Download J BUON

Journal of BUON 12 (Suppl 1): S13-S22, 2007
© 2007 Zerbinis Medical Publications. Printed in Greece
SEMINAR ARTICLE
Hereditary cancer syndromes
Florentia Fostira1,2, Georgia Thodi1,2, Irene Konstantopoulou1, Raphael Sandaltzopoulos2,
Drakoulis Yannoukakos1*
1
Molecular Diagnostics Laboratory, I/RRP, National Centre for Scientific Research “Demokritos”, Athens; 2Laboratory of Gene
Expression, Molecular Diagnosis and Modern Therapeutics, Department of Molecular Biology and Genetics, Democritus University
of Thrace, Alexandroupolis, Greece
Summary
The identification of susceptibility genes for specific
types of cancer provided the necessary information for the
complete characterization of inherited cancer syndromes.
The close observation of carrier families has significantly
enriched our knowledge on distinct phenotypical features,
age of onset and survival rates for each syndrome and gave
the opportunity to further understand the molecular basis
of hereditary cancer. Recent advances in cancer genetics
involve the identification of novel genes with moderate risk to
cause cancer, after synergism with particular environmental
factors, and therefore reinforcing the genetic component in
relation to cancer predisposition. The available genetic tests
can constitute an essential step of primary health care, as
Introduction
The establishment of sensitive genetic tests over
the last years has assisted the identification of genes
conferring susceptibility to tumorigenesis. Cancer
inheritance was successfully spotted in families where
specific types of cancer were clustered amongst family members. The most common types of hereditary
cancers involve breast and ovarian cancer, primarily
caused by mutations in BRCA1 and BRCA2 genes;
colorectal cancer (CRC), caused by mutation in one
of the DNA MMR genes; and mutations within the
APC gene are linked to colorectal adenomatous polyposis. Germline pathogenic mutations of these genes
are inherited as autosomal dominant traits and are
characterized by their high penetrance. Recent studies focus their interest on mutations with unknown
pathogenicity, which seem to collaborate with environmental and/or additional genetic factors for the onset
they can dramatically affect the quality of a cancer patient’s
life and they can also offer prompt diagnosis for the patient’s
close relatives. This review reports the most characteristic
hereditary cancer syndromes along with their phenotypical
and genetic variables that have been described, but it mainly
focuses on Hereditary Non-Polyposis Colorectal Cancer
(HNPCC), which is linked to pathogenic mutations in one
of the mismatch repair (MMR) genes MLH1, MSH2, MSH6,
Familial Adenomatous Polyposis (FAP) caused by highpenetrant mutations within the APC gene and Hereditary
Breast/Ovarian Cancer (HBOC) linked to mutations within
BRCA1 and BRCA2 genes.
Key words: BRCA, FAP, hereditary cancer syndromes,
HNPCC
and progression of cancer. The most crucial event in
achieving successful prediction of a hereditary cancer
syndrome is a well-documented family history, where
all healthy and affected family members, all types of
cancers, characteristic phenotypic features and age of
onset for each inflicted person should be recorded [1].
The appropriate genetic test for the corresponding gene
will then identify the causative mutation maximizing
the patient’s preventative potential.
The cancer syndromes already known along with
their phenotypic features and susceptibility genes are
summarized on Table 1. Recently identified genes
conferring moderate risk of breast or ovarian cancer are
included in the Table although they do not yet constitute
defined cancer syndromes. CRC accounts for 12% of
all cancer cases in the Western World. Up to 15% of
all CRC cases are attributed to familial predisposition,
while 3-5% and 0.5-1% are confirmed to carry a pathogenic mutation in one of the DNA MMR genes and
*Correspondence to: Drakoulis Yannoukakos, PhD, Molecular Diagnostics Laboratory, I/R-RP, National Centre for Scientific Research “Demokritos”,
