheriting predispositions to
Lynch syndrome-related cancers, genetic counseling should
be offered. In circumstances of known cancer-associated
MMR gene mutations being carried within families and
when specific MMR gene mutations are prevalent within determined populations, these individuals can be effectively
tested; mutation carriers are then counseled and offered cancer targeted management programs (Lu, 2008; Lynch and
Casey, 2007; Lynch and de la Chapelle, 1999). See Table 1 for
cardinal features of the Lynch syndrome.
Although combined estrogen–progestin oral contraceptives effectively reduce general population risks for both
endometrial and ovarian cancers; and endometrial cytological
and histological samplings can detect the presence of otherwise occult intrauterine cancer and transvaginal ultrasound
scans are capable of demonstrating endometrial and ovarian
abnormalities that portend endometrial and ovarian neoplasms and carcinomas, even in early stages (Bell et al.,
1998; Bourne et al., 1993; Casey and Madden, 1976; Patai
et al., 2002; Rijcken et al., 2003); as yet there are no available
clinical studies to confirm the efficacy of these prophylactic
and screening measures for preventing morbidity and mortality in Lynch syndrome families (Lu, 2008). On the other hand,
Schmeler et al. (2006) retrospectively matched 61 cancer-assoc
iated MMR gene mutation carriers who had undergone hysterectomy with or without bilateral salpingo-oophorectomy with
210 MMR gene mutation carriers who had not undergone hysterectomy, and noted that occult endometrial cancer was
found in 3 of the extirpated uteri. None of the 61 MMR gene
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
125
Table 1 – Cardinal features of Lynch syndrome.
Autosomal dominant inheritance pattern seen for syndrome cancers in the family pedigree.
Earlier average age of CRC onset than in the general population:
average age of 45 years in Lynch syndrome versus 63 years in the general population
Proximal (right-sided) colonic cancer predilection:
70–85% of Lynch syndrome CRCs are proximal to the splenic flexure.
Accelerated carcinogenesis (tiny adenomas can develop into carcinomas more quickly):
within 2–3 years in Lynch syndrome versus 8–10 years in the general population
High risk of additional CRCs:
25–30% of patients having surgery for a Lynch syndrome-associated CRC will have a second
primary CRC within 10 years of surgical resection if the surgery was less than a subtotal colectomy
Increased risk for malignancy at certain extracolonic sites:
endometrium (40–60% lifetime risk for female mutation carriers)
ovary (12–15% lifetime risk for female mutation carriers)
- stomach (higher risk in families indigenous to the Orient, reason unknown at this time)
- small bowel
- hepatobiliary tract
- pancreas
- upper uro-epithelial tract (transitional cell carcinoma of the ureter and renal pelvis)
- brain (in the Turcot’s syndrome variant of the Lynch syndrome)
Sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas in
the Muir-Torre syndrome variant of Lynch syndrome
Pathology of CRCs is more often poorly differentiated, with an excess of mucoid and
signet-cell features, a Crohn’s-like reaction, and a significant excess of infiltrating lymphocytes within the tumor.
Increased survival from CRC.
The sine qua non for diagnosis is the identification of a germline mutation in a mismatch
repair gene (most commonly MLH1, MSH2, or MSH6) that segregates in the family: i.e., members
who carry the mutation show a much higher rate of syndrome-related cancers than those who do not carry the mutation.
-
mutation carriers who underwent hysterectomy developed either endometrial or ovarian cancer during an average 13.3
years (range, 0.5–38 years) post-surgery follow-up; whereas,
32.7% (69/210) of the MMR gene mutation carriers who did
not have surgery were diagnosed with endometrial cancer
during average follow-up of only 7.4 years (range, 0.1–35
years). Schmeler et al. also matched 46 MMR gene mutation
carriers who had undergone hysterectomy and bilateral salpingo-oophorectomy with 223 MMR gene mutation carriers
who had not undergone hysterectomy, and they found that
no ovarian or peritoneal carcinomas were diagnosed in the
group which had had surgery compared with the diagnosis
of ovarian cancer in 5.4% (12/223) of the group that did not
have surgery during 20 years of follow-up. In this study, the
median age at which ovarian cancer was diagnosed in the
control group of MMR gene mutation carriers who did not
have bilateral salpingo-oophorectomy was 42 years (range,
31–48 years), and the median age at which endometrial cancer
was diagnosed in the control group who did not have hysterectomy was 46 years (range, 30–69 years) (Schmeler et al.,
2006). So the problem is to develop management strategies
that might be offered to protect carriers of mutated MMR
genes and others at high risk for ovarian and endometrial cancers in Lynch syndrome families.
At the University Hospital Groningen in The Netherlands,
Rijcken et al. (2003) enrolled 41 women into their screening
program for members of Lynch syndrome families. Thirtyfour of these subjects fulfilled the Amsterdam criteria for
HNPCC families, but in retrospect 7 subjects were considered
to have <25% risk of being an MMR gene mutation carrier.
Eight of the women were proven to carry MLH1 mutations, 2
women carried mutations in MSH2, and one women carried
a MSH6 mutation. Using annual physical examinations, transvaginal ultrasound scans, and serum CA-125 determinations,
this group was screened for both endometrial and ovarian lesions. Abnormally thickened or irregular endometrium on ultrasound scans led to the diagnosis of atypical complex
hyperplasia of the endometrium in 2 premenopausal and
one postmenopausal enrollees. During the median follow-up
of 5 years (range, 5 monthsto11 years), one subject presented
with postmenopausal bleeding just 5 months after a normal
transvaginal sonogram demonstrated the endometrial thickness to be <5 mm, and endometrioid carcinoma with myometrial invasion though still confined to the uterine corpus was
diagnosed. Eighteen other endometrial sampling procedures
were done without recovery of pathological endometrium,
16 on premenopausal subjects and 2 on postmenopausal subjects, as a result of ultrasound abnormalities. All serum CA125 titers were within normal range, and no ovarian abnormalities were demonstrated during this screening program
of Lynch syndrome subjects. However, Rijcken et al. presented
24 cases of primary gynecologic cancers from Lynch syndrome
patients in their database. These included 18 patients with
endometrioid uterine carcinomas, 3 of which showed clear
carcinoma components, and 3 of the endometrial cancers
were accompanied with simultaneous primary ovarian carcinomas. Five primary ovarian carcinomas without co-existing
uterine cancers were diagnosed; 3 of these were serous
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ovarian carcinomas and 2 were endometrioid ovarian carcinomas. Thirteen of the 18 endometrial cancers in these women
were still confined to the uterine corpus; none of the 13 endometrial cancers were deeply invasive and 8 of the 13 were well
differentiated. Interestingly, in the Groningen database, 6 of
the 7 (86%) ovarian cancers for which staging was noted
were still confined to the ovary, and the other ovarian cancer
was still within the pelvis when diagnosed, though 4 of these
carcinomas were associated with malignant peritoneal cytology. Thus, in this series of gynecological cancers diagnosed in
Lynch syndrome patients, 33% (8/24) of the cancers were
either primary ovarian carcinomas or synchronous primary
ovarian carcinomas co-existing with endometrial carcinomas.
The mean age at which ovarian cancers were diagnosed in the
Groningen series was 50 years (range, 40–61 years), but 4/8
(50%) of the ovarian cancers were diagnosed while patients
still were in their fifth decades of life. The mean age of 45 years
(range, 28–53 years) at which endometrial cancers were diagnosed was even younger. Forty-four per cent (8/18) of the
endometrial cancers in this Lynch syndrome series were diagnosed during the fifth decade, and 3 were diagnosed in women
younger than 40 years (Rijcken et al., 2003). In our own series,
although the median age at which ovarian cancer was diagnosed in MMR gene mutation carries was 46 years (range,
30–69 years), 18% of the ovarian cancers in mutation carriers
were diagnosed before age 40 years, and 39% were before their
50th birthday (CLS, unpublished data).
One retrospective study of 269 women from English and
Dutch registries whose pedigrees suggested them to be at
50% risk or more of carrying a dominantly inherited predisposition of Lynch syndrome, disclosed that no asymptomatic patient was detected by ultrasound scans with either
endometrial or ovarian cancers during periods up to 13 years,
and the only two patients who were found in this review to
have been diagnosed with endometrial cancer both presented
with symptomatic bleeding (Dove-Edwin et al., 2002). However, it should be noted that the older of these patients,
a postmenopausal woman of 51 years followed seven years
post-operatively for synchronous Duke’s A and B colorectal
carcinomas, had only one negative trans-abdominal scan
and was diagnosed with endometrial carcinoma confined to
the uterine corpus, some 27 months thereafter (Dove-Edwin
et al., 2002). We would ordinarily strongly recommend hysterectomy with bilateral adnexectomy at the time of colectomy
in women of this age who are found to have two synchronous
colorectal carcinomas and deemed to be a 50% or greater risk
for Lynch syndrome. Moreover, while transvaginal ultrasound
scanning is capable of detecting early ovarian cancer and, if
negative, lessening the current risk for the presence of postmenopausal asymptomatic endometrial carcinomas, there is
no evidence that trans-abdominal ultrasound scanning holds
this same promise.
Renkonen-Sinisalo et al. (2006) provided surveillance for
175 asymptomatic Finnish women who were proven carriers
of MMR gene mutations from 103 Lynch syndrome families
employing not only transvaginal ultrasound scans and serum
CA-125 determinations but also intrauterine endometrial
sampling. They compared the results of this program with
the diagnoses and outcomes of 83 endometrial cancer patients
from the same families who presented with symptoms prior
to and during their study. In this study, transvaginal ultrasound scans showed endometrial abnormalities in 4 patients
with endometrioid carcinomas, 2 with associated clear cell
carcinoma components, but ultrasound scans missed 6 additional cases of endometrial carcinoma that were detected
with endometrial sampling. All except one of the endometrial
cancers detected by screening were still confined to the uterine corpus. An additional 14 cases of complex endometrial hyperplasia, 4 with atypia, were picked up with endometrial
sampling, but only 6 of these demonstrated endometrial
abnormalities on ultrasound scans. During the median 3.7
years of follow-up, none of the women whose endometrial
cancers were detected by screening died with this disease;
whereas 6/83 (7%) of the symptomatic women died from their
endometrial cancers. Four women enrolled in the Finnish
gynecological surveillance program for MMR gene mutation
carriers were diagnosed with endometrioid ovarian cancers,
but none of these were detected by screening. Two of the ovarian cancers, one confined to the ovary and the other with
intra-abdominal dissemination, were diagnosed in symptomatic women, ages 45years and 41 years, only 2 months and 5
months, respectively, after normal screening. Two of the ovarian carcinomas were diagnosed incidentally in women aged
42 years and 50 years, while still confined to the ovaries, during surgery for endometrial hyperplasia and carcinoma. Only
6 patients reported by Renkonen-Sinisalo et al. had serum CA125 elevations, and half of these were transient. None of the
ovarian cancer patients showed serum CA-125 elevations,
and only one titer of 179 units/ml was associated with an
endometrial carcinoma, which was found to have extended
into the cervix when this was evaluated. In this series, the
mean age of patients whose endometrial cancers were
detected by screening was 51 years, which was comparable
with the 50 year mean age of endometrial cancer diagnosis
in the group’s symptomatic patients. The mean age of ovarian
cancer diagnosis in this Finnish series of MMR gene mutation
carriers was 44.5 years (range, 41–50 years), and 3 of the 4
women diagnosed with ovarian cancers because of symptoms
or incidentally at surgery for endometrial neoplasms were still
in their fifth decade, but none was younger than 40 years
(Renkonen-Sinisalo et al., 2006).
Kwon et al. (2008b) at the University of Texas M.D. Anderson Cancer Center employed Markov decision models to analyze the cost-effectiveness and net benefit in quality-adjusted
life years to test several management strategies for a hypothetical cohort of Lynch syndrome patients, and they concluded that annual surveillance with endometrial sampling,
transvaginal ultrasound scans, and CA-125 determinations
from age 30 years until prophylactic hysterectomy–salpingooophorectomy at age 40 years is the most effective cancer prevention strategy measured in quality-adjusted life years.
Given the efficacy of endometrial cancer screening and later
ages of ovarian cancer diagnosis in these series, with alertness
to symptoms and signs and rapid diagnostic intervention if
they occur, it is reasonable to support female carriers of
MMR gene mutations, who choose to do so, by surveillance
during the childbearing years of their third and fourth decades
and until they may elect bilateral salpingo-oophorectomy–
hysterectomy for surgical prophylaxis (Lynch and Casey,
2007).
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
Notwithstanding the disappointing results of the National
Institutes of Health National Ovarian Cancer Early Detection
Program, as noted in our discussion on management and
screening of women at risk for HBOC, the selection criteria
for that study favored subjects more likely to acquire perhaps
more aggressive fast growing serous carcinomas rather than
non-serous ovarian malignancies, such as may be more common in women from Lynch syndrome families (MJC, unpublished data; Fishman et al., 2005; Rijcken et al., 2003). Given
that ovarian and endometrial carcinomas in MMR gene mutation carriers have been diagnosed as young as their 31st year
in our Lynch syndrome cohort (CLS, unpublished data), and
given lifetime risks of 6–12% for ovarian cancer and 30–60%
for endometrial cancer in these subjects (Aarnio et al., 1999;
Quehenberger et al., 2005; Vasen et al., 1996, 2001; Watson
et al., 2008), and the fact that 5–10% of ovarian cancers in
Lynch syndrome families were diagnosed before their 35th
birthday (Brown et al., 2001; Watson et al., 2008), we recommend that young women from Lynch syndrome kindreds
should receive professional cancer genetics counseling soon
following their 21st birthday. Those who are found to carry
cancer-associated MMR gene mutations, and obligate carriers,
are advised to be engaged in programs of periodic transvaginal
pelvis ultrasound scans and endometrial screening beginning
in their 26th year until they elect prophylactic surgery, which
may cautiously be delayed until they have completed childbearing and before their fifth decade of life, when the risks
for ovarian and endometrial cancers begin to substantially accumulate (CLS, unpublished data; Brown et al., 2001; Watson
et al., 2008). With advances in surgical techniques, these procedures may be safely accomplished with laparoscopic
assistance, delivering the uterus and adnexa en bloc through
the vagina, while also permitting extensive direct
video-visualization of the peritoneal cavity and affording the
opportunity to collect samples for cytological and histological
studies (Casey et al., 1994, 1995).
