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HUMAN MOLECULAR GENETICS
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Oxford Journals
Life Sciences & Medicine
Human Molecular Genetics
Volume13, Issuesuppl 2
Pp. R177-R185.
o Zoe Kemp,
o Cristina Thirlwell,
o Oliver Sieber,
o Andrew Silver,
o and Ian Tomlinson
An update on the genetics of colorectal cancer Hum. Mol. Genet.
(2004) 13(suppl 2): R177-R185 doi:10.1093/hmg/ddh247
1. Hum. Mol. Genet. (2004) 13 (suppl 2): R177-R185. doi:
10.1093/hmg/ddh247 An update on the genetics
of colorectal cancer
Next Section
Abstract
Colorectal carcinoma (CRC) remains a frequent cause of cancer-associated mortality in
the UK and still has a relatively poor outcome. Single gene defects account for up to 2–6%
of cases, but twin studies suggest a hereditary component in 35%. CRC represents a
paradigm for cancer genetics. Almost all the major-gene influences on CRC have been
identified, and the identification of the remaining susceptibility alleles is proving
troublesome. Only a few low-penetrance alleles, such as methylene tetrahydrofolate
reductase C677T, appear convincingly to be associated with CRC risk. To identify the
remaining CRC genes, parallel approaches, including strategies based on linkage and
association and complementary analyses such as searches for modifier genes, must be
2. employed. To gain sufficient evidence to prove that a gene is involved in CRC
predisposition, it is probably necessary for multiple, adequately-powered studies to
demonstrate an association with the disease, especially if the allelic variants have only a
small differential effect on risk. It may also be possible to show how genes interact with
each other and the environment, although this will be even more difficult. Accurate
quantitation of the allele-specific risks in different populations will be necessary, but
problematic, especially if those risks combine in a fashion which is not of a
straightforward additive or multiplicative type. Without any good prior evidence of the
nature of the remaining genetic influence on CRC, the possibility remains that this is a
truly polygenic trait or that multiple, rare variants contribute to the increased risk; in
these cases, identification of the genes involved will be very difficult. Despite these
potential problems, the effectiveness of preventive measures for CRC, especially in high-
risk individuals, means that the search for new predisposition genes is justified.
Previous SectionNext Section
Colorectal cancer (CRC) is the third most common cause of cancer-related death in the
western world. The annual incidence in the United Kingdom is 35 000, and worldwide it
has been estimated to be at least half a million. There exists a number of syndromes with
Mendelian dominant inheritance in which there is a primary predisposition to benign or
malignant tumours of the large bowel (Table 1). Familial adenomatous polyposis (FAP)
patients inherit a mutated copy of the adenomatous polyposis gene ( APC), whereas
hereditary non-polyposis colon cancer (HNPCC) is caused by inheritance of defective DNA
mismatch repair genes (MLH1, MSH2, PMS2 and MSH6). Germline mutations of the
LKB1/STK11 gene have been shown to cause the Peutz–Jeghers syndrome (PJS), and
mutation of SMAD4 or ALK3 underly juvenile polyposis (JPS). In contrast, the MYH-
associated polyposis (MAP) syndrome has autosomal recessive inheritance and results
from bi-allelic mutations in the MYH gene.
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Table 1.
Genes responsible for known polyposis and CRC syndromes
Taken together, these syndromes account only for ∼2–6% of CRC cases. The great
majority of CRCs do not have a recognizable inherited cause, but a number of studies
have suggested a role for genetic factors in predisposition to a substantial minority of
colorectal tumours. The relatives of patients with ‘sporadic’ CRC are themselves at
increased risk of the disease and segregation analysis has suggested dominant
inheritance of the uncharacterized susceptibility genes (1–3). The relative risk in siblings
of affected individuals is 2–3-fold increased for both colorectal adenomas and CRC, the
risk being higher in relatives of patients diagnosed young, and in those with two or more
affected family members. In addition, an extensive analysis of twins has suggested that
35% of CRCs arise through inherited factors (4). Although some high and moderate
penetrance genes are probably undiscovered, inherited predisposition to CRC in humans
is more likely to be the result of low-penetrance alleles at several or many genetic loci. In
support of this contention, experimental data from rodent models have demonstrated
3. that numerous genes with relatively small effects control susceptibility to cancer
including CRC (reviewed in 5). Furthermore, hereditary factors may influence the severity
of the disease in the Mendelian CRC syndromes, as exemplified by the number of
colorectal polyps presenting within FAP families or in individuals with identical germline
APC mutations (6).