Athens, Greece. Tel: + 30 210 6503936, Fax: + 30 210 6524480, E-mail: [email protected]
S14
Table 1. Most common cancer syndromes described along with their susceptible genes and their phenotypical features. The most predominant phenotypical feature for each cancer syndrome is highlighted in bold
Syndrome
Gene
Phenotypic features
Mode of
inheritance
1
Hereditary Breast/Ovarian Cancer
(HBOC) 1
BRCA1
Female breast, ovarian
and colorectal cancer
Dominant
2
Hereditary Breast/Ovarian Cancer
(HBOC) 2
BRCA2
Male and female breast, ovarian,
prostate and pancreatic cancer
Dominant
Moderate Risk Breast/Ovarian
Cancer
CHEK2, ATM, NBS1,
RAD50, BRIP1, PALB2,
FGFR2, TNRC9,
MAP3K1, LSP1, CASP8
Breast and ovarian cancer
3
Familial Adenomatous Polyposis
(FAP)
APC
Multiple colorectal and upper GI
adenomatous polyps, desmoid tumors,
epidermoid cysts and CHRPE
Dominant
4
Hereditary Non-Polyposis
Colorectal Cancer (HNPCC)
MLH1, MSH2, MSH6,
PMS2, PMS1
Colorectal, endometrial, ovarian, gastric,
urinary tract and brain cancer
Dominant
5
MUTYH Associated Polyposis
MYH
Colorectal polyps and colorectal cancer
Recessive
6
Multiple Endocrine Neoplasia
(MEN) 1
MEN1
Parathyroid adenomas, lipomas, enteropancreatic tumors, facial angiofibromas,
gastrinomas, collagenomas, insulinomas,
anterior pituitary tumors
Dominant
7
Multiple Endocrine Neoplasia
(MEN) 2
RET
Medullary thyroid carcinomas, parathyroid
carcinomas, pheochromocytomas
Dominant
8
Li-Fraumeni
TP53
Breast cancer, sarcomas,
leukemia and brain tumors
Dominant
9
Turcot
APC, MLH1, MSH2
Colorectal polyps, medulloblastomas,
glioblastomas and astrocytomas
Dominant
10
Juvenile polyposis
SMAD4, BMPR1A
Hamartomatous intestinal polyps and
stomach polyps (rare)
Dominant
11
Muir-Torre
MLH1, MSH2
Adenomatous colorectal polyps
and endometrial cancer
Dominant
12
Von-Hippel-Lindau
VHL
Renal cell carcinoma, retinal angiomas,
cerebellar and spinal glioblastomas
Dominant
13
Peutz-Jeghers
STK11
Hamartomatous intestinal polyps, lung,
breast, and urinary tract cancer,
hyperpigmented perioral and buccal mucosa
Dominant
14
Hereditary Diffuse Gastric Cancer
(HDGC)
CDH1
Diffuse gastric cancer, lobular breast cancer
Dominant
15
Cowden
PTEN
Breast, gastrointestinal, thyroid, brain, and
skin hamartomas developing in cancer
Dominant
16
Bannayan-Ruvalcaba-Riley
PTEN
Hamartomatous intestinal polyps,
microcephaly, lipomatosis, hemangiomas
Dominant
17
Familial Retinoblastoma
RB1
Primary eye cancer
Recessive
18
Wilm’s tumor
WT1
Kidney cancer
Recessive
19
Familial Melanoma
CDKN2A(p16)
Melanoma
Dominant
20
Ataxia Telangiectasia
ATM
Lymphoma, breast cancer
Recessive
21
Bloom Syndrome
BLM
Solid tumors
Recessive
22
Xeroderma Pigmentosum
XPB, XPD, XPA
Skin cancer
Recessive
23
Fanconi’s Anemia
FANC (A,B,C,D1,D2,
E,F, G,I,J,L,M,N)
FANCD1/BRCA2,
FANCJ/BACH1/BRIP1,
FANCN/PALB2
Acute myeloid leukaemia
Recessive
S15
APC gene, respectively [2]. On the other hand, breast
cancer is the most common type of cancer affecting 1
in 10 women, while 20-30% of these cases underlie
genetic predisposition, 30% of which are caused by
mutations in BRCA1 & BRCA2 genes [3]. This review
will mainly focus in colorectal and breast/ovarian cancer syndromes.
Lynch syndrome (HNPCC)
CRC is amongst the most common cancers (2nd
to 4th) in industrialized countries [4]. HNPCC or Lynch
syndrome, named after the oncologist who pioneered
the study of this disease, accounts for 3-5% of all CRC
cases. It is inherited in an autosomal dominant manner and characterized by 80% and 60% penetrance for
colorectal and endometrial cancer, respectively. Extracolonic cancers are also observed in ovaries, stomach,
brain, small bowel, pancreas, hepatobiliary and urinary
tract, which are estimated to have lifetime risks from
2% to 13%. In addition, there is an excess of synchronous (multiple CRCs within 6 months of surgical intervention) or metachronous CRCs (CRC occurring later
than 6 months or more after surgery) [1,5].
Mutations in the DNA MMR genes (MLH1,
MSH2, MSH6 and PMS2) predispose to Lynch syndrome. The main function of MMR genes involves DNA
repair during replication. Most pathogenic mutations
have been identified in the MSH2 and MLH1 genes.
