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Chapter 1: Hereditary nonpolyposis colorectal cancer (HNPCC)
Colorectal cancer: hereditary and non-hereditary forms
Colorectal cancer is one of the most common cancers among both men and women. The
worldwide incidence and mortality rates for colorectal cancer vary markedly from country to
country and from region to region. Incidence and mortality are high in urban populations in
developed countries, in particular in North America, Northern and Western Europe and
Australia. In Eastern and Southern Europe the incidence is intermediate, while it is low in
Third World countries of South America (excluding Uruguay and Argentina), Asia and Africa
(Ron & Lubin, 1986). The average annual incidence rate for colonic cancer in the USA
(Connecticut, whites) over the period 1978-1982 was 34.1 per 100,000 inhabitants versus 1.8
in India (Madras). For rectal cancer the rate was 22.6 in Israel (born European and American)
versus 3.0 in Kuwait (Kuwaitis) (Fraumeni et al., 1989). The lifetime risk of colorectal cancer
among Caucasians in the Western countries is approximately 4% (Wijnen et al., 1998a). In
the Netherlands, the estimated lifetime risk for colorectal cancer is 5.7% in females and 4.7%
in males (Schouten et al., 1994). Approximately 8,000 new cases were registered in the
Netherlands in 1992, while the mortality due to colorectal cancer in the same year was about
4,000 (Visser et al., 1995).
The great majority of colorectal cancers is diagnosed after the age of 50 years. However,
cases before the age of 50 are seen as well. The only curative treatment for colorectal cancer is
surgery. In a proportion of patients results of treatment can be improved by radiotherapy,
chemotherapy and possibly immunotherapy. Prognosis of colorectal cancer in general
correlates well with both tumour stage and histological grade. Unfortunately, many tumours
present at a late stage, giving the patient a poor prognosis. Five year survival is from 50% to
60%. Consequently, colorectal cancer remains a major public health problem.
The causes of colorectal cancer appear multifactorial. Environmental factors such as diet
play a crucial role in the majority of cases in this disease process. For example, a diet high in
unsaturated fat and low in fibre content derived from fruits and vegetables appears to increase
the risk of developing colorectal cancer. Conversely, diets high in fibre content and low in fat
appear to provide some degree of protection against the colorectal cancer (Winawer et al.,
1997). An increased risk of colorectal cancer is associated with inflammatory bowel diseases
(ulcerative colitis, Crohn’s disease) (Lynch et al., 1997a). Besides environmental factors
genetic predispositions do play a role. There seems to be an overall increased risk to develop
colorectal cancer of approximately two to three-fold for individuals with one affected first
degree relative (Houlston et al., 1990; Fuches et al., 1994). According to present estimates,
between 10% and 20% of the total colorectal cancer burden is due to inherited colorectal
cancer syndromes (Lynch, 1998a) (Fig. 1). The majority of the hereditary colorectal cancer
are hereditary nonpolyposis colorectal cancer (HNPCC) with few colonic polyps and a
relatively young age of onset. The frequency of HNPCC is not precisely known, but estimates
range from 2% (Aaltonen et al., 1998) to 13% (Houlston et al., 1992) of all colorectal
cancers. A second colorectal cancer syndrome, familial adenomatous polyposis (FAP) with
multiple colonic polyps, accounts for less than 1% of the colorectal cancers (Lynch et al.,
1997b). In addition to FAP, there are several rare hereditary disorders in which colonic polyps
occur giving a higher risk of colorectal cancer, e.g. Peutz-Jeghers syndrome and Familial
FAP < 1%
HNPCC up to 13%
"familial aggregation"
of colorectal cancer
up to 20%
Sporadic colorectal
cancer > 66%
Figure 1. Distribution of hereditary and non-hereditary colorectal cancers
polyposis (Lynch et al., 1997a). Besides these hereditary cancer syndromes, there are families
(10%-20%) (Giardiello et al., 1997) with several members having colorectal cancer, but not
fulfilling the criteria for either HNPCC or other hereditary disorders predisposing to
colorectal cancer. Such pedigrees might be categorised as “familial aggregation” of colorectal
Hereditary nonpolyposis colorectal cancer (HNPCC)
Clinical characteristics
The history of the cancer syndrome now known as HNPCC dates back to 1895, when Aldred
S. Warthim was told by his seamstress that she would die of cancer of her bowels or female
organs because “most of my family members die of these cancers”. Indeed, she died of
endometrial carcinoma at young age. Endometrial carcinoma, along with gastric and
colorectal cancer, occurred repeatedly in her family. The family, known as family G, was
extensively studied by Warthin (1913), later by Hauser & Weller (1936), and Lynch (1966).