9.5.
Future prospects: DNA variants modify HBOC and
LS cancer risk
What does the future hold with respect to molecular genetics
and cancer control in hereditary cancer, inclusive of HBOC and
Lynch syndrome? This projection relates to the truism that cancer-causing mutations do not act in a vacuum, since they are
likely to be impacted by additional low-penetrant modifier
genes in concert with myriad environmental events. For example, in the HBOC syndrome, the work of Smith et al. (2007) estimated that in high-risk families the breast cancer risk might
be caused not only by the BRCA/2 mutation, but also may be increased by modifier genes. This is important, since in genetic
counseling we have ensured mutation-negative family members from BRCA kindreds that they are at general population
risk rather than at extremely high cancer risk. The implication
is that they do not require intensive screening recommendation.
However, if these findings are confirmed, then patients testing
negative for a BRCA mutation in the setting of HBOC families
with BRCA relatives, should be considered for continued surveillance, perhaps less than we would consider should they be positive for the BRCA mutation but, nevertheless, more than we
127
would recommend for those individuals who are judged to be
more truly sporadic and thereby at general population risk.
However, these findings merit confirmation in a well-designed
prospective study (Gronwald et al., 2007).
In the case of Lynch syndrome, Wijnen et al. (2009) have
shown that genome-wide association studies have identified
common low-risk variants impacting CRC. These investigators genotyped these variants in 675 individuals from the
Dutch Lynch Syndrome Registry who were known carriers of
Lynch syndrome-associated mutations. They genotyped
8q24.21, 8q23.3, 10p14, 11q23.1, 15q13.3, and 18q21.1. Results
disclosed a significant association between CRC risk in these
Lynch syndrome mutation carriers and the single nucleotide
polymorphisms (SNPs) rs16892766 on chromosome 8q23.3
and rs3802842 on chromosome 11q23.1. They concluded that
the two loci which they identified may be helpful in identifying Lynch syndrome family members who require more intensive surveillance specifically for CRC. The possibility exists
that the presence of one of these identified low-risk variants
may slightly increase risk of CRC for members of Lynch syndrome families who are negative for an MMR mutation.
Acknowledgments
This paper was supported by revenue from Nebraska cigarette
taxes awarded to Creighton University by the Nebraska
Department of Health and Human Services. Its contents are
solely the responsibility of the authors and do not necessarily
represent the official views of the State of Nebraska or the
Nebraska Department of Health and Human Services. Support
was also given by the National Institutes of Health through
grant #1U01 CA 86389.
Dr. Henry Lynch’s work is partially funded through the
Charles F. and Mary C. Heider Chair in Cancer Research, which
he holds at Creighton University.
Support was provided to Dr. Andrew K. Godwin by the
Ovarian Cancer Research Fund and the Ovarian Cancer SPORE
at Fox Chase Cancer Center (P50 CA083638).
R E F E R E N C E S
Aaltonen, L.A., Peltomaki, P., Leach, F.S., Sistonen, P., Pylkkanen,
L., Mecklin, J.-P., et al., 1993. Clues to the pathogenesis of
familial colorectal cancer. Science 260, 812–816.
Aaltonen, L.A., Salovaara, R., Kristo, P., Canzian, F., Hemminki, A.,
Peltomäki, P., et al., 1998. Incidence of hereditary nonpolyposis
colorectal cancer and the feasibility of molecular screening for
the disease. N. Engl. J. Med. 338, 1481–1487.
Aarnio, M., Sankila, R., Pukkala, E., Salovaara, R., Aaltonen, L.A.,
de la Chapelle, A., Peltomäki, P., Mecklin, J.-P., Järvinen, H.J.,
1999. Cancer risk in mutation carriers of DNA-mismatchrepair genes. Int. J. Cancer 81, 214–218.
Acharya, S., Wilson, T., Gradia, S., Kane, M.F., Guerrette, S.,
Marsischky, G.T., Kolodner, R., Fishel, R., 1996. hMSH2 forms
specific mispair-binding complexes with hMSH3 and hMSH6.
Proc. Natl. Acad. Sci. U.S.A. 93, 13629–13634.
Agoff, S.N., Mendelin, J.E., Grieco, V.S., Garcia, R.L., 2002.
Unexpected gynecologic neoplasm in patients with proven or
128
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
suspected BRCA-1 or -2 mutations: implications for gross
examination, cytology, and clinical follow-up. Am. J. Surg.
Pathol. 26, 171–178.
Aida, H., Takakuwa, K., Nagata, H., Tsuneki, I., Takano, M.,
Tsuji, S., Takahashi, T., Sonoda, T., Hatae, M., Takahashi, K.,
et al., 1998. Clinical features of ovarian cancer in Japanese
women with germ-line mutations of BRCA1. Clin. Cancer Res.
4, 235–240.
Akiyama, Y., Sato, H., Yamada, T., Nagasaki, H., Tsuchiya, A.,
Abe, R., Yuasa, Y., 1997. Germ-line mutation of the hMSH6/
GTBP gene in an atypical hereditary nonpolyposis colorectal
cancer kindred. Cancer Res. 57, 3920–3923.
Ali-Fehmi, R., Khalifeh, I., Bandyopadhyay, S., Lawrence, W.D.,
Silva, E., Liao, D., Sarkar, F.H., Munkarah, A.R., 2006. Patterns
of loss of heterozygosity at 10q23.3 and microsatellite
instability in endometriosis, atypical endometriosis, and
ovarian carcinoma arising in association with endometriosis.
Int. J. Gynecol. Pathol. 25, 223–229.
Antoniou, A.C., Gayther, S.A., Stratton, J.F., Ponder, B.A.J.,
Easton, D.F., 2000. Risk models for familial ovarian and breast
cancer. Genet. Epidemiol. 18, 173–190.
Antoniou, A., Pharoah, P.D., Narod, S., Risch, H.A., Eyfjord, J.E.,
Hopper, J.L., et al., 2003. Average risks of breast and ovarian
cancer associated with BRCA1 and BRCA2 mutations detected
in case series unselected for family history: a combined
analysis of 22 studies. Am. J. Hum. Genet. 72, 1117–1130.
Arboleda, M.J., Lyons, J.F., Kabbinavar, F.F., Bray, M.R., Snow, B.E.,
Ayala, R., Danino, M., Karlan, B.Y., Slamon, D.J., 2003.
Overexpression of AKT2/protein kinase Bb leads to upregulation of b1 integrins, increased invasion, and metastasis of
human breast and ovarian cancer cells. Cancer Res. 63, 196–206.
Auersperg, N., Wong, A.S., Choi, K.C., Kang, S.K., Leung, P.C., 2001.
Ovarian surface epithelium: biology, endocrinology, and
pathology. Endocr. Rev. 22, 255–288.
Aziz, S., Kuperstein, G., Rosen, B., Cole, D., Nedelcu, R.,
McLaughlin, J., Narod, S.A., 2001. A genetic epidemiological study
of carcinoma of the fallopian tube. Gynecol. Oncol. 80, 341–345.
Baldwin, R.L., Nemeth, E., Tran, H., Shvartsman, H., Cass, I.,
Narod, S., Karlan, B.Y., 2000. BRCA1 promoter region
hypermethylation in ovarian carcinoma: a population-based
study. Cancer Res. 60, 5329–5333.
Bassis, M.L., 1960. An embryologically derived classification of
ovarian tumors. JAMA 174, 1316–1319.
Beiner, M.E., Finch, A., Rosen, B., Lubinski, J., Moller, P.,
Ghadirian, P., et al., 2007. The risk of endometrial cancer in
women with BRCA1 and BRCA2 mutations. A prospective
study. Gynecol. Oncol. 104, 7–10.
Bell, D.A., 2005. Origins and molecular pathology of ovarian
cancer. Modern Pathol. 18 (Suppl. 2), S19–S32.
Bell, R., Petticrew, M., Sheldon, T., 1998. The performance of
screening tests for ovarian cancer: results of a systematic
review. Br. J. Obstet. Gynaecol. 105, 1136–1147.
Bellacosa, A., de Feo, D., Godwin, A.K., Bell, D.W., Cheng, J.Q.,
Altomare, D.A., et al., 1995. Molecular alterations of the AKT2
oncogene in ovarian and breast carcinomas. Int. J. Cancer 64,
280–285.
Ben David, Y., Chetrit, A., Hirsh-Yechezkel, G., Friedman, E.,
Beck, B.D., Beller, U., Ben-Baruch, G., Fishman, A., Levavi, H.,
Lubin, F., et al., 2002. Effect of BRCA mutations on the length of
survival in epithelial ovarian tumors. J. Clin. Oncol. 20, 463–466.
Bergman, L., Beelen, M.L., Gallee, M.P., Hollema, H., Benraadt, J., van
Leeuwen, F.E., 2000. Risk and prognosis of endometrial cancer
after tamoxifen for breast cancer. Comprehensive Cancer
Centres’ ALERT Group. Assessment of liver and endometrial
cancer risk following tamoxifen. Lancet 356, 881–887.
Bernstein, L., Deapen, D., Cerhan, J., Schwartz, S.M., Liff, J.,
McGann-Maloney, E., Perlman, J., Ford, L., 1999. Tamoxifen
therapy for breast cancer and endometrial cancer risk. J. Natl.
Cancer Inst. 91, 1654–1662.
Bewtra, C., Watson, P., Conway, T., Read-Hippee, C., Lynch, H.T.,
1992. Hereditary ovarian cancer: a clinicopathological study.
Int. J. Gynecol. Pathol. 11, 180–187.
Biron-Shental, T., Drucker, L., Altaras, M., Bernheim, J.,
Fishman, A., 2006. High incidence of BRCA1-2 germline
mutations, previous breast cancer and familial cancer history
in Jewish patients with uterine serous papillary carcinoma.
Eur. J. Surg. Oncol. 32, 1097–1100.
Boland, C.R., Koi, M., Chang, D.K., Carethers, J.M., 2008. The
biochemical basis of microsatellite instability and abnormal
immunohistochemistry and clinical behavior in Lynch
syndrome: from bench to bedside. Fam. Cancer 7, 41–52.
Boland, C.R., Thibodeau, S.N., Hamilton, S.R., Sidransky, D.,
Eshleman, J.R., Burt, R.W., et al., 1998. A National Cancer
Institute workshop on microsatellite instability for cancer
detection and familial predisposition: development of
international criteria for the determination of microsatellite
instability in colorectal cancer. Cancer Res. 58, 5248–5257.
Borg, A., Isola, J., Chen, J., Rubio, C., Johansson, U., Werelius, B.,
Lindblom, A., 2000. Germline BRCA1 and HMLH1 mutations in
a family with male and female breast carcinoma. Int. J. Cancer
85, 796–800.
Bosse, K., Rhiem, K., Wappenschmidt, B., Hellmich, M.,
Madeja, M., Ortmann, M., Mallmann, P., Schmutzler, R., 2006.
Screening for ovarian cancer by transvaginal ultrasound and
serum CA125 measurement in women with a familial
predisposition: a prospective cohort study. Gynecol. Oncol.
103, 1077–1082.
Bourne, T.H., Campbell, S., Reynolds, K.M., Whitehead, M.I.,
Hampson, J., Royston, P., Crayford, T.J., Collins, W.P., 1993.
Screening for early familial ovarian cancer with transvaginal
ultrasonography and colour blood flow imaging. BMJ 306,
1025–1029.
Boyd, J., 1998. Molecular genetics of hereditary ovarian cancer.
Oncology 12, 399–406.
Boyd, J., Sonoda, Y., Federici, M.G., Bogomolniy, F., Rhei, E.,
Maresco, D.L., Saigo, P.E., Almadrones, L.A., Barakat, R.R.,
Brown, C.L., et al., 2000. Clinicopathologic features of BRCAlinked and sporadic ovarian cancer. JAMA 283, 2260–2265.
Bronner, C.E., Baker, S.M., Morrison, P.T., Warren, G., Smith, L.G.,
Lescoe, M.K., et al., 1994. Mutation in the DNA mismatch
repair gene homologue hMLH1 is associated with hereditary
nonpolyposis colon cancer. Nature 368, 258–261.
Brose, M.S., Rebbeck, T.R., Calzone, K.A., Stopfer, J.E.,
Nathanson, K.L., Weber, B.L., 2002. Cancer risk estimates for
BRCA1 mutation carriers identified in a risk evaluation
program. J. Natl. Cancer Inst. 94, 1365–1372.
Brown, G.J., St. John, D.J., Macrae, F.A., Aittomaki, K., 2001. Cancer
risk in young women at risk of hereditary nonpolyposis
colorectal cancer: implications for gynecologic surveillance.
Gynecol. Oncol. 80, 346–349.
Buller, R.E., Shahin, M.S., Geisler, J.P., Zogg, M., De Young, B.R.,
Davis, C.S., 2002. Failure of BRCA1 dysfunction to alter ovarian
cancer survival. Clin. Cancer Res. 8 (5*), 1196–1202 (*Due to
a page numbering error, an unrelated article with this same
volume and start page citation appears in the 8(4) issue of Clin.
Cancer Res.).
Byrd, L.M., Shenton, A., Maher, E.R., Woodward, E., Belk, R.,
Lim, C., Lalloo, F., Howell, A., Jayson, G.C., Evans, G.D., 2008.
Better life expectancy in women with BRCA2 compared with
BRCA1 mutations is attributable to lower frequency and later
onset of ovarian cancer. Cancer Epidemiol. Biomarkers Prev.
17, 1535–1542.