MSH2 mutations account for about 39% of HNPCC
cases, whereas MLH1 mutations account for about 50%
of the cases. Mutations are scattered throughout the
coding regions of the MLH1 and MSH2 genes without
obvious hotspots and therefore mutation screening
strategies must cover the entirety of these genes [6].
MSH6 mutations account for 10-15% of all HNPCC
germline mutations. A characteristic feature of families with MSH6 mutations is the older age at onset as
compared to families carrying MLH1 and/or MSH2
mutations. This may be due to the fact that the mismatch
repair capacity is partially retained in MSH6 mutated
cells. Nevertheless, approximately in half of the MSH6
families studied, at least one member developed CRC
or endometrial cancer by her/his fourth decade of life.
This indicates a significant variability of penetrance
as a function of age, probably reflecting the influence
of additional genetic and/or environmental factors.
Furthermore, the frequency of CRC is lower in MSH6
families, whereas the frequency of extracolonic tumors,
especially of endometrial cancer, seems to be higher
compared to the MSH2 families [7].
Pinto and coworkers conducted a research to
identify the presence of germline MSH6 mutations in
patients diagnosed with CRC before the age of 45 with
no HNPCC family history. It was evident that MSH6
mutations contributed to a subset of early-onset CRC,
whereas MLH1 and MSH2 mutations were scarce in this
group of “high-risk” patients. Further studies should
be conducted to identify the genetic and environmental
factors which modify the risk conferred by mutations in
the MSH6 gene [8].
The clinical diagnosis of Lynch syndrome was
mainly based on the Amsterdam I criteria, which were
proposed by the International Collaborative group of
HNPCC. A characteristic pedigree of Lynch syndrome
is depicted in Figure 1. Because these clinical criteria
proved too strict, they were modified in order to become more applicable (Amsterdam criteria II, Box 1).
Although the Amsterdam II criteria are characterized
by 98% specificity, they are still not sensitive enough
[1, 9]. Therefore, the revised Bethesda guidelines (Box
2) were introduced for the selection of tumor specimens
which should be subjected to microsatellite instability (MSI) analysis. The National Cancer Institute has
proposed a panel of 5 markers for the assessment of
the MSI levels. Nearly all HNPCC-related colorectal
tumors exhibit high levels of MSI (MSI-H) as a consequence of the MMR deficiency. However, 15% of
sporadic CRC cases may also be characterized as MSI-
Figure 1. Pedigree indicative of Lynch syndrome. Arrow indicates
the proband.
S16
Box 1: Modified Amsterdam Criteria
• ≥ 3 relatives with HNPCC-related cancer (colorectal, endometrial, stomach, ovarian, brain, small bowel, hepatobiliary &
urothelial tract) (≥ 1 must be first-degree relative of the other
2)
• ≥ 2 successive generations affected
• ≥ 1 individual diagnosed with cancer at an age < 50 years
• Familial adenomatous polyposis should have been excluded
Box 2: Revised Bethesda Guidelines
Tumors should be tested for MSI when one or more of the following exists:
• CRC in a patient younger than 50 years
• Synchronous or metachronous CRC or other HNPCC-associated tumors regardless of age
• MSI-H colon tumor or with particular histology* in a patient
<60 years
• CRC or tumor associated with HNPCC <50 years in at least
one first-degree relative
• CRC or tumor associated with HNPCC at any age in 2 first- or
second-degree relatives
*Presence of tumor infiltrating lymphocytes, Crohn disease-like lymphocytic reaction, mucinous or signet-ring differentiation, or medullary
growth pattern. For abbreviations see text.
H, due to acquired changes in the MLH1 gene. For that
reason, MSI-H samples should be further screened for
the presence of BRAF V600E, a mutation strongly associated with sporadic CRC [10]. BRAF mutations are
rare or absent in Lynch syndrome tumor samples [11].
Although the revised Bethesda guidelines may show
up to 95% sensitivity, they are characterized by 38%
specificity only [9].
As the identification of mutation carriers is really
important for their further clinical management, various
algorithms combining family history data with molecular tumor characteristics have been developed to facilitate the diagnosis of Lynch syndrome. Recently, 3 new
algorithms were presented for the evaluation of the
likelihood of carrying a germline mutation in a MMR
gene [12].
• Balmana et al. have developed the PREMM1,2 model, which is available at http://www.dfci.org/premm.
This model incorporates personal and family history
(first-, second-degree relatives) of cancer and adenomas and can help the clinician to determine the most
appropriate family member for genetic testing [13].
• Barnetson et al. have developed another model,
which is available at www1.hgu.mrc.au.uk/Softdata/
MMRpredict.php for the identification of mutation
carriers in MMR genes among patients with CRC.