The significance of Warthin’s description was not fully realised until 1966, when the G
family and similar families were investigated by Lynch and co-workers. Where in Warthin’s
initial description, gastric carcinoma was the predominant cancer in the family, Lynch &
Krush (1971) reported predominance of colorectal cancers in association with extracolonic
tumours in different branches of this family. Based on the findings in the G family and
comparable families, the terms Lynch syndrome I and II were proposed (Boland & Troncale,
1984). In Lynch syndrome I colorectal cancer is the only cancer observed, whereas in Lynch
syndrome II besides colorectal cancer also tumours of other organs are present (Watson &
Lynch, 1993). Many investigators now believe, mainly because of current genetic findings,
that a clear distinction between these two syndromes cannot be made.
Based on a series of international collaborative studies the term hereditary nonpolyposis
colorectal cancer (HNPCC) was introduced in 1989 (Vasen et al., 1989). HNPCC is an
autosomal dominant inherited cancer syndrome which is clinically characterised by a family
history of colorectal cancer at early age, predominance of tumours in the proximal colon, a
high frequency of synchronous and metachronous colorectal cancers, and an association with
extracolorectal cancers (Table 1). The median age to develop colorectal cancer is 44 years
with a range of onset from 15 to 75 years, and a life time risk to develop colorectal cancer of
about 80% (Aarnio et al., 1995; Vasen et al., 1996).
Table 1. Features of colorectal carcinomas
Sporadic CRC
Age (yrs)a
Proximal locationa
Poorly differentiateda
Crohn’s-like reactiona
a: from Lynch & Smyrk (1996). b: from Fitzgibbons & Lynch (1987).
Although HNPCC is not associated with multiple colonic polyps, carcinomas in HNPCC
patients probably develop from pre-existing adenomas, via the so-called adenoma-carcinoma
sequence as proposed by Morson (1974). Patients with HNPCC have a higher incidence of
adenomas, mainly located in the more proximal portion of the colon, than sporadic cases
(Lanspa et al., 1990). In HNPCC patients, adenomas containing villous and tubulovillous
components develop at a younger age, and reach a larger size than adenomas in patients with
sporadic colorectal cancer (D’Emilia et al., 1995). Adenomas in patients with HNPCC also
seem to be more prone to malignant transformation and faster development from adenoma →
carcinoma than adenomas in non-hereditary cases.
Colorectal cancers in HNPCC patients have no histological features that precisely identify
them as HNPCC-associated, although certain histological findings have a higher prevalence
in individuals with HNPCC than in individuals with sporadic colorectal carcinomas (Mecklin
et al., 1986; Lynch et al., 1993; Jass et al., 1994). These findings include poor differentiation,
a higher proportion of signet-ring cell carcinomas, increased mucin production, and marked
host-lymphocytic infiltration and lymphoid aggregation around the tumour margin (Crohns’slike reaction) (Table 1).
Poor differentiation, a higher proportion of signet-ring cell, and increased mucin
production, are considered as signs of an aggressive tumour behaviour, whereas peritumoural
lymphoid response and a Crohn’s-like pattern might be indicative of a host defence
mechanism, suggesting a favourable prognosis. Although most carcinomas in HNPCC have
aggressive histological features, it has been suggested that the prognosis of HNPCC colorectal
cancers in general is better than that of sporadic cases (Jarvinen et al., 1995; Mecklin et al.,
1986; Merlo et al., 1996).