Cai, K.Q., Albarracin, C., Rosen, D., Zhong, R., Zheng, W.,
Luthra, R., Broaddus, R., Liu, J., 2004. Microsatellite instability
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
and alteration of the expression of hMLH1 and hMSH2 in
ovarian clear cell carcinoma. Hum. Pathol. 35, 552–559.
Cai, K.Q., Klein-Szanto, A., Karthik, D., Edelson, M., Daly, M.B.,
Ozols, R.F., Lynch, H.T., Godwin, A.K., Xu, X.X., 2006. Agedependent morphological alterations of human ovaries from
populations with and without BRCA mutations. Gynecol.
Oncol. 103, 719–728.
Callahan, M.J., Crum, C.P., Medeiros, F., Kindelberger, D.W.,
Elvin, J.A., Garber, J.E., Feltmate, C.M., Berkowitz, R.S.,
Muto, M.G., 2007. Primary fallopian tube malignancies in
BRCA-positive women undergoing surgery for ovarian cancer
risk reduction. J. Clin. Oncol. 25, 3985–3990.
Canistra, S.A., 1997. BRCA mutations and survival in women with
ovarian cancer. N. Engl. J. Med. 336, 1254 (letter).
Carethers, J.M., Hawn, M.T., Chauhan, D.P., Luce, M.C., Marra, G.,
Koi, M., Boland, C.R., 1996. Competency in mismatch repair
prohibits clonal expansion of cancer cells treated with
N-methyl-N0 -nitro-N-nitrosoguanidine. J. Clin. Invest. 98, 199–206.
Casarsa, S., Puglisi, F., Baudi, F., De Paola, L., Venuta, S., Piga, A.,
Di Loreto, C., Marchesoni, D., D’Elia, A.V., Damante, G., 2004.
BRCA2 germline mutations in primary cancer of the fallopian
tube. Oncol. Rep. 12, 313–316.
Casey, M.J., 1977. Estrogens, menopause and cancer. Conn. Med.
41, 776.
Casey, M.J., Bewtra, C., 2004. Peritoneal carcinoma in women with
genetic susceptibility: implications for Jewish populations.
Fam. Cancer 3, 265–281.
Casey, M.J., Bewtra, C., Garcia-Padial, J., Lynch, H.T., 1995.
Laparoscopic examination and assisted bilateral salpingooophorectomy hysterectomy for prophylactic removal of the
ovaries and uterus in women at genetic risk for ovarian
cancer. J. Gynecol. Tech. 1, 111–114.
Casey, M.J., Bewtra, C., Hoehne, L.L., Tatpati, A.D., Lynch, H.T.,
Watson, P., 2000. Histology of prophylactically removed
ovaries from BRCA1 and BRCA2 mutation carriers compared
with noncarriers in hereditary breast ovarian cancer
syndrome kindreds. Gynecol. Oncol. 78, 278–287.
Casey, M.J., Garcia-Padial, J., Johnson, C., Osborne, N.G.,
Sotolongo, J., Watson, P., 1994. A critical analysis of
laparoscopic assisted vaginal hysterectomies compared with
vaginal hysterectomies unassisted by laparoscopy and
transabdominal hysterectomies. J. Gynecol. Surg. 10, 7–14.
Casey, M.J., Madden, T.J., 1976. Gravlee jet irrigator as a screening
method? JAMA 236, 2051–2052.
Casey, M.J., Snyder, C., Bewtra, C., Narod, S.A., Watson, P.,
Lynch, H.T., 2005. Intra-abdominal carcinomatosis after
prophylactic oophorectomy in women of hereditary breast
ovarian cancer syndrome kindreds associated with BRCA1 and
BRCA2 mutations. Gynecol. Oncol. 97, 457–467.
Cass, I., Baldwin, R.L., Varkey, T., Moslehi, R., Narod, S.A.,
Karlan, B.Y., 2003. Improved survival in women with BRCAassociated ovarian carcinoma. Cancer 97, 2187–2195.
Cass, I., Holschneider, C., Datta, N., Barbuto, D., Walts, A.E.,
Karlan, B.Y., 2005. BRCA-mutation-associated fallopian tube
carcinoma: a distinct clinical phenotype? Obstet. Gynecol. 106,
1327–1334.
Catasús, L., Bussaglia, E., Rodrı́guez, I., Gallardo, A., Pons, C.,
Irving, J.A., Prat, J., 2004. Molecular genetic alterations in
endometrioid carcinomas of the ovary: similar frequency of
beta-catenin abnormalities but lower rate of microsatellite
instability and PTEN alterations than in uterine endometrioid
carcinomas. Hum. Pathol. 35, 1360–1368.
Cauley, J.A., Norton, L., Lippman, M.E., Eckert, S., Krueger, K.A.,
Purdie, D.W., et al., 2001. Continued breast cancer risk
reduction in postmenopausal women treated with raloxifene:
4-year results from the MORE trial. Multiple outcomes of
raloxifene evalutation. Breast Cancer Res. Treat. 65, 125–134.
129
Chang, D.K., Ricciardiello, L., Goel, A., Chang, C.L., Boland, C.R.,
2000. Steady-state regulation of the human DNA mismatch
repair system. J. Biol. Chem. 275, 18424–18431.
Chang, J., Powles, T.J., Ashley, S.E., Gregory, R.K., Tidy, V.A.,
Teleaven, J.G., Singh, R., 1996. The effect of tamoxifen and
hormone replacement therapy on serum cholesterol, bone
mineral density and coagulation factors in healthy
postmenopausal women participating in a randomized,
controlled tamoxifen prevention study. Ann. Oncol. 7, 671–675.
Chen, X., Truong, T.T., Weaver, J., Bove, B.A., Cattie, K.,
Armstrong, B.A., Daly, M.B., Godwin, A.K., 2006. Intronic
alterations in BRCA1 and BRCA2: effect on mRNA splicing
fidelity and expression. Hum. Mutat. 27, 427–435.
Chen, X., Weaver, J., Bove, B.A., Vanderveer, L.A., Weil, S.C.,
Miron, A., Daly, M.B., Godwin, A.K., 2008. Allelic imbalance in
BRCA1 and BRCA2 gene expression is associated with an
increased breast cancer risk. Hum. Mol. Genet. 17, 1336–1348.
Cheng, J.Q., Godwin, A.K., Bellacosa, A., Taguchi, T., Franke, T.F.,
Hamilton, T.C., Tsichlis, P.N., Testa, J.R., 1992. AKT2, a putative
oncogene encoding a member of a subfamily of proteinserine/threonine kinases, is amplified in human ovarian
carcinomas. Proc. Natl. Acad. Sci. U.S.A. 89, 9267–9271.
Chetrit, A., Hirsh-Yechezkel, G., Ben-David, Y., Lubin, F.,
Friedman, E., Sadetzki, S., 2008. Effect of BRCA1/2 mutations
on long-term survival of patients with invasive ovarian
cancer: the national Israeli study of ovarian cancer. J. Clin.
Oncol. 26, 20–25.
Claus, E.B., Schildkraut, J.M., Thompson, W.D., Risch, N.J., 1996.
The genetic attributable risk of breast and ovarian cancer.
Cancer 77, 2318–2324.
Clendenning, M., Baze, M.E., Sun, S., Walsh, K., Liyanarachchi, S.,
Fix, D., et al., 2008. Origins and prevalence of the American
founder mutation of MSH2. Cancer Res. 68, 2145–2153.
Colgan, T.J., Murphy, J., Cole, D.E., Narod, S., Rosen, B., 2001.
Occult carcinoma in prophylactic oophorectomy specimens:
prevalence and association with BRCA germline mutation
status. Am. J. Surg. Pathol. 25, 1283–1289.
Creasman, W.T., Odicino, F., Maisonneuve, P., Beller, U.,
Benedet, J.L., Heintz, A.P., Ngan, H.Y., Pecorelli, S., 2003.
Carcinoma of the corpus uteri. Int. J. Gynaecol. Obstet. 83
(Suppl. 1), 79–118.
Crijnen, Th.E.M., Janssen-Heijnen, M.L.G., Gelderblom, H.,
Morreau, J., Nooij, M.A., Kenter, G.G., Vasen, H.F.A., 2005.
Survival of patients with ovarian cancer due to a mismatch
repair defect. Fam. Cancer 4, 301–305.
Crum, C.P., Drapkin, R., Kindelberger, D., Drapkin, R., Miron, A.,
Ince, T.A., Muto, M., Kindelberger, D.W., Lee, Y., 2007a. The
distal fallopian tube: a new model for pelvic serous
carcinogenesis. Curr. Opin. Obstet. Gynecol. 19, 3–9.
Crum, C.P., Drapkin, R., Kindelberger, D., Medeiros, F., Miron, A.,
Lee, Y., 2007b. Lessons from BRCA: the tubal fimbria emerges
as an origin for pelvic serous cancer. Clin. Med. Res. 5, 35–44.
Cuzick, J., Powles, T., Veronesi, U., Forbes, J., Edwards, R.,
Ashley, S., Boyle, P., 2003. Overview of the main outcomes in
breast-cancer prevention trials. Lancet 361, 296–300.
Das Gupta, R., Kolodner, R.D., 2000. Novel dominant mutations in
Saccharomyces cerevisiae MSH6. Nat. Genet. 24, 53–56.
Desai, D.C., Lockman, J.C., Chadwick, R.B., Gao, X., Percesepe, A.,
Evans, D.G.R., et al., 2000. Recurrent germline mutation in
MSH2 arises frequently de novo. J. Med. Genet. 37, 646–652.
Dorum, A., Heimdal, K., Lovslett, K., Kristensen, G., Hansen, L.J.,
Sandvei, R., et al., 1999. Prospectively detected cancer in
familial breast/ovarian cancer screening. Acta Obstet.
Gynecol. Scand. 78, 906–911.
Dove-Edwin, I., Boks, D., Goff, S., Kenter, G.G., Carpenter, R.,
Vasen, H.F.A., Thomas, H.J.W., 2002. The outcome of
endometrial carcinoma surveillance by ultrasound scan in
130
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
women at risk of hereditary nonpolyposis colorectal carcinoma
and familial colorectal carcinoma. Cancer 94, 1708–1712.
Drummond, J.T., Li, G.-M., Longley, M.J., Modrich, P., 1995.
Isolation of an hMSH2-p160 heterodimer that restores DNA
mismatch repair to tumor cells. Science 268, 1909–1912.
Dunlop, M.G., Farrington, S.M., Carothers, A.D., Wyllie, A.H.,
Sharp, L., Burn, J., Liu, B., Kinzler, K.W., Vogelstein, B., 1997.
Cancer risk associated with germline DNA mismatch repair
gene mutations. Hum. Mol. Genet. 6, 105–110.
Easton, D.F., Bishop, D.T., Ford, D., Crockford, G.P., The Breast
Cancer Linkage Consortium, 1993. Genetic linkage analysis in
familial breast and ovarian cancer: results from 214 families.
Am. J. Hum. Genet. 52, 678–701.
Easton, D.F., Ford, D., Bishop, D.T., The Breast Cancer Linkage
Consortium, 1995. Breast and ovarian cancer incidence in
BRCA1 mutation carriers. Am. J. Hum. Genet. 56, 265–271.
Easton, D.F., Steele, L., Fields, P., Ormiston, W., Averill, D.,
Daly, P.A., et al., 1997. Cancer risks in two large breast cancer
families linked to BRCA2 on chromosome 13q12–13. Am. J.
Hum. Genet. 61, 120–128.
Eisen, A., Lubinski, J., Klijn, J., Moller, P., Lynch, H.T., Offit, K., et
al., 2005. Breast cancer risk following bilateral oophorectomy
in BRCA1 and BRCA2 mutation carriers: an international case–
control study. J. Clin. Oncol. 23, 7491–7496.
Elie, C., Geay, J.F., Morcos, M., Le Tourneau, A., Girre, V., Broët, P.,
et al., 2004. Lack of relationship between EGFR-1
immunohistochemical expression and prognosis in
a multicentre clinical trial of 93 patients with advanced
primary ovarian epithelial cancer (GINECO Group). Br. J.
Cancer 91, 470–475.
Eltabbakh, G.H., Piver, M.S., Hempling, R.E., Recio, F.O., Paczos, T.,
1999. Laparoscopic management of women with a family
history of ovarian cancer. J. Surg. Oncol. 72, 9–13.
Eshleman, J.R., Lang, E.Z., Bowerfind, G.K., Parsons, R.,
Vogelstein, B., Willson, J.K., Veigl, M.L., Sedwick, W.D.,
Markowitz, S.D., 1995. Increased mutation rate at the hprt
locus accompanies microsatellite instability in colon cancer.
Oncogene 10, 33–37.
Esteller, M., Silva, J.M., Dominguez, G., Bonilla, F., Matias-Guiu, X.,
Lerma, E., et al., 2000. Promoter hypermethylation and BRCA1
inactivation in sporadic breast and ovarian tumors. J. Natl.
Cancer Inst. 92, 564–569.
Fathalla, M.F., 1971. Incessant ovulation – a factor in ovarian
neoplasia? Lancet ii (7716), 163.
Feeley, K.M., Wells, M., 2001. Hormone replacement therapy and
the endometrium. J. Clin. Pathol. 54, 435–440.
Fishel, R., Lescoe, M.K., Rao, M.R.S., Copeland, N.G., Jenkins, N.A.,
Garber, J., Kane, M., Kolodner, R., 1993. The human mutator
gene homolog MSH2 and its association with hereditary
nonpolyposis colon cancer. Cell 75, 1027–1038.
Fisher, B., Costantino, J.P., Wickerham, D.L., Redmond, C.K.,
Kavanah, M., Cronin, W.M., et al., 1998. Tamoxifen for
prevention of breast cancer: report of the National Surgical
Adjuvant Breast and Bowel Project P-1 Study. J. Natl. Cancer
Inst. 90, 1371–1388.
Fishman, D.A., Cohen, L., Blank, S.V., Shulman, L., Singh, D.,
Bozorgi, K., Tamura, R., Timor-Tritsch, I., Schwartz, P.E., 2005.