The carrier probability is estimated using the follow-
ing clinical features: age at diagnosis, tumor location
(proximal or distal), presence of synchronous or metachronous tumor, age of youngest relative with CRC,
and presence of endometrial cancer within the family [9].
• Chen et al. have created the MMRpro software, which
is available at http://astor.som.jhmi.edu/BayesMendel/. This model evaluates the risk of genetic susceptibility to Lynch syndrome based on estimates of
mutation prevalence and penetrance of the MMR
genes in a population [14].
Mutation carriers, as well as their relatives or individuals with high clinical suspicion of Lynch syndrome should be subjected to a particular surveillance
programme. The International Collaborative group on
HNPCC recommends colonoscopy every 1 to 2 years,
starting around the age of 20 or 10 years earlier than the
age (at the time of diagnosis) of the youngest patient in
the immediate family diagnosed with CRC. Endometrial screening is also recommended, which includes
transvaginal ultrasonography and measurement of CA125 every 1 to 2 years, beginning around the age of 30.
There are no standard screening recommendations for
the other extracolonic tumors. If the clinician observes
a particular tumor spectrum in a family, screening for
the specific tumors may be offered [7].
Familial adenomatous polyposis (FAP)
FAP is one of the most well described forms of
hereditary CRC accounting for 1% of all CRC cases.
Germline mutations in the tumor-suppressor APC
gene, which is located at locus 5q21 encoding a 2843
amino acid protein and composed by 15 exons, are the
genetic cause of FAP syndrome. These FAP-causing
mutations result in truncated and, therefore, non-functional APC protein [15]. APC mutations are inherited
in an autosomal dominant manner and achieve almost
100% penetrance. Through binding of APC protein to
β-catenin, the cellular levels of β-catenin are regulated.
Inactivation of APC protein results in the accumulation
of β-catenin in the cytoplasm and nucleus. β-catenin is
implicated in the upregulation of the Wnt-pathway, affecting the expression of numerous oncogenes [16].
The phenotypic hallmark of FAP is the development of hundreds to thousands adenomatous polyps
in the colon and rectum of the affected individuals
diagnosed before the third decade of life. Malignant
transformation takes place by the fourth to fifth decade
of life, if these polyps are not surgically removed [17].
Figure 2 represents schematically the transition of
normal epithelium to adenoma and carcinoma. One
S17
Figure 2. Schematic representation of the sequence formation from normal epithelium
to polyp and to cancer formation.
quite common clinical manifestation observed in FAP
patients is the appearance of numerous fundic gland
polyps (FGPs) in the stomach, which occurs at a young
age. These polyps are small sessile growths characterized by hyperplasia of fundic glands [18]. Figure 3 represents a typical family carrying an APC mutation.
The majority of FAP patients develop extracolonic
manifestations. Most of them do not affect the clinical
condition of the patient, but on the other hand, some of
them can be lethal [19]. Thyroid cancer is a type of malignancy that is usually diagnosed around the age of 30
in APC-mutation carriers. These tumors tend to be nonaggressive and have a low metastatic potential, while
they seem to have a strong preference to females with
a fascinating ratio female:male of 17:1 [20]. Additionally, rapidly progressive hepatoblastomas, which are in
most cases lethal, are often seen in families with FAP
syndrome, affecting children around the age of 2 [21].
Figure 3. Typical pedigree in a family-carrier of an APC mutation.
Although desmoid tumors are quite rare, they
comprise one of the leading causes of death of FAP patients [22]. The median age at diagnosis is 32 years and
they manifest in the abdomen, and specifically in the
small bowel mesentery or the abdominal wall. A very
interesting observation is that occurrence of sebaceous
cysts and osteomas in FAP patients predispose to desmoid tumor development, which can be helpful for an
early diagnosis [23]. Brain tumors, and predominantly
astrocytomas and medulloblastomas in patients that
have not completed their first decade of life have also
been reported in few APC-mutation carriers [24].
A great proportion of FAP patients (almost 90%)
develop characteristic ophthalmic flat pigmented lesions, bilateral in most cases, at the level of the retinal
pigment epithelium, generally referred to as congenital
hypertrophy of the retinal pigment epithelium (CHRPE)
[25]. Although this characteristic phenotypic feature
does not affect the patient’s clinical status, it is considered as a great disease marker and diagnostic tool, as it
specifically affects FAP patients.
A FAP variant, called attenuated FAP (AFAP)
is basically characterized by a milder progression of
the phenotypic features accompanying the syndrome.