Apart from colorectal cancer, tumours of endometrium, small bowel, pancreas, biliary
tract, stomach, ovary, urinary tract and brain occur more frequently in HNPCC families and
are considered to be part of the HNPCC tumour spectrum (Table 2). An increased incidence of
breast cancer has been reported in female family members of HNPCC families (Itoh et al.,
1990; Risinger et al., 1996a). Obviously, due to the high incidence of breast cancer in the
general population, it is difficult to demonstrate an association of breast cancer and HNPCC.
Table 2. Extracolonic tumours in HNPCC
Endometrial cancer
Stomach cancer
Cancer of small bowel
Pancreatic cancer
Cancer of biliary tract
Ovarian cancer
MSIa found or not
Cancer of the urinary tract
Skin cancer
Brain tumours
Laryngeal cancer
Breast cancer
Second most common tumour in HNPCC
More common in older HNPCC patients
A rare tumour in HNPCC
Increased incidence in HNPCC
Increased incidence in HNPCC
Increased incidence in female members
of HNPCC families
Increased incidence in HNPCC
Skin lesions of Muir-Torre syndrome
a variant of HNPCC
Glioblastoma in some
HNPCC patients
Case report in one HNPCC family
Case reports in female members
of HNPCC families
a: microsatellite instability.
b: from Lynch et al., 1988; Itoh et al., 1990; Watson & Lynch, 1993; Hamilton et al., 1995;
Risinger et al., 1996a.
In HNPCC families the mean age of onset for endometrial tumours is 46 years, for stomach
cancer 54, and for cancer of the small intestine 53. In all instances, the mean age of cancer
onset in HNPCC is approximately 20 years lower than that of the same tumours in their
sporadic form (Watson et al., 1994; Aarnio et al., 1995).
There also are several syndromes which might be linked to HNPCC. Under the name MuirTorre syndrome a cancer syndrome is known, which is characterised by cutaneous tumour
manifestations in addition to the HNPCC tumour spectrum (Lynch et al., 1981). This
syndrome is now considered to be a subtype of HNPCC due to the genetic findings (Suspiro et
al., 1998). Furthermore, also Turcot syndrome (Turcot et al., 1959), characterised by brain
tumours within families with a high incidence of colorectal cancer, can be associated with
HNPCC, but it is also sometimes found associated with FAP. Interestingly, in combination
with HNPCC only glioblastoma is found, whereas other brain tumour types, especially
medulloblastoma, occur in association with FAP (Hamilton et al., 1995).
Diagnostic criteria
The International Collaborative Group on HNPCC (ICG-HNPCC) proposed a set of criteria
primarily for research purposes to define HNPCC, the so-called Amsterdam criteria (Vasen et
al., 1991). These criteria define HNPCC as follows: occurrence of histologically colorectal
cancer in at least three relatives (one of whom is a first-degree relative of the other two) in at
least two successive generations, and an age at onset of colorectal cancer of less than 50 years
in one of the relatives (Table 3). A substantial proportion of families, in which familial
polyposis is excluded, might be called HNPCC-suspected, as several but not all of the criteria
are met. The Amsterdam criteria for HNPCC have contributed enormously to uniformity in
diagnosis of this disease. It should be noted, however, that these criteria ignore certain
histopathological findings which seem to be more prevalent in HNPCC compared with
colorectal carcinoma in general, and that they also fail to acknowledge the contribution of
extracolonic cancers. In particular the fact that extracolonic tumours are not taken into
account, may lead to an underdiagnosis of the syndrome.