There are two factors that, in combination, make the search for additional CRC
predisposition genes so important. First, identification and removal of colorectal
adenomas (and possibly other types of bowel polyp) almost certainly greatly reduce
cancer incidence; identification of cancers before they present clinically may have similar
benefits. Second, regular, frequent and effective screening for colorectal tumours is not
currently available at the population level. The identification of controlling genetic factors
therefore allows individual cancer risk assessment and the targeting of screening to
those at highest risk; there may also be spin-offs in terms of effective chemoprevention
and the development of new therapies. The challenge, therefore, is to identify all the
relevant genes, and to specify their contribution in controlling CRC predisposition and
severity in human populations. A major part of this challenge is to choose the most
appropriate methods to locate and identify novel susceptibility genes.
In this short review, we shall detail some of the recent developments in the study of
inherited susceptibility to CRC. Progress has been made in the understanding of the
Mendelian syndromes and towards the identification of the small number of remaining
high-penetrance CRC genes. We shall also present recent evidence for low-penetrance
CRC alleles and for modifier genes of the Mendelian syndromes' phenotypes. We
complete our review by outlining future strategies for use in the continued search for
genes predisposing to CRC.
Previous SectionNext Section
PROGRESS IN UNDERSTANDING THE HEREDITARY
COLORECTAL TUMOUR SYNDROMES
MYH-associated polyposis
MYH is a DNA glycosylase involved in the response to oxidative damage of DNA by base
excision repair (BER). MYH was identified as a recessive CRC and adenoma predisposition
gene by Al-Tassan et al. (7), who found an unusual somatic APC mutation spectrum
(mostly G→T changes) in the polyps of a family that they were investigating for the
pathogenic effects of the APC missense variant E1317Q. The MAP phenotype generally
resembles attenuated (<100 adenomas) or mild, classical (100–1000 adenomas) FAP (8),
although MAP tumours seem to be confined to the gastrointestinal tract. MAP individuals
with early-onset CRC but no detected colorectal adenomas have been reported (9),
although small adenomas can be missed using colonoscopy without dye-spray. MAP
accounts for about 1% of all CRCs and one-third of patients with 15–100 colorectal
adenomas (8,10). MYH screening should be considered in patients with multiple
colorectal adenomas, although APC remains as a much stronger candidate in families
with vertical transmission of disease. Testing MYH in patients with early-onset CRC and
no adenomas would be justified if further data support those of Wang et al. (9). Mutation
testing should be tailored to the ethnic group, with mutations Y165C and G382D more
common in Caucasians, Y90X in Pakistanis, E466X in Indians and nt1395delGGA in those
of Mediterranean origin (10–13). The site-specific nature of MAP tumours remains
4. puzzling. BER deficiency does not specifically target APC and many MAP tumours harbour
specific G→T changes in K-ras (14). The few MAP cancers studied so far are
microsatellite-stable and near-diploid (14).
AXIN2
Apart from APC, studies have generally failed to find germline mutations in other
components of the Wnt pathway (such as beta-catenin, APC2, axin, conductin (axin2) and
glycogen synthase kinase 3-beta) in patients with multiple or early-onset colorectal
tumours (15). Recently, however, a Finnish family with dominantly-transmitted
oligodontia and colorectal polyps was shown to carry a germline R656X mutation in
AXIN2 (16). The colorectal phenotype in the family was highly variable, ranging from 68
adenomas through 10 hyperplastic polyps to no disease. Loss of the wild-type AXIN2
allele was not tested in the polyps.
Peutz–Jeghers syndrome
Germline mutations of the serine/threonine kinase gene LKB1(STK11) cause PJS. PJS
patients develop harmatomatous polyps of the gastrointestinal tract, and characteristic
freckling, and are at increased risk of colorectal and other cancers. LKB1 has been
reported to function in a variety of pathways, including those involving mTOR/AMP-
activated protein kinase, Wnt, COX2, NF-kappaB, VEGF, cell polarity and p53 (17–25). It
remains to be seen whether mutations in such genes play a role in PJS. From a strictly
genetic perspective, there is ongoing controversy as to the existence of a second PJS
locus, primarily because LKB1 mutations cannot be found in 30–80% of PJS patients. PJS
kindreds unlinked to LKB1 (26) and some linked to 19q13 (27) have been reported, but
no second locus has been identified. In this regard, it should be noted that, although PJS
polyps are probably pathognomic, several conditions have pigmented lesions that may
mimic PJS (28).