Specifically, 10-100 adenomatic flat polyps manifest
at AFAP patient’s proximal colon with a delayed onset
compared to the classic FAP, whilst CRC arises later,
around the age of 55. Generally, these individuals lack
extracolonic features, with the exception of the presence of few gastric polyps [26].
Quite recently, an autosomal recessive type of
S18
polyposis with a mild phenotype has been characterized, called the MUTYH-associated polyposis (MAP).
MUTYH mutations are susceptible for the specific
phenotype, where individuals show few adenomatous
polyps (5-50) around the age of 50 and a delayed onset
of CRC. MUTYH gene is a base excision repair gene
and its inactivation causes accumulation of mutations within the APC gene [27]. The phenotypical and
molecular differences between the 3 FAP variants are
summarized in Table 2.
The severity of FAP, age of onset and detailed pathological findings that may (or may not) be associated
to cancerous lesions can dramatically help in the identification of the specific coding region within the APC
gene that is pathogenically mutated. A characteristic example is the occurrence of CHRPE, which is associated
with mutations between codons 311 to 1444 [28]. This
phenotype to genotype correlation is quite persistent
even between different populations and can help reduce
the cost of genetic tests. Apart from the classic surgical procedure of proctocolectomy, the pharmaceutical
therapy that seems to have a beneficial effect towards
colorectal polyp formation in APC mutation carriers is
the administration of cyclooxygenase-2 inhibitors, such
as celecoxib [29].
Hereditary breast and ovarian cancer syndrome (HBOC)
Breast cancer is the second leading cause of cancer-related deaths while ovarian cancer is the sixth most
common cancer amongst women [30]. In the past decade, 2 major familial breast and ovarian cancer susceptibility conferring genes were discovered through ge-
netic linkage studies [31]. Mutations in BRCA1 and
BRCA2 tumor suppressor genes are identified in approximately 30% of families with severe history burden
of these cancers [32]. BRCA1 and BRCA2 genes contribute to genome integrity (DNA repair, cell-cyclecheckpoint control, protein ubiquitilation, chromatin
remodelling) [33]. According to a recent meta-analysis
the mean cumulative risks for mutation carriers at the
age of 70 are the following:
• ovarian cancer risk of 40% for BRCA1 and 18% for
BRCA2 mutation carriers
• breast cancer risk of 57% for BRCA1 and 49% for
BRCA2 mutation carriers [34].
Mutations in the aforementioned genes account
for only 2-3% of all breast cancer cases [33]. Several
other “breast cancer” genes have been identified, such
as CHEK2, ATM, NBS1, RAD50, BRIP1, and PALB2.
Mutations in the so-called moderate or low penetrance
alleles may double the risk for breast cancer development [35]. Additionally, new susceptibility loci conferring for breast and ovarian cancer moderate risk have
been identified, containing the following plausible
causative genes: FGFR2, TNRC9, MAP3K1, LSP1,
CASP8 [36,37]. It has been assumed that a third highpenetrant gene exists, named BRCA3, as a substantial
proportion of typical breast cancer families have no genetic explanation. Up to date, the search for the BRCA3
locus has not yielded any conclusive result [33], and
therefore the polygenic model seems to explain a part
of these cases [36,37].
Up to now, hundreds of distinct mutations, polymorphisms and unclassified variants have been recorded
in the Breast Cancer Information Core Database (BIC),
which are characterized by variable penetrance and
prevalence in different populations. For instance, ac-
Table 2. Summary of phenotypic and genetic features of the 3 FAP variants: Classic FAP, AFAP and MAP
Features
Gene/location
Mode of inheritance
Polyps’morphology
No. of polyps
CRC diagnosis
Desmoid tumors
Fundic gland polyps in stomach
CHRPE
Thyroid cancer
Hepatoblastomas
Brain cancer
For abbreviations see text
FAP
APC (MCR exon 15)
Autosomal
dominant
3-D structure and
pedunculated
100-5000
30-40 yrs
Yes
Yes
Yes
Yes
Yes
Yes
FAP variants
AFAP
MAP
APC (5’-end)
Autosomal
dominant
flat
MUTYH
Autosomal
recessive
flat
10-100
40-50 yrs
No
Rare
No
No
No
No
5-50
50-70 yrs
No
No
Rare
No
No
No
S19
cording to surveys conducted in the Greek population,
despite its genetic heterogeneity, there is a mutation
cluster region which is located within exon 20 of the
BRCA1 gene. Figure 4 illustrates a graphic representation of the mutational spectrum in Greek population.