Table 3. Criteria for hereditary nonpolyposis colorectal cancer
Amsterdam criteria (Vasen et al., 1991)
1. The presence of histologically verified colorectal cancer in at least three relatives; one of
whom is a first-degree relative of the other two (the various polyposis syndromes must be
rule out)
2. The presence of the colorectal cancer in at least two successive generations
3. One of the relatives should be diagnosed at less than 50 years of age
Bethesda criteria (Rodriguez-Bigas et al., 1997)
1. Individuals with cancer in families that meet the Amsterdam criteria
2. Individuals with two HNPCC-related cancers, including synchronous and metachronous
colorectal cancers or associated extracolonic cancers
3. Individuals with colorectal cancer and a first-degree relative with colorectal cancer and /or
HNPCC-related extracolonic cancer and/or a colorectal adenoma: one of the cancers
diagnosed at age <45 y, and the adenoma diagnosed at age <40 y
4. Individuals with colorectal cancer or endometrial cancer diagnosed at age <45 y
5. Individuals with right-sided colorectal cancer with an undifferentiated pattern
(solid/cribriform) on histopathology diagnosed at age <45 y
6. Individuals with signet-ring-cell-type colorectal cancer diagnosed at age <45 y
7. Individuals with adenomas diagnosed at age <45 y
To overcome some of the disadvantages of the Amsterdam criteria, several groups have
proposed less restrictive clinical criteria, including the Japanese criteria (Kunitomo et al.,
1992) and the Korean criteria (Yuan et al., 1998). These criteria are dependent on both family
history and clinicopathological characteristics of the tumour and on the association with
extracolonic cancers. Recently, a group of investigators have developed a set of consensus
criteria, the so-called Bethesda criteria (Rodriguez-Bigas et al., 1997), which are mainly based
on recent genetic findings (Table 3).
Genetic dissection of HNPCC
The first clue which led to the identification of the genes involved in HNPCC was the
discovery of microsatellite instability (MSI) in sporadic and in familial colorectal carcinomas
(Aaltonen et al., 1993; Ionov et al., 1993; Thibodeau et al., 1993). Microsatellites are repeats
of very short nucleotide sequences (e.g. mono-, di-, tri-, tetra-nucleotide repeats), usually
repeated 10-50 times and in 100,000 copies distributed throughout the human genome. These
repeating sequences are highly polymorphic throughout the population, although their repeat
length is uniform in the DNA of all cells of an individual (for review see Marra & Boland,
1995). Instability of microsatellites is seen as band shifts in tumour DNA caused by the
somatic insertion or deletion of one or more copies of the repeat unit of a microsatellite. This
is believed to result from slippage by DNA polymerases during DNA replication (Kunkel,
1992). Since DNA replication is involved, MSI is also often referred to as replication errors
(RER) (Aaltonen et al., 1993).
A similar instability of microsatellites had previously been observed in bacteria and yeast
(Strand et al., 1993). The reason for this instability was a mismatch repair (MMR) defect. The
finding of MSI in colorectal tumours of HNPCC patients pointed, therefore, to a possible
involvement of MMR genes. Both positional cloning efforts and a search for human
homologues of the bacterial and yeast MMR genes were started to find the genes involved.
Linkage analysis led to the identification of the first HNPCC susceptibility locus on
chromosome 2p (Peltomäki et al., 1993a). Simultaneously two groups cloned a human
homologue of the bacterial MutS gene (Fishel et al., 1993; Leach et al., 1993). The gene,
termed hMSH2, mapped to the region of chromosome 2 previously linked to HNPCC and
germline mutations were identified in affected members of HNPCC families (Peltomäki et al.,
By linkage analysis it became apparent that on chromosome 3 there should be a second
major gene involved in a large proportion of HNPCC families. Several genes were discovered
which proved to be homologues of the bacterial MMR genes (Papadopoulos et al., 1994;
Bronner et al., 1994), and one of these, termed hMLH1, mapped on the short arm of
chromosome 3 close to markers previously linked with HNPCC (Nyström-Lahti et al., 1994a;
1994b). Also in this gene germline mutations were found in affected members of HNPCC
families (Papadopoulos et al., 1994).
In addition to hMSH2 and hMLH1, four other human MMR genes, named hMSH3 (also
designated DUG1 or Rep-3) (Lahue et al., 1989; Shinya & Shimada, 1994), hPMS1
(Nicolaides et al., 1994), hPMS2 (Nicolaides et al., 1994), and hMSH6 (also designated GTBP
or the p160 gene) (Palombo et al., 1995; Papadopoulos et al., 1995a; Drummond et al., 1995),
located on chromosomes 5q, 2q, 7p and 2p, respectively, have been identified. Proof that
hPMS1, hPMS2 and hMSH6 cause susceptibility to HNPCC was obtained by the finding of
germline mutations segregating with the disease phenotype in HNPCC families (Nicolaides et
al., 1994; Miyaki et al., 1997; Akiyama et al., 1997; Wu et al., submitted [Appendix 4]).