The role of ultrasound evaluation in the detection of earlystage epithelial ovarian cancer. Am. J. Obstet. Gynecol. 192,
1214–1221.
Folkins, A.K., Jarboe, E.A., Saleemuddin, A., Lee, Y., Callahan, M.J.,
Drapkin, R., Garber, J.E., Muto, M.G., Tworoger, S., Crum, C.P.,
2008. A candidate precursor to pelvic serous cancer (p53
signature) and its prevalence in ovaries and fallopian tubes from
women with BRCA mutations. Gynecol. Oncol. 109, 168–173.
Ford, D., Easton, D.F., Bishop, D.T., Narod, S.A., Goldgar, D.E.,
Breast Cancer Linkage Consortium, 1994. Risks of cancer in
BRCA1-mutation carriers. Lancet 343, 692–695.
Ford, D., Easton, D.F., Peto, J., 1995. Estimates of the gene
frequency of BRCA1 and its contribution to breast and ovarian
cancer incidence. Am. J. Hum. Genet. 57, 1457–1462.
Ford, D., Easton, D.F., Stratton, M., Narod, S., Goldgar, D.,
Devilee, P., et al., 1998. Genetic heterogeneity and penetrance
analysis of the BRCA1 and BRCA2 genes in breast cancer
families. Am. J. Hum. Genet. 62, 676–689.
Foulkes, W.D., Thiffault, I., Gruber, S.B., Horwitz, M., Hamel, N.,
Lee, C., et al., 2002. The founder mutation MSH2*1906G 2 C is
an important cause of hereditary nonpolyposis colorectal
cancer in the Ashkenazi Jewish population. Am. J. Hum.
Genet. 71, 1395–1412.
Fraumeni Jr., J.F., Grundy, G.W., Creagan, E.T., Everson, R.B., 1975.
Six families prone to ovarian cancer. Cancer 36, 364–369.
Friedman, L.S., Szabo, C.I., Ostermeyer, E.A., Dowd, P., Butler, L.,
Park, T., Lee, M.K., Goode, E.L., Rowell, S.E., King, M.-C., 1995.
Novel inherited mutations and variable expressivity of BRCA1
alleles, including the founder mutation 185delAG in
Ashkenazi Jewish families. Am. J. Hum. Genet. 57, 1284–1297.
Fujita, M., Enomoto, T., Yoshino, K., Nomura, T., Buzard, G.S.,
Inoue, M., Okudaira, Y., 1995. Microsatellite instability and
alterations in the hMSH2 gene in human ovarian cancer. Int. J.
Cancer (Pred. Oncol.) 64, 361–366.
Gaarenstroom, K.N., van der Hiel, B., Tollenaar, R.A.E.M.,
Vink, G.R., Jansen, F.W., van Asperen, C.J., Kenter, G.G., 2006.
Efficacy of screening women at high risk of hereditary ovarian
cancer: results of an 11-year cohort study. Int. J. Gynecol.
Cancer 16 (Suppl. 1), 54–59.
Gamallo, C., Palacios, J., Moreno, G., Calvo de Mora, J., Suárez, A.,
Armas, A., 1999. b-Catenin expression pattern in stage I and II
ovarian carcinomas: relationship with b-catenin gene
mutations, clinicopathological features, and clinical outcome.
Am. J. Pathol. 155, 527–536.
Gambrell Jr., R.D., 1977. Estrogens, progestogens and endometrial
cancer. J. Reprod. Med. 18, 301–316.
Gambrell Jr., R.D., Bagnell, C.A., Greenblatt, R.B., 1983. Role of
estrogens and progesterone in the etiology and prevention of
endometrial cancer: review. Am. J. Obstet. Gynecol. 146,
696–707.
Gayther, S.A., Mangion, J., Russell, P., Seal, S., Barfoot, R.,
Ponder, B.A.J., Stratton, M.R., Easton, D., 1997. Variation of
risks of breast and ovarian cancer associated with different
germline mutations of the BRCA2 gene. Nat. Genet. 15,
103–105.
Gayther, S.A., Warren, W., Mazoyer, S., Russell, P.A.,
Harrington, P.A., Chiano, M., et al., 1995. Germline mutations
of the BRCA1 gene in breast and ovarian cancer families
provide evidence for a genotype–phenotype correlation. Nat.
Genet. 11, 428–433.
Genschel, J., Littman, S.J., Drummond, J.T., Modrich, P., 1998.
Isolation of MutSb from human cells and comparison of the
mismatch repair specificities of MutSb and MutSa. J. Biol.
Chem. 273, 19895–19901.
Gotlieb, W.H., Chetrit, A., Menczer, J., Hirsh-Yechezkel, G.,
Lubin, F., Friedman, E., Modan, B., Ben-Baruch, G.National
Israel Ovarian Cancer Study Group, 2005. Demographic and
genetic characteristics of patients with borderline ovarian
tumors as compared to early stage invasive ovarian cancer.
Gynecol. Oncol. 97, 780–783.
Gras, E., Catasus, L., Argüelles, R., Moreno-Bueno, G.,
Palacios, J., Gamallo, C., Matias-Guiu, X., Prat, J., 2001.
Microsatellite instability, MLH-1 promoter
hypermethylation, and frameshift mutations at coding
mononucleotide repeat microsatellites in ovarian tumors.
Cancer 92, 2829–2836.
Gray, L.A., Barnes, M.L., 1962. Carcinoma of the ovary: a report of
106 cases: 1. A further effort at pathological differentiation.
Ann. Surg. 155, 722–732.
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
Green, R.C., Narod, S.A., Morasse, J., Young, T.L., Cox, J.,
Fitzgerald, G.W., et al., 1994. Hereditary nonpolyposis colon
cancer: analysis of linkage to 2p15–16 places the COCA1 locus
telomeric to D2S123 and reveals genetic heterogeneity in
seven Canadian families. Am. J. Hum. Genet. 54, 1067–1077.
Gronwald, J., Cybulski, C., Lubinski, J., Narod, S.A., 2007.
Phenocopies in breast cancer 1 (BRCA1) families: implications
for genetic counseling. J. Med. Genet. 44, e76.
Hall, J.M., Lee, M.K., Newman, B., Morrow, J.E., Anderson, L.A.,
Huey, B., King, M.C., 1990. Linkage of early-onset breast cancer
to chromosome 17q21. Science 250, 1684–1689.
Han, H.J., Yanagisawa, A., Kato, Y., Park, J.G., Nakamura, Y., 1993.
Genetic instability in pancreatic cancer and poorly
differentiated type of gastric cancer. Cancer Res. 53,
5087–5089.
Hartley, A., Rollason, T., Spooner, D., 2000. Clear cell carcinoma of
the fimbria of the fallopian tube in a BRCA1 carrier undergoing
prophylactic surgery. Clin. Oncol. (R. Coll. Radiol.) 12, 58–59.
Hébert-Blouin, M.N., Koufogianis, V., Gillett, P., Foulkes, W.D.,
2002. Fallopian tube cancer in a BRCA1 mutation carrier: rapid
development and failure of screening. Am. J. Obstet. Gynecol.
186, 53–54.
Hendriks, Y.M.C., Wagner, A., Morreau, H., Menko, F.,
Stormorken, A., Quehenberger, F., et al., 2004. Cancer risk in
hereditary nonpolyposis colorectal cancer due to MSH6
mutations: impact on counseling and surveillance.
Gastroenterology 127, 17–25.
Hilton, J.L., Geisler, J.P., Rathe, J.A., Hattermann-Zogg, M.,
DeYoung, B., Buller, R.E., 2002. Inactivation of BRCA1 and
BRCA2 in ovarian cancer. J. Natl. Cancer Inst. 94, 1396–1406.
Hornreich, G., Beller, U., Lavie, O., Renbaum, P., Cohen, Y., LevyLahad, E., 1999. Is uterine serous carcinoma a BRCA1-related
disease? Case report and review of the literature. Gynecol.
Oncol. 75, 300–304.
Huang, J., Kuismanen, S.A., Liu, T., Chadwick, R.B., Johnson, C.K.,
Stevens, M.W., et al., 2001. MSH6 and MSH3 are rarely involved
in genetic predisposition to nonpolypotic colon cancer. Cancer
Res. 61, 1619–1623.
Iaccarino, I., Marra, G., Palombo, F., Jiricny, J., 1998. hMSH2 and
hMSH6 play distinct roles in mismatch binding and contribute
differently to the ATPase activity of hMutSa. EMBO J. 17,
2677–2686.
Ionov, Y.M., Peinado, M.A., Malkhosyan, S., Shibata, D.,
Perucho, M., 1993. Ubiquitous somatic mutations in simple
repeated sequences reveal a new mechanism for colonic
carcinogenesis. Nature 363, 558–561.
Jarboe, E., Folkins, A., Nucci, M.R., Kindelberger, D., Drapkin, R.,
Miron, A., Lee, Y., Crum, C.P., 2008a. Serous carcinogenesis in
the fallopian tube: a descriptive classification. Int J Gynecol.
Pathol. 27, 1–9.
Jarboe, E.A., Folkins, A.K., Drapkin, R., Ince, T.A., Agoston, E.S.,
Crum, C.P., 2008b. Tubal and ovarian pathways to pelvic
epithelial cancer: a pathological perspective. Histopathology
53, 127–138.
Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Murray, T., Thun, M.J.,
2008. Cancer statistics, 2008. CA Cancer J. Clin 58, 71–96.
Jick, S.S., Walker, A.M., Jick, H., 1993. Estrogens, progesterone, and
endometrial cancer. Epidemiology 4, 20–24.
Johannesdottir, G., Gudmundsson, J., Bergthorsson, J.T.,
Arason, A., Agnarsson, B.A., Eiriksdottir, G., et al., 1996. High
prevalence of the 999del5 mutation in Icelandic breast and
ovarian cancer patients. Cancer Res. 56, 3663–3665.
Jóhannsson, O.T., Ranstam, J., Borg, A., Olsson, H., 1998. Survival
of BRCA1 breast and ovarian cancer patients: a populationbased study from southern Sweden. J. Clin. Oncol. 16, 397–404.
Jongsma, A.P., Piek, J.M., Zweemer, R.P., Verheijen, R.H., Klein
Gebbinck, J.W., van Kamp, G.J., Jacobs, I.J., Shaw, P., van
Diest, P.J., Kenemans, P., 2002. Molecular evidence for putative
131
tumour suppressor genes on chromosome 13q specific to
BRCA1 related ovarian and fallopian tube cancer. Mol. Pathol.
55, 305–309.
Kauff, N.D., Domchek, S.M., Friebel, T.M., Robson, M.E., Lee, J.,
Garber, J.E., et al., 2008. Risk-reducing salpingo-oophorectomy
for the prevention of BRCA1- and BRCA2-associated breast
and gynecologic cancer: a multicenter, prospective study. J.
Clin. Oncol. 26, 1331–1337.
Kauff, N.D., Hurley, K.E., Hensley, M.L., Robson, M.E., Lev, G.,
Goldfrank, D., et al., 2005. Ovarian carcinoma screening in
women at intermediate risk: impact on quality of life and need
for invasive follow-up. Cancer 104, 314–320.
Kauff, N.D., Satagopan, J.M., Robson, M.E., Scheuer, L.,
Hensley, M., Hudis, C.A., et al., 2002. Risk-reducing salpingooophorectomy in women with a BRCA1 or BRCA2 mutation.
N. Engl. J. Med. 346, 1609–1615.
Kindelberger, D.W., Lee, Y., Miron, A., Hirsch, M.S., Feltmate, C.,
Medeiros, F., et al., 2007. Intraepithelial carcinoma of the
fimbria and pelvic serous carcinoma: evidence for a causal
relationship. Am. J. Surg. Pathol. 31, 161–169.
King, M.C., Marks, J.H., Mandell, J.B.New York Breast Cancer Study
Group, 2003. Breast and ovarian cancer risks due to inherited
mutations in BRCA1 and BRCA2. Science 302, 643–646.
King, M.C., Wieand, S., Hale, K., Lee, M., Walsh, T., Owens, K., et
al., 2001. Tamoxifen and breast cancer incidence among
women with inherited mutations in BRCA1 and BRCA2:
National Surgical Adjuvant Breast and Bowel Project (NSABPP1) breast cancer prevention trial. JAMA 286, 2251–2256.
Kobayashi, H., Yamada, Y., Sado, T., Sakata, M., Yoshida, S.,
Kawaguchi, R., et al., 2008. A randomized study of screening
for ovarian cancer: a multicenter study from Japan. Int. J.
Gynecol. Cancer 18, 414–420.
Kohler, M.F., Kerns, B.J., Humphrey, P.A., Marks, J.R., Bast Jr., R.C.,
Berchuck, A., 1993. Mutation and overexpression of p53 in
early-stage epithelial ovarian cancer. Obstet. Gynecol. 81,
643–650.
Koi, M., Umar, A., Chauhan, D.P., Cherian, S.P., Carethers, J.M.,
Kunkel, T.A., Boland, C.R., 1994. Human chromosome 3
corrects mismatch repair deficiency and microsatellite
instability and reduces N-methyl-N0 -nitro-N-nitrosoguanidine
tolerance in colon tumor cells with homozygous hMLH1
mutation. Cancer Res. 54, 4308–4312.
Kong, D., Suzuki, A., Zou, T.T., Sakurada, A., Kemp, L.W.,
Wakatsuki, S., 1997. PTEN1 is frequently mutated in primary
endometrial carcinomas. Nat. Genet. 17, 143–144.
Kringen, P., Wang, Y., Dumeaux, V., Nesland, J.M., Kristensen, G.,
Borresen-Dale, A.L., Dorum, A., 2005. TP53 mutations in
ovarian carcinomas from sporadic cases and carriers of two
distinct BRCA1 founder mutations; relation to age at diagnosis
and survival. BMC Cancer 5, 134.
Kuismanen, S.A., Moisio, A.L., Schweizer, P., Truninger, K.,
Salovaara, R., Arola, J., Butzow, R., Jiricny, J., NystromLahti, M., Peltomaki, P., 2002. Endometrial and colorectal
tumors from patients with hereditary nonpolyposis colon
cancer display different patterns of microsatellite instability.