Two mutations were identified as the most frequently
encountered in the Greek population: 5382insC and the
missense G1738R. The latter one seems to be a Greek
founder mutation according to the results of haplotype
analysis. Hence, sequencing of exon 20 of BRCA1 gene
is proposed as the first step in a mutation screening protocol adjusted to the distinct mutation spectrum of the
Greek population [38]. In addition, genomic rearrangements have been shown to account for approximately
10% of the BRCA1 mutations in Greek patients with
breast and ovarian cancer family history and therefore,
screening for genomic rearrangements in the BRCA1
gene seems to be worthwhile in the Greek population
[39]. Other populations are also characterized by the
presence of particular pathogenic germline mutations
in BRCA1 and BRCA2 genes, such as Ashkenazi Jews,
Icelanders and Norwegians. Screening for the particular
alterations has been incorporated in the routine clinical
practice as far as high-risk patients are concerned [38].
Certain clinical criteria have been developed for the
selection of the appropriate candidates for genetic testing
for BRCA1 or BRCA2 mutations (Box 3) [32]. Figure 5
depicts an indicative of HBOC syndrome pedigree. The
following mathematical models were also developed to
predict carrier likelihood and cancer risks:
• The BRCAPRO model calculates the probability of
each family member to carry a germline mutation
in BRCA1 and BRCA2 genes. It is based on data regarding mutation prevalence and disease penetrance
proposed either from Claus et al. [40,41] or from
Ford et al. [42].
• The MENDEL algorithm estimates cancer risk based on locus and pedigree information, which is
Figure 4. Mutational spectrum of BRCA1 and BRCA2 genes found in Greek families with history of breast and/or ovarian cancer. Red
bars show mutation positions along the BRCA1 gene, with height relative to times found.
S20
Box 3: Criteria for BRCA gene mutation analysis
• Multiple cases of breast cancer (particularly where diagnosis
occurred <50 years) and /or ovarian cancer (any age) in the
family in more than one generation
• One woman with breast cancer <40 years
• A family member with both breast and ovarian cancer
• Breast and/or ovarian cancer in Askenazi Jewish families
• Family member(s) with primary cancer in bilateral breast
cancer (one or both <50 years)
• A family member with invasive serous ovarian cancer at any
age
• One person with breast or ovarian cancer <50 years and a
second BRCA-related cancer at any age (breast, ovarian,
endometrial, bowel, gastric, biliary, pancreatic, prostate,
melanoma, sarcoma)
• One first-degree male relative with breast cancer at any age
Figure 5. A typical pedigree of hereditary breast/ovarian cancer.
The arrow indicates the proband.
available at http://www.genetics.ucla.edu/software/mendel.html [43].
BRCA1-related cancers seem to possess some
distinct pathological features, whereas BRCA2-related cancers have the tendency to resemble sporadic
cancers. BRCA1-related breast cancers are commonly
high grade infiltrating ductal carcinomas and are characterized as estrogen receptor, progesterone receptor
and HER2 or p27kip negative. In addition, they usually
express high levels of p53, cytokeratin and cyclin E,
while on the other hand, BRCA2-related cancers over-
express cyclin D1, more commonly found in sporadic
tumor specimens.
It is noteworthy that women with BRCA1 mutations, and especially those with node-negative disease,
seem to have worse survival than BRCA2 mutation
carriers or mutation-negative patients. Indeed, there
is only a weak relation between the size of the primary
cancer and the number of infiltrated axillary lymph
nodes. This provides an explanation to the fact that the
pathological stage at diagnosis in BRCA1 cases shows
weak or no association with survival. Hence, the timely
identification of the mutational status of a woman who
belongs to the high-risk group, when it comes to developing breast or ovarian cancer, is essential for her
further clinical management [31,44].
Salpingo-oophorectomy is well established as an
efficient prophylactic procedure in both BRCA1 and
BRCA2 mutation carriers. Moreover, this procedure
has been proven to have a protective effect with regard
to breast cancer development, by reducing the risk as
much as 60% for the particular type of cancer and it is
strongly advised to female carriers after completing
childbearing. As far as the use of tamoxifen in BRCA1
and BRCA2 mutation carriers is concerned, its protective effect is still under debate [45].
Conclusion
The collaboration between clinicians and geneticists could lead to a significant reduction of morbidity
and mortality from hereditary forms of cancer. If a
clinician accomplishes to classify an individual in
a “high-risk” group based on her/his family history,
genetic counseling should be offered to her/him. Then,
if the individual is willing to undertake the appropriate
genetic tests, the initial clinical risk classification may
be verified or not. Once a pathogenic germline mutation is identified, the opportunity to choose between
an intense surveillance program and a prophylactic
treatment (surgical mostly) will be offered to the carrier. The offered options should be based on detailed
clinical data about the benefits and the drawbacks of
the required procedures. The family relatives can be
screened for the particular mutation or may receive an
assessment of their risk to develop a specific type of
cancer. This aims to support the right decision-making on whether to follow a tailored program for cancer
prevention or not.