Germline mutations in hMSH3 have never been observed yet. However, somatic hMSH3
mutations have been identified in sporadic endometrial, colorectal and gastric carcinomas
(Risinger et al., 1996b; Jing et al., 1997).
Recently, a gene called hEXO1, encoding an exonuclease required for mismatch repair
(Tishkoff et al., 1998), and a new MutS homologue gene, hMSH5 (Her & Doggett, 1998) have
been identified. They are located on chromosomes 1q, and 6p, respectively. No germline
mutations have yet been reported.
Mismatch repair and cancer predisposition
According to the concept of Kinzler and Vogelstein (1996), genes involved in tumour
development can be subdivided into two groups, “gatekeepers” and “caretakers’. The
gatekeepers are directly involved in cell cycle regulation, their protein products control
tumour progression by promoting or inhibiting the processes associated with cell division. The
gatekeepers include well-known genes such as APC (adenomatous polyposis coli), DCC
(deleted in colon carcinoma), TGFßIIR (transforming growth factor ß II receptor). The
caretakers are involved in genomic stabilisation. Inactivation of caretaker proteins results in
genomic destabilisation, gives rise to an accumulation of mutations and enhances the
probability of mutation in the gatekeepers. The mismatch repair genes are a paradigm of
caretakers. Caretakers also include suppressor genes, such as TP53, whose products do not
directly operate in the DNA repair system, but take part in setting a “checking-point” for
DNA before admitting the cell to the next cell cycle stage.
As in almost all inherited cancers, a germline mutation of a single gene does not cause
neoplastic growth. Similar to tumour suppressor genes, the second allele of an MMR gene
also needs to be inactivated before uncontrolled cell growth will start. For patients from
HNPCC families it has been shown that in their tumours the wild-type allele is somatically
deleted or mutated (for review see Kolodner, 1995). In sporadic tumours, both alleles need to
be mutated (for review see Papadopoulos & Lindblom, 1997).
Although the loss of both copies of an MMR gene are required for tumour development,
the lack of an MMR protein in itself is not the direct cause of neoplastic growth. However,
through that lack, mutations are 102-fold to 103-fold more likely to occur at each round of
DNA replication (Loeb, 1991; 1994). As alterations accumulate, mutations will also hit
critical oncogenes and tumour suppressor genes without being repaired. Vogelstein and
colleagues (Vogelstein et al., 1988; Fearon & Vogelstein, 1990) developed a model that
described the accumulation of genetic events during the development of colorectal cancer,
including the loss of APC, DCC, and TP53 gene function and the dysregulated activation of
the KRAS proto-oncogene. The discovery of mismatch repair deficiency as the genetic basis of
HNPCC raised the possibility that development of HNPCC and of most sporadic colorectal
cancers may follow different genetic pathways. In sporadic colorectal cancer, inactivation of
tumour suppressor genes by loss of large chromosomal regions is a common event (Vogelstein
et al., 1988). In HNPCC tumour development, however, loss of heterozygosity is rarely
observed. Instead, functional allelic loss occurs by frameshift mutations (Thibodeau et al.,
1993; Konishi et al., 1996). Mutations of the APC, TP53, and KRAS genes that are common
in sporadic colorectal cancer occur less frequently in HNPCC tumours (Wu et al., 1994;
Konishi et al., 1996 ). Although an inverse relationship between microsatellite instability and
mutation of the APC, TP53, and KRAS genes has not been observed in all studies (Aaltonen et
al., 1993; Huang et al., 1996), the spectrum of somatic mutation of the APC gene in HNPCC
is significantly different from that in sporadic colorectal cancer (Huang et al., 1996). In
particular, frameshift mutations involving a polyadenine tract located in the coding sequence
of genes controlling cell growth, such as TGFßIIR (Markowitz et al., 1995), BAX (Rampino et
al., 1997), and insulin-like growth factor II receptor (IGFIIR) (Souza et al., 1996), have been
found in HNPCC-associated tumours with microsatellite instability. It is the inactivation of
the proteins encoded by these genes that ultimately gives rise to uncontrolled cell growth.