Am. J. Pathol. 160, 1953–1958.
Kupryjanczyk, J., Thor, A.D., Beauchamp, R., Merritt, V.,
Edgerton, S.M., Bell, D.A., Yandell, D.W., 1993. p53 Gene
mutations and protein accumulation in human ovarian
cancer. Proc. Natl. Acad. Sci. U.S.A. 90, 4961–4965.
Kurman, R.J., Shih le, M., 2008. Pathogenesis of ovarian
cancer: lessons from morphology and molecular biology
and their clinical implications. Int. J. Gynecol. Pathol. 27,
151–160.
Kwon, J.S., Lenehan, J., Carey, M., Ainsworth, P., 2008a. Prolonged
survival among women with BRCA germline mutations and
advanced endometrial cancer: a case series. Int. J. Gynecol.
Cancer 18, 546–549.
132
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
Kwon, J.S., Sun, C.C., Peterson, S.K., White, K.G., Daniels, M.S.,
Boyd-Rogers, S.G., Lu, K.H., 2008b. Cost-effectiveness analysis
of prevention strategies for gynecologic cancers in Lynch
syndrome. Cancer 113, 326–335.
Lacey Jr., J.V., Brinton, L.A., Lubin, J.H., Sherman, M.E.,
Schatzkin, A., Schairer, C., 2005. Endometrial carcinoma risks
among menopausal estrogen plus progestin and unopposed
estrogen users in a cohort of postmenopausal women. Cancer
Epidemiol. Biomarkers Prev. 14, 1724–1731.
Lafky, J.M., Wilken, J.A., Baron, A.T., Maihle, N.J., 2008. Clinical
implications of the ErbB/epidermal growth factor (EGF)
receptor family and its ligands in ovarian cancer. Biochim.
Biophys. Acta 1785, 232–265.
Laframboise, S., Nedelcu, R., Murphy, J., Cole, D.E., Rosen, B., 2002.
Use of CA-125 and ultrasound in high-risk women. Int. J.
Gynecol. Cancer 12, 86–91.
Lakhani, S.R., Manek, S., Penault-Llorca, F., Flanagan, A.,
Arnout, L., Mettett, S., et al., 2004. Pathology of ovarian cancers
in BRCA1 and BRCA2 carriers. Clin. Cancer Res. 10, 2473–2481.
Lamb, J.D., Garcia, R.L., Goff, B.A., Paley, P.J., Swisher, E.M., 2006.
Predictors of occult neoplasia in women undergoing risk-reducing
salpingo-oophorectomy. Am. J. Obstet. Gynecol. 194, 1702–1709.
Landen Jr., C.N., Birrer, M.J., Sood, A.K., 2008. Early events in the
pathogenesis of epithelial ovarian cancer. J. Clin. Oncol. 26,
995–1005.
Lauchlan, S.C., 1972. The secondary mullerian system. Obstet.
Gynecol. Surv. 27, 133–146.
Lavie, O., Hornreich, G., Ben-Arie, A., Rennert, G., Cohen, Y.,
Keidar, R., Sagi, S., Lahad, E.L., Auslander, R., Beller, U., 2004.
BRCA germline mutations in Jewish women with uterine
serous papillary carcinoma. Gynecol. Oncol. 92, 521–524.
Leach, F.S., Nicolaides, N.C., Papadopoulos, N., Liu, B., Jen, J.,
Parsons, R., et al., 1993. Mutations of a mutS homolog in
hereditary nonpolyposis colorectal cancer. Cell 75, 1215–1225.
Lee, Y., Medeiros, F., Kindelberger, D., Callahan, M.J., Muto, M.G.,
Crum, C.P., 2006. Advances in the recognition of tubal
intraepithelial carcinoma: applications to cancer screening and
the pathogenesis of ovarian cancer. Adv. Anat. Pathol. 13, 1–7.
Lee, Y., Miron, A., Drapkin, R., Nucci, M.R., Medeiros, F.,
Saleemuddin, A., et al., 2007. A candidate precursor to serous
carcinoma that originates in the distal fallopian tube. J. Pathol.
211, 26–35.
Leeper, L., Garcia, R., Swisher, E., Goff, B., Greer, B., Paley, P., 2002.
Pathologic findings in prophylactic oophorectomy specimens
in high-risk women. Gynecol. Oncol. 87, 52–56.
Levanon, K., Crum, C., Drapkin, R., 2008. New insights into the
pathogenesis of serous ovarian cancer and its clinical impact.
J. Clin. Oncol. 26, 5284–5293.
Levine, D.A., Argenta, P.A., Yee, C.J., Marshall, D.S., Olvera, N.,
Bogomolniy, F., et al., 2003. Fallopian tube and primary
peritoneal carcinomas associated with BRCA mutations. J.
Clin. Oncol. 21, 4222–4227.
Levine, D.A., Lin, O., Barakat, R.R., Robson, M.E., McDermott, D.,
Cohen, L., Satagopan, J., Offit, K., Boyd, J., 2001. Risk of
endometrial carcinoma associated with BRCA mutation.
Gynecol. Oncol. 80, 395–398.
Levine, R.L., Cargile, C.B., Blazes, M.S., van Rees, B., Kurman, R.J.,
Ellenson, L.H., 1998. PTEN mutations and microsatellite
instability in complex atypical hyperplasia, a precursor lesion
to uterine endometrioid carcinoma. Cancer Res. 58, 3254–3258.
Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S.I., et al.,
1997. PTEN, a putative protein tyrosine phosphatase gene
mutated in human brain, breast, and prostate cancer. Science
275, 1943–1947.
Liede, A., Karlan, B.Y., Baldwin, R.L., Platt, L.D., Kuperstein, G.,
Narod, S.A., 2002. Cancer incidence in a population of Jewish
women at risk of ovarian cancer. J. Clin. Oncol. 20, 1570–1577.
Lindblom, A., Tannergard, P., Werelius, B., Nordenskjold, M., 1993.
Genetic mapping of a second locus predisposing to hereditary
nonpolyposis colorectal cancer. Nat. Genet. 5, 279–282.
Liu, B., Parsons, R., Papadopoulos, N., Nicolaides, N.C.,
Lynch, H.T., Watson, P., et al., 1996. Analysis of mismatch
repair genes in hereditary non-polyposis colorectal cancer
patients. Nat. Med. 2, 169–174.
Liu, J., Albarracin, C.T., Chang, K.-H., Thompson-Lanza, J.A.,
Zheng, W., Gershenson, D.M., Broaddus, R., Luthra, R., 2004.
Microsatellite instability and expression of hMLH1 and hMSH2
proteins in ovarian endometrioid cancer. Mod. Pathol. 17, 75–80.
Lu, K.H., 2008. Hereditary gynecologic cancers: differential
diagnosis, surveillance, management and surgical
prophylaxis. Fam. Cancer 7, 53–58.
Lu, K.H., Cramer, D.W., Muto, M.G., Li, E.Y., Niloff, J., Mok, S.C.,
1999. A population-based study of BRCA1 and BRCA2
mutations in Jewish women with epithelial ovarian cancer.
Obstet. Gynecol. 93, 34–37.
Lubinski, J., Phelan, C.M., Ghadirian, P., Lynch, H.T., Garber, J.,
Weber, B., et al., 2004. Cancer variation associated with the
position of the mutation in the BRCA2 gene. Fam. Cancer 3, 1–10.
Lynch, H.T., Bewtra, C., Lynch, J.F., 1986. Familial peritoneal
ovarian carcinomatosis: a new clinical entity? Med. Hypoth.
21, 171–177.
Lynch, H.T., Boland, C.R., Gong, G., Shaw, T.G., Lynch, P.M.,
Fodde, R., Lynch, J.F., de la Chapelle, A., 2006a. Phenotypic and
genotypic heterogeneity in the Lynch syndrome: diagnostic,
surveillance and management implications. Eur. J. Hum.
Genet. 14, 390–402.
Lynch, H.T., Casey, M.J., 2007. Prophylactic surgery prevents
endometrial and ovarian cancer in the Lynch syndrome. Nat.
Clin. Pract. Oncol. 4, 672–673.
Lynch, H.T., Casey, M.J., Lynch, J., White, T.E.K., Godwin, A.K.,
1998. Genetics and ovarian carcinoma. Sem. Oncol. 25,
265–281.
Lynch, H.T., Cavalieri, R.J., Lynch, J.F., Casey, M.J., 1992.
Gynecologic clues to Lynch syndrome II diagnosis: a family
report. Gynecol. Oncol. 44, 198–203.
Lynch, H.T., Coronel, S.M., Okimoto, R., Hampel, H., Sweet, K.,
Lynch, J.F., et al., 2004. A founder mutation of the MSH2 gene
and hereditary nonpolyposis colorectal cancer in the United
States. JAMA 291, 718–724.
Lynch, H.T., de la Chapelle, A., 1999. Genetic susceptibility to nonpolyposis colorectal cancer. J. Med. Genet. 36, 801–818.
Lynch, H.T., de la Chapelle, A., Hampel, H., Wagner, A., Fodde, R.,
Lynch, J.F., et al., 2006b. The American founder mutation for
Lynch syndrome: prevalence estimates and implications.
Cancer 106, 448–452.
Lynch, H.T., Guirgis, H.A., Albert, S., Brennan, M., Lynch, J.,
Kraft, C., Pocekay, D., Vaughns, C., Kaplan, A., 1974. Familial
association of carcinoma of the breast and ovary. Surg.
Gynecol. Obstet. 138, 717–724.
Lynch, H.T., Krush, A.J., 1967. Heredity and adenocarcinoma of
the colon. Gastroenterology 53, 517–527.
Lynch, H.T., Krush, A.J., 1971. Carcinoma of the breast and ovary
in three families. Surg. Gynecol. Obstet. 133, 644–648.
Lynch, H.T., Krush, A.J., Lemon, H.M., Kaplan, A.R., Condit, P.T.,
Bottomley, R.H., 1972. Tumor variation in families with breast
cancer. JAMA 222, 1631–1635.
Lynch, H.T., Lynch, J.F., Lynch, P.M., Attard, T., 2008. Hereditary
colorectal cancer syndromes: molecular genetics, genetic
counseling, diagnosis and management. Fam. Cancer 7, 27–39.
Lynch, H.T., Lynch, P.M., 1979. The cancer-family syndrome:
a pragmatic basis for syndrome identification. Dis. Colon
Rectum 22, 106–110.
Lynch, H.T., Shaw, M.W., Magnuson, C.W., Larsen, A.L.,
Krush, A.J., 1966. Hereditary factors in cancer: study of
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
two large Midwestern kindreds. Arch. Intern. Med. 117,
206–212.
Mæhle, L., Apold, J., Paulsen, T., Hagen, B., Løvslett, K., Fiane, B.,
Van Ghelue, M., Clark, N., Møller, P., 2008. High risk for ovarian
cancer in a prospective series is restricted to BRCA1/2
mutation carriers. Clin. Cancer Res. 14, 7569–7573.
Maihle, N.J., Baron, A.T., Barrette, B.A., Boardman, C.H.,
Christensen, T.A., Cora, E.M., et al., 2002. EGF/ErbB receptor
family in ovarian cancer. Cancer Treat. Res. 107, 247–258.
Malander, S., Rambech, E., Kristoffersson, U., Halvarsson, B.,
Ridderheim, M., Borg, Å., Nilbert, M., 2006. The contribution of
the hereditary nonpolyposis colorectal cancer syndrome to
the development of ovarian cancer. Gynecol. Oncol. 101,
238–243.
Malkhosyan, S., Rampino, N., Yamamoto, H., Perucho, M., 1996.
Frameshift mutator mutations. Nature 382, 499–500.
Malpica, A., Deavers, M.T., Lu, K., Bodurka, D.C., Atkinson, E.N.,
Gershenson, D.M., Silva, E.G., 2004. Grading ovarian serous
carcinoma using a two-tier system. Am. J. Surg. Pathol. 28,
496–504.
Marsischky, G.T., Filosi, N., Kane, M.F., Kolodner, R., 1996.
Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in
MSH2-dependent mismatch repair. Genes Dev. 10, 407–420.
Martini, M., Ciccarone, M., Garganese, G., Maggiore, C.,
Evangelista, A., Rahimi, S., Zannoni, G., Vittori, G.,
Larocca, L.M., 2002. Possible involvement of the hMLH1,
p16INK4a and PTEN in the malignant transformation of
endometriosis. Int. J. Cancer 102, 398–406.
Martino, S., Cauley, J.A., Barrett-Connor, E., Powles, T.J.,
Mershon, J., Disch, D., Secrest, R.J., Cummings, S.R., CORE
Investigators, 2004. Continuing outcomes relevant to Evista:
breast cancer incidence in postmenopausal osteoporotic
women in a randomized trial of raloxifene. J. Natl. Cancer Inst.
96, 1751–1761.
Matsuyama, Y., Tominaga, T., Nomura, Y., Koyama, H.,
Kimura, M., Sano, M., et al., 2000. Second cancers after
adjuvant tamoxifen therapy for breast cancer in Japan. Ann.
Oncol. 11, 1537–1543.
Maxwell, G.L., Risinger, J.I., Gumbs, C., Shaw, H., Bentley, R.C.,
Barrett, J.C., 1998. Mutation of the PTEN tumor suppressor
gene in endometrial hyperplasias. Cancer Res. 58, 2500–2503.
Medeiros, F., Muto, M.G., Lee, Y., Elvin, J.A., Callahan, M.J.,
Feltmate, C., Garber, J.E., Cramer, D.W., Crum, C.P., 2006. The
tubal fimbria is a preferred site for early adenocarcinoma in
women with familial ovarian cancer syndrome. Am. J. Surg.
Pathol. 30, 230–236.
Meeuwissen, P.A., Seynaeve, C., Brekelmans, C.T., MeijersHeijboer, H.J., Klijn, J.G., Burger, C.W., 2005. Outcome of
surveillance and prophylactic salpingo-oophorectomy in
asymptomatic women at high risk for ovarian cancer.