Although the hereditary forms of cancer correspond to a relatively small percentage of cancer incidents when compared to the total number of cancer
cases, there are still many aspects of the genetic basis of
cancer to be explored. The so-called unclassified variants as well as common polymorphisms which confer
variable risks for the development of a specific cancer
S21
type, and the interplay amongst genes or between a gene
and environmental factors that may function as modifiers of the penetrance of specific genetic alterations still
remain to be elucidated.
15.
16.
Acknowledgements
This work is funded by 75% from the European
Union - European Social Fund (E.S.F) and by 25%
from the Greek Ministry of Development - General
Secretary for Research & Technology (GSRT) and the
private sector in the frame of Measure 8.3 of the Operational Program - Competitiveness - 3rd Framework
program.
17.
18.
19.
20.
21.
References
22.
1. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N
Engl J Med 2003; 348: 919-31.
2. Potter JD. Colorectal cancer: molecules and populations. J
Natl Cancer Inst 1999; 91: 916-932.
3. Ford D, Easton DF, Peto J. Estimates of the gene frequency
of BRCA1 and its contribution to breast and ovarian cancer
incidence. Am J Hum Genet 1995; 57: 1457-1462.
4. de la Chapelle A. Genetic predisposition to colorectal cancer.
Nat Rev Cancer 2004; 4: 769-780.
5. Jarvinen HJ. Hereditary cancer: guidelines in clinical practice.
Colorectal cancer genetics. Ann Oncol 2004; 15 (Suppl 4):
iv127-131.
6. Peltomaki P, Vasen H. Mutations associated with HNPCC
predisposition - Update of ICG-HNPCC/INSiGHT mutation
database. Dis Markers 2004; 20: 269-276.
7. Plaschke J, Engel C, Kruger S et al. Lower incidence of
colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared
with families with MLH1 or MSH2 mutations: The German
Hereditary Nonpolyposis Colorectal Cancer Consortium. J
Clin Oncol 2004; 22: 4486-4494.
8. Pinto C, Veiga I, Pinheiro M et al. MSH6 germline mutations
in early-onset colorectal cancer patients without family history of the disease. Br J Cancer 2006; 95: 752-756.
9. Barnetson RA, Tenesa A, Farrington SM et al. Identification
and survival of carriers of mutations in DNA mismatch-repair
genes in colon cancer. N Engl J Med 2006; 354: 2751-2763.
10. Domingo E, Niessen RC, Oliveira C et al. BRAF-V600E is
not involved in the colorectal tumorigenesis of HNPCC in
patients with functional MLH1 and MSH2 genes. Oncogene
2005; 24: 3995-3998.
11. Domingo E, Laiho P, Ollikainen M et al. BRAF screening as
a low-cost effective strategy for simplifying HNPCC genetic
testing. J Med Genet 2004: 41: 664-668.
12. Ford JM, Whittemore AS. Predicting and preventing hereditary colorectal cancer. JAMA 2006; 296: 1521-1523.
13. Balmana J, Stockwell DH, Steyerberg EW et al. Prediction
of MLH1 and MSH2 mutations in Lynch syndrome. JAMA
2006; 296: 1469-1478.
14. Chen S, Wang W, Shing L et al. Prediction of germline muta-
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
tions and cancer risk in the Lynch syndrome. JAMA 2006;
296: 1479-1487.
Kinzler KW, Nilbert MC, Su LK et al. Identification of FAP
locus genes from chromosome 5q21.Science 1991; 253:
661-665.
Fearnhead NS, Britton MP, Bodmer WF. The ABC of APC.
Hum Mol Genet 2001; 10: 721-733.
Nishisho I, Nakamura Y, Miyoshi Y et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients.
Science 1991; 253: 665-669.
Galiatsatos P, Foulkes WD. Familial adenomatous polyposis.
Am J Gastroenterol 2006; 101: 385-398.
Ficari F, Cama A, Valanzano R et al. APC gene mutations and
colorectal adenomatosis in familial adenomatous polyposis.
Br J Cancer 2000; 82: 348-353.
Truta B, Allen BA, Conrad PG et al. Genotype and phenotype
of patients with both familial adenomatous polyposis and
thyroid carcinoma. Fam Cancer 2003; 2: 95-99.
Giardiello FM, Petersen GM, Brensinger JD et al. Hepatoblastoma and APC gene mutation in familial adenomatous
polyposis. Gut 1996; 39: 867-873.
Arvanitis ML, Jagelman DG, Fazio VW et al. Mortality in
patients with familial adenomatous polyposis. Dis Colon
Rectum 1990; 33: 639-642.
Bisgaard ML, Bulow S. Familial adenomatous polyposis
(FAP): genotype correlation to FAP phenotype with osteomas
and sebaceous cysts. Am J Med Genet 2006; 140: 200-204.
Attard TM, Giglio P, Koppula S, Snyder C, Lynch HT. Brain
tumors in individuals with familial adenomatous polyposis:
a cancer registry experience and pooled case report analysis.
Cancer 2007; 109: 761-766.
Shields CL, Mashayekhi A, Ho T et al. Solitary congenital hypertrophy of the retinal pigment epithelium: clinical features
and frequency of enlargement in 330 patients. Ophthalmology
2003; 110: 1968-1976.
Lynch HT, Smyrk T, McGinn T et al. Attenuated familial
adenomatous polyposis (AFAP). A phenotypically and
genotypically distinctive variant of FAP. Cancer 1995; 76:
2427-2433.
Sampson JR, Jones S, Dolwani S, Cheadle JP. MutYH (MYH)
and colorectal cancer. Biochem Soc Trans 2005; 33: 679-683.
Caspari R, Olschwang S, Friedl W et al. Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic
lesions (CHRPE) associated with APC mutations beyond
codon 1444. Hum Mol Genet 1995; 4: 337-340.
Steinbach G, Lynch PM, Phillips RK et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous
polyposis. N Engl J Med 2000; 342: 1946-1952.
Bermejo-Perez MJ, Marquez-Calderon S, LIanos-Mendez A.
Effectiveness of preventive interventions in BRCA1/2 gene
mutation carriers : A systematic review. Int J Cancer 2007;
121: 225-231.
Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and
beyond. Nat Rev Cancer 2004; 4: 665-676.
James PA, Doherty R, Harris M et al. Optimal selection of
individuals for BRCA mutation testing: A comparison of
available methods. J Clin Oncol 2006; 24: 707-715.
Wooster R, Weber BL. Breast and ovarian cancer. N Engl J
Med 2003; 348: 2339-2347.
Chen S, Parmigianni G. Meta-analysis of BRCA1 and
BRCA2 penetrance, J Clin Oncol 2007; 25: 1329-1333.
Walsh T, King MC. Ten genes for inherited breast cancer.
S22
Cancer Cell 2007; 11: 103-105.
36. Easton DF, Pooley KA, Dunning AM et al. Genome-wide
association study identifies novel breast cancer susceptibility
loci. Nature 2007; 447: 1087-1093.
37. Cox A, Dunning AM, Garcia-Closas M et al. A common
coding variant in CASP8 is associated with breast cancer
risk. Nat Genet 2007; 39: 352-358.
38. Konstantopoulou I, Rampias T, Ladopoulou A et al. Greek
BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers among high-risk breast/
ovarian cancer patients. Breast Cancer Res Treat 2007; Apr
24 [Epub ahead of print].
39. Armaou S, Konstantopoulou I, Anagnostopoulos T et al.
Novel genomic rearrangements in the BRCA1 gene detected
in Greek breast/ovarian cancer patients. Eur J Cancer 2007;
43: 443-453.
40. Claus EB, Risch N, Thompson WD. Genetic analysis of breast
41.
42.
43.
44.
45.
cancer in the cancer and steroid hormone study. Am J Hum
Genet 1991; 48: 232-242.
Claus RB, Risch N, Thompson WD. Autosomal dominant
inheritance of early-onset breast cancer. Implications for risk
prediction. Cancer 1994; 73: 643-651.
Ford D, Easton DF, Stratton M et al. Genetic heterogeneity
and penetrance analysis of the BRCA1 and BRCA2 genes
in breast cancer families.The Breast Cancer Linkage Consortium. Am J Hum Genet 1998; 62: 676-689.
Fasching PA, Bani MR, Nestle-Kramling C et al. Evaluation
of mathematical models for breast cancer risk assessment in
routine clinical use. Eur J Cancer Prev 2007; 16: 216-224.
Foulkes WD. BRCA1 and BRCA2: Chemosensitivity, treatment,
outcomes and prognosis. Fam Cancer 2006; 5: 135-142.
Moller P, Evans DG, Reis MM et al. Surveillance for familial
breast cancer: Differences in outcome according to BRCA
mutation status. Int J Cancer 2007; 121: 1017-1020.