Gynecol. Oncol. 97, 476–482.
Merajver, S.D., Pham, T.M., Caduff, R.F., Chen, M., Poy, E.L.,
Cooney, K.A., Weber, B.L., Collins, F.S., Johnston, C.,
Frank, T.S., 1995. Somatic mutations in the BRCA1 gene in
sporadic ovarian tumours. Nat. Genet. 9, 439–443.
Mignotte, H., Lasset, C., Bonadona, V., Lesur, A., Luporsi, E.,
Rodier, J.-F., et al., 1998. Iatrogenic risks of endometrial
carcinoma after treatment for breast cancer in a large French
case–control study. Int. J. Cancer 76, 325–330.
Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P.A.,
Harshman, K., Tavtigian, S., et al., 1994. A strong candidate for
the breast and ovarian cancer susceptibility gene BRCA1.
Science 266, 66–71.
Milne, R.L., Osorio, A., Cajal, T.R., Vega, A., Llort, G., de la Hoya, M.,
et al., 2008. The average cumulative risks of breast and ovarian
cancer for carriers of mutations in BRCA1 and BRCA2
attending genetic counseling units in Spain. Clin. Cancer Res.
14, 2861–2869.
133
Miyaki, M., Konishi, M., Tanaka, K., Kikuchi-Yanoshita, R.,
Muraoka, M., Yasuno, M., Igari, T., Koike, M., Chiba, M., Mori, T.,
1997. Germline mutation of MSH6 as the cause of hereditary
nonpolyposis colorectal cancer. Nat. Genet. 17, 271–272.
Moisio, A.-L., Sistonen, P., Weissenbach, J., de la Chapelle, A.,
Peltomaki, P., 1996. Age and origin of two common MLH1
mutations predisposing to hereditary colon cancer. Am. J.
Hum. Genet. 59, 1243–1251.
Mok, S.C., Bell, D.A., Knapp, R.C., Fishbaugh, P.M., Welch, W.R.,
Muto, M.G., Berkowitz, R.S., Tsao, S.W., 1993. Mutation of Kras protooncogene in human ovarian epithelial tumors of
borderline malignancy. Cancer Res. 53, 1489–1492.
Morice, P., Mercier, S., Spatz, A., L’homme, C., Duvillard, P.,
Gerbault, A., Castaigne, D., 1999. Laparoscopic prophylactic
oophorectomy in women with inherited risk of ovarian
cancer. Eur. J. Gynaecol. Oncol. 20, 202–204.
Mutter, G.L., Lin, M.-C., Fitzgerald, J.T., Kum, J.B., Baak, J.P.A.,
Lees, J.A., Weng, L.-P., Eng, C., 2000. Altered PTEN expression
as a diagnostic marker for the earliest endometrial
precancers. J. Natl. Cancer Inst. 92, 924–931.
Myrhoj, T., Bisgaard, M.L., Bernstein, I., Svendsen, L.B.,
Sondergaard, J.O., Bülow, S., 1997. Hereditary non-polyposis
colorectal cancer: clinical features and survival: results from
the Danish HNPCC Register. Scand. J. Gastroenterol. 32, 572–576.
Nakagawa, H., Lockman, J.C., Frankel, W.L., Hampel, H.,
Steenblock, K., Burgart, L.J., Thibodeau, S.N., de la Chapelle, A.,
2004. Mismatch repair gene PMS2: disease-causing germline
mutations are frequent in patients whose tumors stain negative
for PMS2 protein, but paralogous genes obscure mutation
detection and interpretation. Cancer Res. 64, 4721–4727.
Nakayama, K., Nakayama, N., Kurman, R.J., Cope, L., Pohl, G.,
Samuels, Y., Velculescu, V.E., Wang, T.L., Shih, I.-M., 2006.
Sequence mutations and amplification of PIK3CA and AKT2
genes in purified ovarian serous neoplasms. Cancer Biol. Ther.
5, 779–785.
Narod, S., Ford, D., Devilee, P., Barkardottir, R.B., Eyfjord, J.,
Lenoir, G., Serova, O., Easton, D., Goldgar, D., Breast Cancer
Linkage Consortium, 1995a. Genetic heterogeneity of breast–
ovarian cancer revisited. Am. J. Hum. Genet. 57, 957–958.
Narod, S.A., Brunet, J.-S., Ghadirian, P., Robson, M., Heimdal, K.,
Neuhausen, S.L., et al., 2000. Tamoxifen and risk of
contralateral breast cancer in BRCA1 and BRCA2 mutation
carriers: a case–control study. Lancet 356, 1876–1881.
Narod, S.A., Feunteun, J., Lynch, H.T., Watson, P., Conway, T.,
Lenoir, G.M., 1991. Familial breast–ovarian cancer locus on
chromosome 17q12–q23. Lancet 388, 82–83.
Narod, S.A., Ford, D., Devilee, P., Barkardottir, R.B., Lynch, H.T.,
Smith, S.A., et al., 1995b. An evaluation of genetic
heterogeneity in 145 breast–ovarian cancer families. Am. J.
Hum. Genet. 56, 254–264.
National Center for Biotechnology Information, 2008. Gene.
National Institutes of Health. Available at: http://
www.ncbi.nlm.nih.gov/sites/entrez?db¼gene (Accessed on 21
January 2009).
Newcomb, P.A., Trentham-Dietz, A., 2003. Patterns of
postmenopausal progestin use with estrogen in relation to
endometrial cancer (United States). Cancer Causes Control 14,
195–201.
Nicolaides, N.C., Papadopoulos, N., Liu, B., Wei, Y.-F., Carter, K.C.,
Ruben, S.M., et al., 1994. Mutations of two PMS homologues in
hereditary nonpolyposis colon cancer. Nature 371, 75–80.
Nyström-Lahti, M., Kristo, P., Nicolaides, N.C., Chang, S.Y.,
Aaltonen, L.A., Moisio, A.-L., et al., 1995. Founding mutations
and Alu-mediated recombination in hereditary colon cancer.
Nat. Med. 1, 1203–1206.
Nyström-Lahti, M., Sistonen, P., Mecklin, J.-P., Pylkkänen, L.,
Aaltonen, L.A., Järvinen, H., Weissenbach, J., de la Chapelle, A.,
Peltomäki, P., 1994. Close linkage to chromosome 3p and
134
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
conservation of ancestral founding haplotype in hereditary
nonpolyposis colorectal cancer families. Proc. Natl. Acad. Sci.
U.S.A. 91, 6054–6058.
Nyström-Lahti, M., Wu, Y., Moisio, A.-L., Hofstra, R.M.W.,
Osinga, J., Mecklin, J.-P., et al., 1996. DNA mismatch repair
gene mutations in 55 kindreds with verified or putative
hereditary nonpolyposis colorectal cancer. Hum. Mol. Genet.
5, 763–769.
Obata, K., Morland, S.J., Watson, R.H., Hitchcock, A., ChenevixTrench, G., Thomas, E.J., Campbell, I.G., 1998. Frequent PTEN/
MMAC1 mutations in endometrioid but not serous or
mucinous epithelial ovarian tumors. Cancer Res. 58,
2095–2097.
Oei, A.L., Massuger, L.F., Bulten, J., Ligtenberg, M.J.,
Hoogerbrugge, N., de Hullu, J.A., 2006. Surveillance of women
at high risk for hereditary ovarian cancer is inefficient. Br. J.
Cancer 94, 814–819.
Olivier, R.I., Lubsen-Brandsma, M.A., Verhoef, S., van Beurden, M.,
2006. CA125 and transvaginal ultrasound monitoring in highrisk women cannot prevent the diagnosis of advanced ovarian
cancer. Gynecol. Oncol. 100, 20–26.
Olivier, R.I., van Beurden, M., Lubsen, M.A., Rookus, M.A.,
Mooij, T.M., van de Vijver, M.J., van’t Veer, L.J., 2004. Clinical
outcome of prophylactic oophorectomy in BRCA1/BRCA2
mutation carriers and events during follow-up. Br. J. Cancer
90, 1492–1497.
Osborne, R.J., Leech, V., 1994. Polymerase chain reaction
allelotyping of human ovarian cancer. Br. J. Cancer 69,
429–438.
Ozols, R.F., Rubin, S.C., Thomas, G.M., Robboy, S.J., 2005. Epithelial
ovarian cancer. In: Hoskins, W.J., Perez, C.A., Young, R.C.,
Barakat, R.R., Markman, M., Randall, M.E. (Eds.), Principles and
Practice of Gynecologic Oncology, fifth ed. Lippincott Williams
& Wilkins, Philadelphia, PA, pp. 903–904.
Pal, T., Permuth-Wey, J., Kapoor, R., Cantor, A., Sutphen, R., 2007.
Improved survival in BRCA2 carriers with ovarian cancer.
Fam. Cancer 6, 113–119.
Pal, T., Permuth-Wey, J., Betts, J.A., Krischer, J.P., Fiorica, J.,
Arango, H., et al., 2005. BRCA1 and BRCA2 mutations account
for a large proportion of ovarian carcinoma cases. Cancer 104,
2807–2816.
Pal, T., Permuth-Wey, J., Kumar, A., Sellers, T.A., 2008a.
Systematic review and meta-analysis of ovarian cancers:
estimation of microsatellite-high frequency and
characterization of mismatch repair deficient tumor histology.
Clin. Cancer Res. 14, 6847–6854.
Pal, T., Permuth-Wey, J., Sellers, T.A., 2008b. A review of the
clinical relevance of mismatch-repair deficiency in ovarian
cancer. Cancer 113, 733–742.
Paley, P.J., Swisher, E.M., Garcia, R.L., Agoff, S.N., Greer, B.E.,
Peters, K.L., Goff, B.A., 2001. Occult cancer of the fallopian tube
in BRCA-1 germline mutation carriers at prophylactic
oophorectomy: a case for recommending hysterectomy as
surgical prophylaxis. Gynecol. Oncol. 80, 176–180.
Palombo, F., Gillinari, P., Iaccarino, I., Lettieri, T., Hughes, M.,
D’Arrigo, A., Truong, O., Hsuan, J.J., Jiricny, J., 1995. GTBP,
a 160-kilodalton protein essential for mismatch-binding
activity in human cells. Science 268, 1912–1914.
Papadopoulos, N., Nicolaides, N.C., Wei, Y.-F., Ruben, S.M.,
Carter, K.C., Rosen, C.A., et al., 1994. Mutation of
a mutL homolog in hereditary colon cancer. Science 263,
1625–1629.
Parmley, T.H., Woodruff, J.D., 1974. The ovarian mesothelioma.
Am. J. Obstet. Gynecol. 120, 234–241.
Patai, K., Szentmariay, F., Jakab, Z., Szilagyi, G., 2002. Early
detection of endometrial cancer by combined use of vaginal
ultrasound and endometrial vacuum sampling. Int. J. Gynecol.
Cancer 12, 261–264.
Peiffer, S.L., Herzog, T.J., Tribune, D.J., Mutch, D.G., Gersell, D.J.,
Goodfellow, P.J., 1995. Allelic loss of sequences from the long
arm of chromosome 10 and replication errors in endometrial
cancers. Cancer Res. 55, 1922–1926.
Peltomäki, P., 2003. Role of DNA mismatch repair defects in the
pathogenesis of human cancer. J. Clin. Oncol. 21, 1174–1179.
Peltomäki, P., Aaltonen, L., Sistonen, P., Pylkkänen, L., Mecklin, J.P., Järvinen, H., et al., 1993. Genetic mapping of a locus
predisposing to human colorectal cancer. Science 260, 810–812.
Peltomäki, P., Vasen, H., 2004. Mutations associated with HNPCC
predisposition – update of ICG-HNPCC/INSiGHT mutation
database. Dis. Markers 20, 269–276.
Peltomäki, P., Vasen, H.F.A.International Collaborative Group on
Hereditary Nonpolyposis Colorectal Cancer, 1997. Mutations
predisposing to hereditary nonpolyposis colorectal cancer:
database and results of a collaborative study.
Gastroenterology 113, 1146–1158.
Peters-Engl, C., Frank, W., Danmayr, E., Friedl, H.P., Leodolter, S.,
Medl, M., 1999. Association between endometrial cancer and
tamoxifen treatment of breast cancer. Breast Cancer. Res.
Treat. 54, 255–260.
Peyton-Jones, B., Olaitan, A., Murdoch, J.B., 2002. Incidental
diagnosis of primary fallopian tube carcinoma during
prophylactic salpingo-oophorectomy. BJOG 109, 1413–1414.
Pharoah, P.D., Easton, D.F., Stockton, D.L., Gayther, S.,
Ponder, B.A., 1999. Survival in familial, BRCA1-associated, and
BRCA2-associated epithelial ovarian cancer. United Kingdom
Coordinating Committee for Cancer Research (UKCCCR)
Familial Ovarian Cancer Study Group. Cancer Res. 59, 868–871.
Piek, J., Kenemans, P., Verheijen, R., 2004. Intraperitoneal serous
adenocarcinoma: a critical appraisal of three hypotheses on
its cause. Am. J. Obstet. Gynecol. 191, 718–732.
Piek, J.M., Torrenga, B., Hermsen, B., Verheijen, R.H.,
Zweemer, R.P., Gille, J.J., Kenemans, P., Van Piest, P.J.,
Menko, F.H., 2003a. Histopathological characteristics of
BRCA1- and BRCA2-associated intraperitoneal cancer: a clinicbased study. Fam. Cancer 2, 73–78.
Piek, J.M., Verheijen, R.H., Menko, F.H., Jongsma, A.P.,
Weegenaar, J., Gille, J.J., Pals, G., Kenemans, P., van Diest, P.J.,
2003b. Expression of differentiation and proliferation related
proteins in epithelium of prophylactically removed ovaries
from women with a hereditary female adnexal cancer
predisposition. Histopathology 43, 26–32.
Piver, M.S., Goldberg, J.M., Tsukada, Y., Mettlin, C.J., Jiski, M.G.,
Natardjen, N., 1996. Characteristics of familial ovarian
cancer: a report of the first 1,000 families in the Gilda Radner
Familial Ovarian Cancer Registry. Eur. J. Gynecol. Oncol. 17,
169–176.
Plaschke, J., Krüger, S., Jeske, B., Theissig, F., Kreuz, F.R.,
Pistorius, S., Saeger, H.D., Iaccarino, I., Marra, G.,
Schackert, H.K., 2004. Loss of MSH3 protein expression is
frequent in MLH1-deficient colorectal cancer and is associated
with disease progression. Cancer Res. 64, 864–870.
Powell, C.B., 2006. Occult ovarian cancer at the time of riskreducing salpingo-oophorectomy. Gynecol. Oncol. 100, 1–2.
Powell, C.B., Kenley, E., Chen, L.M., Crawford, B., McLennan, J.,
Zaloudek, C., Komaromy, M., Beattie, M., Ziegler, J., 2005. Riskreducing salpingo-oophorectomy in BRCA mutation carriers:
role of serial sectioning in the detection of occult malignancy.
J. Clin. Oncol. 23, 127–132.
Pukkla, E., Kyyronen, P., Sankila, R., Holli, K., 2002. Tamoxifen and
toremifen treatment of breast cancer and risk of subsequent
endometrial cancer: a population-based case–control study.
Int. J. Cancer 100, 337–341.
Quehenberger, F., Vasen, H.F., van Houwelingen, H.C., 2005. Risk
of colorectal and endometrial cancer for carriers of mutations
of the hMLH1 and hMSH2 gene: correction for ascertainment.
J. Med. Genet. 42, 491–496.
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
Rafnar, T., Benediktsdottir, K.R., Eldon, B.J., Gestsson, T.,
Saemundsson, H., Olafsson, K., Salvarsdottir, A.,
Steingrimsson, E., Thorlacius, S., 2004. BRCA2, but not BRCA1,
mutations account for familial ovarian cancer in Iceland:
a population-based study. Eur. J. Cancer 40, 2788–2793.
Ramus, S.J., Fishman, A., Pharoah, P.D., Yarkoni, S., Altaras, M.,
Ponder, B.A., 2001. Ovarian cancer survival in Ashkenazi
Jewish patients with BRCA1 and BRCA2 mutations. Eur. J. Surg.
Oncol. 27, 278–281.
Rebbeck, T.R., Friebel, T., Wagner, T., Lynch, H.T., Garber, J.E.,
Daly, M.B., et al., 2005. Effect of short-term hormone replacement
therapy on breast cancer risk reduction after bilateral
prophylactic oophorectomy in BRCA1 and BRCA2 mutation
carriers: the PROSE Study Group. J. Clin. Oncol. 23, 7804–7810.
Rebbeck, T.R., Lynch, H.T., Neuhausen, S.L., Narod, S.A., van’t
Veer, L., Garber, J.E., et al., 2002. Prophylactic oophorectomy in
carriers of BRCA1 or BRCA2 mutations. N. Engl. J. Med. 346,
1616–1622.
Renkonen-Sinisalo, L., Butzow, R., Leminen, A., Lehtovirta, P.,
Mecklin, J.P., Järvinen, H.J., 2006. Surveillance for endometrial
cancer in hereditary nonpolyposis colorectal cancer
syndrome. Int. J. Cancer 120, 821–824.
Ricciardone, M.D., Özçelik, T., Cevher, B., Özdag, H., Tuncer, M.,
Gürgey, A., et al., 1999. Human MLH1 deficiency predisposes to
hematological malignancy and neurofibromatosis type I.
Cancer Res. 59, 290–293.
Rijcken, F.E.M., Mourits, M.J.E., Kleibeuker, J.H., Hollema, H., van
der Zee, A.G.J., 2003. Gynecologic screening in hereditary
nonpolyposis colorectal cancer. Gynecol. Oncol. 91, 74–80.
Risinger, J.I., Hayes, A.K., Berchuck, A., Barrett, J.C., 1997. PTEN/
MMAC1 mutations in endometrial cancers. Cancer Res. 57,
4736–4738.
Rose, P.G., Shrigley, R., Siesner, G.L., 2000. Germline BRCA2
mutation in a patient with fallopian tube carcinoma: a case
report. Gynecol. Oncol. 77, 319–320.
Rosen, D.G., Cai, K.Q., Luthra, R., Liu, J., 2006.
Immunohistochemical staining of hMLH1 and hMSH2 reflects
microsatellite instability status in ovarian carcinoma. Modern
Pathol. 19, 1414–1420.
Rubin, S.C., Benjamin, I., Behbakht, K., Takahashi, H.,
Morgan, M.A., LiVolsi, V.A., et al., 1996. Clinical and
pathological features of ovarian cancer in women with germline mutations of BRCA1. N. Engl. J. Med. 335, 1413–1416.
Rubin, S.C., Blackwood, M.A., Bandera, C., Behbakht, K.,
Benjamin, I., Rebbeck, T.R., Boyd, J., 1998. BRCA1, BRCA2, and
hereditary nonpolyposis colorectal cancer gene mutations in
an unselected ovarian cancer population: relationship to
family history and implications for genetic testing. Am. J.
Obstet. Gynecol. 178, 670–677.
Rutter, J.L., Wacholder, S., Chetrit, A., Lubin, F., Menczer, J.,
Ebbers, S., Tucker, M.A., Struewing, J.P., Hartge, P., 2003.
Gynecologic surgeries and risk of ovarian cancer in women
with BRCA1 and BRCA2 Ashkenazi founder mutations: an
Israeli population-based case–control study. J. Natl. Cancer
Inst. 95, 1072–1078.
Sakurada, A., Hamada, H., Fukushige, S., Yokoyama, T.,
Yoshinaga, K., Furukawa, T., et al., 1999. Adenovirus-mediated
delivery of the PTEN gene inhibits cell growth by induction of
apoptosis in endometrial cancer. Int. J. Oncol. 15, 1069–1074.
Salazar, H., Godwin, A.K., Daly, M.B., Laub, P.B., Hogan, W.M.,
Rosenblum, N., Boente, M.P., Lynch, H.T., Hamilton, T.C., 1996.
Microscopic benign and invasive malignant neoplasms and
a cancer-prone phenotype in prophylactic oophorectomies. J.
Natl. Cancer Inst. 88, 1810–1820.
Salovaara, R., Loukola, A., Kristo, P., Kääriäinen, H., Ahtola, H.,
Eskelinen, M., et al., 2000. Population-based molecular
detection of hereditary nonpolyposis colorectal cancer. J. Clin.
Oncol. 18, 2193–2200.
135
Sarrió, D., Moreno-Bueno, G., Sánchez-Estévez, C., BañónRodriguez, I., Hernández-Cortés, G., Hardisson, D., Palacios, J.,
2006. Expression of cadherins and catenins correlates with
distinct histologic types of ovarian carcinomas. Hum. Pathol.
37, 1042–1049.
Satagopan, J.M., Boyd, J., Kauff, N.D., Robson, M., Scheuer, L.,
Narod, S., Offit, K., 2002. Ovarian cancer risk in Ashkenazi Jewish
carriers of BRCA1 and BRCA2. Clin. Cancer Res. 8, 3776–3781.
Sato, N., Tsunoda, H., Nishida, M., Morishita, Y., Takimoto, Y.,
Kubo, T., Noguchi, M., 2000. Loss of heterozygosity on 10q23.3
and mutation of the tumor suppressor gene PTEN in benign
endometrial cyst of the ovary: possible sequence progression
from benign endometrial cyst to endometrioid carcinoma and
clear cell carcinoma of the ovary. Cancer Res. 60, 7052–7056.
Scambia, G., Benedetti Panici, P., Battaglia, F., Ferrandina, G.,
Baiocchi, G., Greggi, S., De Vincenzo, R., Mancuso, S., 1992.
Significance of epidermal growth factor receptor in advanced
ovarian carcinoma. J. Clin. Oncol. 10, 529–535.
Scheuer, L., Kauff, N., Robson, M., Kelly, B., Barakat, R.,
Satagopan, J., et al., 2002. Outcome of preventive surgery and
screening for breast and ovarian cancer in BRCA mutation
carriers. J. Clin. Oncol. 20, 1260–1268.
Schmeler, K.M., Lynch, H.T., Chen, L.-M., Munsell, M.F.,
Soliman, P.T., Clark, M.B., et al., 2006. Prophylactic surgery to
reduce the risk of gynecologic cancers in the Lynch syndrome.
N. Engl. J. Med. 354, 261–269.
Schmutte, C., Marinescu, R.C., Copeland, N.G., Jenkins, N.A.,
Overhauser, J., Fishel, R., 1998. Refined chromosomal
localization of the mismatch repair and hereditary
nonpolyposis colorectal cancer genes hMSH2 and hMSH6.
Cancer Res. 58, 5023–5026.
Schubert, E.L., Lee, M.K., Mefford, H.C., Argonza, R.H.,
Morrow, J.E., Hull, J., Dann, J.L., King, M.-C., 1997. BRCA2 in
American families with four or more cases of breast or ovarian
cancer: recurrent and novel mutations, variable expression,
and the possibility of families whose cancer is not attributable
to BRCA1 or BRCA2. Am. J. Hum. Genet. 60, 1031–1040.
Schweizer, P., Moisio, A.L., Kuismanen, S.A., Truninger, K.,
Vierumaki, R., Salovaara, R., et al., 2001. Lack of MSH2 and
MSH6 characterizes endometrial but not colon carcinomas in
hereditary nonpolyposis colorectal cancer. Cancer Res. 61,
2813–2815.
Seidman, J.D., Russell, P., Kurman, R.J., 2002. Surface epithelial
tumors of the ovary. In: Kurman, R.J. (Ed.), Blaustein’s
Pathology of Ovarian Cancer, fifth ed. Springer Publishers,
New York, pp. 791–805.
Shaw, P.A., McLaughlin, J.R., Zweemer, R.P., Narod, S.A.,
Risch, H., Verheijen, R.H., Ryan, A., Menko, F.H.,
Kenemans, P., Jacobs, I.J., 2002. Histopathologic features of
genetically determined ovarian cancer. Int. J. Gynecol.
Pathol. 21, 407–411.
Shelly, W., Draper, M.W., Krishman, V., 2008. Selective estrogen
receptor modulator: an update on recent clinical findings.
Obstet. Gynecol. Surv. 63, 163–181.
Shih le, M., Kurman, R.J., 2004. Ovarian tumorigenesis: a proposed
model based on morphological and molecular genetic
analysis. Am. J. Pathol. 164, 1511–1518.
Simard, J., Tonin, P., Durocher, F., Morgan, K., Rommens, J.,
Gingras, S., et al., 1994. Common origins of BRCA1 mutations
in Canadian breast and ovarian cancer families. Nat. Genet. 8,
392–398.
Singer, G., Oldt 3rd, R., Cohen, Y., Wang, B.G., Sidransky, D.,
Kurman, R.J., Shih, I.-M., 2003a. Mutations in BRAF and KRAS
characterize the development of low-grade ovarian serous
carcinoma. J. Natl. Cancer Inst. 95, 484–486.
Singer, G., Shih, I.-M., Truskinovsky, A., Umudum, H.,
Kurman, R.J., 2003b. Mutational analysis of K-ras segregates
ovarian serous carcinomas into two types: invasive MPSC
136
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
(low-grade tumor) and conventional serous carcinoma (highgrade tumor). Int. J. Gynecol. Pathol. 22, 37–41.
Singer, G., Stöhr, R., Cope, L., Dehari, R., Hartmann, A., Cao, D.F.,
Wang, T.L., Kurman, R.J., Shih, I.-M., 2005. Patterns of p53
mutations separate ovarian serous borderline tumors and
low- and high-grade carcinomas and provide support for
a new model of ovarian carcinogenesis: a mutational analysis
with immunohistochemical correlation. Am. J. Surg. Pathol.
29, 218–224.
Skilling, J.S., Sood, A., Niemann, T., Lager, D.J., Buller, R.E., 1996.
An abundance of p53 null mutations in ovarian carcinoma.
Oncogene 13, 117–123.
Smith, A., Moran, A., Boyd, M.C., Bulman, M., Shenton, A.,
Smith, L., et al., 2007. Phenocopies in BRCA1 and BRCA2
families: evidence for modifier genes and implications for
screening. J. Med. Genet. 44, 10–15.
Soegaard, M., Kjaer, S.K., Cox, M., Wozniak, E., Høgdall, E.,
Høgdall, C., Blaakaer, J., Jacobs, I.J., Gayther, S.A., Ramus, S.J.,
2008. BRCA1 and BRCA2 mutation prevalence and clinical
characteristics of a population-based series of ovarian cancer
cases from Denmark. Clin. Cancer Res. 14, 3761–3767.
Sood, A.K., Holmes, R., Hendrix, M.J., Buller, R.E., 2001.
Application of the National Cancer Institute international
criteria for determination of microsatellite instability in
ovarian cancer. Cancer Res. 61, 4371–4374.
Struewing, J.P., Hartge, P., Wacholder, S., Baker, S.M., Berlin, M.,
McAdams, M., Timmerman, M.M., Brody, L.C., Tucker, M.A., 1997.
The risk of cancer associated with specific mutations of BRCA1
and BRCA2 among Ashkenazi Jews. N. Engl. J. Med. 336, 1401–1408.
Struewing, J.P., Watson, P., Easton, D.F., Ponder, B.A.J.,
Lynch, H.T., Tucker, M.A., 1995. Prophylactic oophorectomy in
inherited breast/ovarian cancer families. J. Natl. Cancer Inst.
Monogr. 17, 33–35.
Sun, S., Greenwood, C.M., Thiffault, I., Hamel, N., Chong, G.,
Foulkes, W.D., 2005. The HNPCC associated MSH2*1906G 2 C
founder mutation probably originated between 1440 CE and 1715
CE in this Ashkenazi Jewish population. J. Med. Genet. 42, 766–768.
Tailor, A., Bourne, T.H., Campbell, S., Okokon, E., Dew, T.,
Collins, W.P., 2003. Results from an ultrasound-based familial
ovarian cancer screening clinic: a 10-year observational study.
Ultrasound Obstet. Gynecol. 21, 378–385.
Tan, D.S., Rothermundt, C., Thomas, K., Bancroft, E., Eeles, R.,
Shanley, S., Ardern-Jones, A., Norman, A., Kaye, S.B., Gore, M.E.,
2008. ‘‘BRCAness’’ syndrome in ovarian cancer: a case–control
study describing the clinical features and outcome of patients
with epithelial ovarian cancer associated with BRCA1 and
BRCA2 mutations. J. Clin. Oncol. 26, 5530–5536.
Tannergård, P.M., Zabarovsky, E., Stanbridge, E.,
Nordenskjöld, M., Lindblom, A., 1994. Sublocalization of
a locus at 3-21.3-23 predisposing to hereditary nonpolyposis
colon cancer. Hum. Genet. 94, 210–214.
Tashiro, H., Blazes, M.S., Wu, R., Cho, K.R., Bose, S., Wang, S.I.,
Li, J., Parsons, R., Ellenson, L.H., 1997. Mutations in PTEN are
frequent in endometrial carcinoma but rare in other common
gynecological malignancies. Cancer Res. 57, 3935–3940.
Teneriello, M.G., Ebina, M., Linnoila, R.I., Henry, M., Nash, J.D.,
Park, R.C., Birrer, M.J., 1993. p53 and Ki-ras gene mutations in
epithelial ovarian neoplasms. Cancer Res. 53, 3103–3108.
The Anglian Breast Cancer Study Group, 2000. Prevalence of
BRCA1 and BRCA2 mutations in a large population based series
of breast cancer cases. Br. J. Cancer 83, 1301–1308.
The Breast Cancer Linkage Consortium, 1999. Cancer risks in
BRCA2 mutation carriers. J. Natl. Cancer Inst. 91, 1310–1316.
Thibodeau, S.N., Bren, G., Schaid, D., 1993. Microsatellite instability
in cancer of the proximal colon. Science 260, 816–819.
Thompson, D., Easton, D., Breast Cancer Linkage Consortium,
2001. Variation in cancer risks, by mutation position, in BRCA2
mutation carriers. Am. J. Hum. Genet. 68, 410–419.
Thompson, D., Easton, D., Breast Cancer Linkage Consortium,
2002a. Variation in BRCA1 cancer risks by mutation position.
Cancer Epidemiol. Biomarkers Prev. 11, 329–336.
Thompson, D., Easton, D.F., Breast Cancer Linkage Consortium,
2002b. Cancer incidence in BRCA1 mutation carriers. J. Natl.
Cancer Inst. 94, 1358–1365.
Tobias, D.H., Eng, C., McCurdy, L.D., Kalir, T., Mandelli, J.,
Dottino, P.R., Cohne, C.J., 2000. Founder BRCA 1 and 2
mutations among a consecutive series of Ashkenazi Jewish
ovarian cancer patients. Gynecol. Oncol. 78, 148–151.
Tong, D., Stimpfl, M., Reinthaller, A., Vavra, N., Müllauer-Ertl, S.,
Leodolter, S., Zeillinger, R., 1999. BRCA1 gene mutations in
sporadic ovarian carcinomas: detection by PCR and reverse allelespecific oligonucleotide hybridization. Clin. Chem. 45, 976–981.
Tonin, P., Moslehi, R., Green, R., Rosen, B., Cole, D., Boyd, N., et al.,
1995. Linkage analysis of 26 Canadian breast and breast–
ovarian cancer families. Hum. Genet. 95, 545–550.
Tulinius, H., Olafsdottir, G.H., Sigvaldason, H., Arason, A.,
Barkardottir, R.B., Egilsson, V., Ogmundsdottir, H.M.,
Tryggvadottir, L., Gudlaugsdottir, S., Eyfjord, J.E., 2002. The
effect of a single BRCA2 mutation on cancer in Iceland. J. Med.
Genet. 39, 457–462.
Ursic-Vrscaj, M., Kovacic, J., Bebar, S., Djurisic, A., Fras, P.A.,
Robie, V., 2001. Endometrial and other primary cancers after
tamoxifen treatment of breast cancer – results of retrospective
cohort study. Eur. J. Obstet. Gynecol. Reprod. Biol. 95, 105–110.
van der Klift, H., Wijnen, J., Wagner, A., Verkuilen, P., Tops, C.,
Otway, R., et al., 2005. Molecular characterization of the
spectrum of genomic deletions in the mismatch repair genes
MSH2, MLH1, MSH6, and PMS2 responsible for hereditary
nonpolyposis colorectal cancer (HNPCC). Genes Chromosomes
Cancer 44, 123–138.
van Nagell Jr., J.R., DePriest, P.D., Reedy, M.B., Gallion, H.H.,
Ueland, F.R., Pavlik, E.J., Kryscio, R.J., 2000. The efficacy of
transvaginal sonographic screening in asymptomatic women
at risk for ovarian cancer. Gynecol. Oncol. 77, 350–356.
Vasen, H.F., Tesfay, E., Boonstra, H., Mourits, M.J., Rutgers, E.,
Verheyen, R., Oosterwijk, J., Beex, L., 2005. Early detection of
breast and ovarian cancer in families with BRCA mutations.
Eur. J. Cancer 41, 549–554.
Vasen, H.F.A., Stormorken, A., Menko, F.H., Nagengast, F.M.,
Kleibeuker, J.H., Griffioen, G., Taal, B.G., Moller, P., Wijnen, J.T.,
2001. MSH2 mutation carriers are at higher risk of cancer than
MLH1 mutation carriers: a study of hereditary nonpolyposis
colorectal cancer families. J. Clin. Oncol. 19, 4074–4080.
Vasen, H.F.A., Watson, P., Mecklin, J.-P., Lynch, H.T., Icg-Hnpcc,
1999. New clinical criteria for hereditary nonpolyposis
colorectal cancer (HNPCC, Lynch syndrome) proposed by the
International Collaborative Group on HNPCC.
Gastroenterology 116, 1453–1456.
Vasen, H.F.A., Wijnen, J.T., Menko, F.H., Kleibeuker, J.H.,
Taal, B.G., Griffioen, G., et al., 1996. Cancer risk in families with
hereditary nonpolyposis colorectal cancer diagnosed by
mutation analysis. Gastroenterology 110, 1020–1027.
Vilkki, S., Tsao, J.-L., Loukola, A., Pöyhönen, M., Vierimaa, O.,
Herva, R., Aaltonen, L.A., Shibata, D., 2001. Extensive somatic
microsatellite mutations in normal human tissue. Cancer Res.
61, 4541–4544.
Vivanco, I., Sawyers, C.L., 2002. The phosphatidylinositol 3-kinase
AKT pathway in human cancer. Nat. Rev. Cancer 2, 489–501.
Vogel, V.G., Costantino, J.P., Wickerham, D.L., Cronin, W.M.,
Cecchini, R.S., Atkins, J.N., et al., 2006. Effects of tamoxifen vs
raloxifene on the risk of developing invasive breast cancer and
other disease outcomes: the NSABP Study of Tamoxifen and
Raloxifene (STAR) P-2 trial. JAMA 295, 2727–2741.
Wagner, A., Barrows, A., Wijnen, J.T., van der Klift, H., Franken, P.F.,
Verkuijlen, P., et al., 2003. Molecular analysis of hereditary
nonpolyposis colorectal cancer in the United States: high
M O L E C U L A R O N C O L O G Y 3 (2009) 97–137
mutation detection rate among clinically selected families and
characterization of an American founder genomic deletion of
the MSH2 gene. Am. J. Hum. Genet. 72, 1088–1100.
Wagner, A., van der Klift, H., Franken, P., Wijnen, J., Breukel, C.,
Bezrookove, V., et al., 2002. A 10 Mb paracentric inversion of
chromosome arm 2p inactivates MSH2 and is responsible for
HNPCC in a North-American kindred. Genes Chromosomes
Cancer 35, 49–57.
Wang, Q., Lasset, C., Desseigne, F., Frappaz, D., Bergeron, C.,
Navarro, C., Ruano, E., Puisieux, A., 1999. Neurofibromatosis
and early onset of cancers in hMLH1-deficient children. Cancer
Res. 59, 294–297.
Watson, P., Lin, K., Rodriguez-Bigas, M.A., Smyrk, T., Lemon, S.,
Shashidharan, M., Franklin, B., Karr, B., Thorson, A.,
Lynch, H.T., 1998. Colorectal carcinoma survival among
hereditary nonpolyposis colorectal cancer family members.
Cancer 83, 259–266.
Watson, P., Lynch, H.T., 2001. Cancer risk in mismatch repair
gene mutation carriers. Fam. Cancer 1, 57–60.
Watson, P., Vasen, H.F.A., Mecklin, J.-P., Bernstein, I., Aarnio, M.,
Järvinen, H.J., Myrhøj, T., Sunde, L., Wijnen, J.T., Lynch, H.T.,
2008. The risk of extra-colonic, extra-endometrial cancer in
the Lynch syndrome. Int. J. Cancer 123, 444–449.
Whitmore, S.E., 1997. BRCA1 mutations and survival in women
with ovarian cancer. N. Engl. J. Med. 336, 1254–1255 (letter).
Whiteside, D., McLeod, R., Graham, G., Steckley, J.L., Booth, K.,
Somerville, M.J., Andrew, S.E., 2002. A homozygous germ-line
mutation in the human MSH2 gene predisposes to
hematological malignancy and multiple café-au-lait spots.
Cancer Res. 62, 359–362.
Wijnen, J., de Leeuw, W., Vasen, H., van der Klift, H., Møller, P.,
Stormorken, A., et al., 1999. Familial endometrial cancer in female
carriers of MSH6 germline mutations. Nat. Genet. 23, 142–144.
Wijnen, J., van der Klift, H., Vasen, H., Khan, P.M., Menko, F.,
Tops, C., Heijboer, H.M., Lindhout, D., Møller, P., Fodde, R.,
1998. MSH2 genomic deletions are a frequent cause of HNPCC.
Nat. Genet. 20, 326–328.
Wijnen, J.T., Brohet, R.M., van Eijk, R., Jagmohan-Changur, S.,
Middeldorp, A., Tops, C.M., et al., 2009. Chromosome 8q23.3
and 11q23.1 variants modify colorectal cancer risk in Lynch
syndrome. Gastroenterology 136, 131–137.
Woodruff, J.D., 1979. The pathogenesis of ovarian neoplasia.
Johns Hopkins Med. J. 144, 117–120.
Woodward, E.R., Sleightholme, H.V., Considine, A.M.,
Williamson, S., McHugo, J.M., Cruger, D.G., 2007. Annual
137
surveillance by CA125 and transvaginal ultrasound for ovarian
cancer in both high-risk and population risk women is
ineffective. BJOG 114, 1500–1509.
Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J.,
et al., 1995. Identification of the breast cancer susceptibility
gene BRCA2. Nature 378, 789–792.
Wooster, R., Neuhausen, S.L., Mangion, J., Quirk, Y., Ford, D.,
Collins, N., et al., 1994. Localization of a breast cancer
susceptibility gene, BRCA2, to chromosome 13q12–13. Science
265, 2088–2090.
Wright, K., Wilson, P., Morland, S., Campbell, I., Walsh, M.,
Hurst, T., Ward, B., Cummings, M., Chenevix-Trench, G., 1999.
Beta-catenin mutation and expression analysis in ovarian
cancer: exon 3 mutations and nuclear translocation in 16% of
endometrioid tumours. Int. J. Cancer 82, 625–629.
Wu, R., Zhai, Y., Fearon, E.R., Cho, K.R., 2001. Diverse mechanisms
of beta-catenin deregulation in ovarian endometrioid
adenocarcinomas. Cancer Res. 61, 8247–8255.
Wu, Y., Berends, M.J.W., Mensink, R.G.J., Kempinga, C.,
Sijmons, R.H., van der Zee, A.G.J., Hollema, H., Kleibeuker, J.H.,
Buys, C.H.C.M., Hofstra, R.M.W., 1999. Association of
hereditary nonpolyposis colorectal cancer-related tumors
displaying low microsatellite instability with MSH6 germline
mutations. Am. J. Hum. Genet. 65, 1291–1298.
Yuan, Z.Q., Wong, N., Foulkes, W.D., Alpert, L., Manganaro, F.,
Andreutti-Zaaugg, C., et al., 1999. A missense mutation in both
hMSH2 and APC in an Ashkenazi Jewish HNPCC kindred:
implications for clinical screening. J. Med. Genet. 36, 790–793.
Zhai, Q.J., Rosen, D.G., Lu, K., Liu, J., 2008. Loss of DNA mismatch
repair protein hMSH6 in ovarian cancer is histotype-specific.
Int. J. Clin. Exp. Pathol. 1, 502–509.
Ziogas, A., Gildea, M., Cohen, P., Bringman, D., Taylor, T.H.,
Seminara, D., et al., 2000. Cancer risk estimates for family
members of a population-based family registry for breast and
ovarian cancer. Cancer Epidemiol. Biomarkers Prev. 9,
103–111.
Zweemer, R.P., van Diest, P.J., Verheijen, R.H., Ryan, A., Gille, J.J.,
Sijmons, R.H., Jacobs, I.J., Menko, F.H., Kenemanas, P., 2000.
Molecular evidence linking primary cancer of the fallopian
tube to BRCA1 mutations. Gynecol. Oncol. 76, 45–50.
Zweemer, R.P., Verheijen, R.H., Coebergh, J.W., Jacobs, I.J., van
Diest, P.J., Gille, J.J., Skates, S., Menko, F.H., Ten Kate, L.P.,
Kenemans, P., 2001. Survival analysis in familial ovarian
cancer, a case control study. Eur. J. Obstet. Gynecol. Reprod.
Biol. 98, 219–223.