Hereditary non-polyposis CRC
Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant disorder
characterized by early-onset CRC (often right-sided), few adenomas and specific extra-
colonic cancers, including those of the ovary, stomach, small bowel and uroepithelial
tract. HNPCC accounts for 1–5% of CRCs and results from germline mutations in MLH1
and MSH2 in about 90% of cases and more rarely in PMS2 and MSH6 (remaining 10% of
cases). HNPCC cancers are characterized by microsatellite instability (MSI). The MMR
genes are not mutated in sporadic CRCs, although MLH1 is silenced by promoter
methylation in 10–15% of these tumours, most of which are right-sided and tend to occur
in older females. In the light of these data, Suter et al. (29) hypothesized that methylation
of the MLH1 promoter could occur in the germline and act as an alternative to mutation
in predisposing to HNPCC. They found evidence of such a MLH1 ‘epimutation’ in two
patients with multiple, MSI+ primary tumours which showed mismatch repair deficiency.
The epimutation occurred as a mosaic and was also present in spermatozoa of one of the
individuals, indicating a germline defect and the potential for transmission to offspring. It
was not clear whether an uncharacterized, primary genetic defect had led to the
epimutation. Other workers have focussed on the role of additional MMR genes in the
HNPCC families, with evidence that MLH3 (30–32) and EXO1 (33–36) might be involved in
a small number of cases, although data are inconsistent. There is also accumulating
evidence to show that the genetic pathways of sporadic, MSI+ CRCs and HNPCC CRCs are
non-identical. Johnson et al. (37), for example, showed that beta-catenin mutations were
5. specific to MSI+ carcinomas from HNPCC, but were rare in the HNPCC adenomas,
suggesting that Wnt activation was not always an early event in HNPCC tumorigenesis.
Two further issues the functions of MMR proteins outside simple DNA repair (38) and
whether or not MMR loss initiates tumorigenesis in HNPCC, remain under close scrutiny.
Familial adenomatous polyposis and APC modifier genes
FAP is caused by germline APC mutations. Affected individuals develop hundreds to
thousands of adenomatous colorectal polyps during the second and third decades,
progressing to cancer in nearly 100% of cases without treatment. Specific extra-colonic
features exist (39). We shall focus on three aspects of recent FAP research. First, it is
clear, in both FAP and sporadic CRCs, that APC is not a simple tumour suppressor gene:
the ‘two hits’ are strongly associated in terms of their location within the gene (39–42).
This association probably provides an optimal level of Wnt signalling for tumour growth,
mediated through beta-catenin levels. The mutation spectrum, and presumably optimal
level of Wnt signalling, varies among tissues (40,43). The ‘first hit–second hit’ association
at APC has also provided a new mechanism for determining disease severity (40), given
that certain ‘second hits’ such as allelic loss probably occur spontaneously at a relatively
high frequency and are only selected in certain FAP patients (with mutations close to
codon 1300), who consequently have severe disease. Second, clues have emerged as to
the cause of attenuated disease (AFAP, AAPC) in individuals with germline APC mutations
in exons 1–4, 9 and the latter half of exon 15, owing to the discovery of ‘third hits’ in the
tumours of some of these patients (44). In order to explain the paradox that a
requirement for ‘third hits’ should in theory cause AFAP patients to have no more
tumours than the general population, Su et al. (45) suggested that a broader spectrum of
somatic mutations was selected in AFAP individuals than in those with no germline APC
mutation (although their model was not placed in the context of the ‘first hit–second hit’
associations described earlier). Third, the site of the germline APC mutations cannot
explain all the phenotypic variation which is seen in FAP and AFAP. It is likely that
modifier genes distinct from APC influence features such as the number of tumours in
each region of the gastrointestinal tract (46), the development of desmoids (47) and
progression to cancer. In ApcMin mice, a modifier gene, Mom1/Pla2g2a, influences polyp
number (48–50). FAP modifier genes in humans are likely to be common polymorphisms,
and candidate gene approaches have been used to analyse these. One study has
suggested effects of polymorphisms in the N-acetyltransferases (NAT1 and NAT2) on
polyp numbers in FAP (51).
APC I1307K
The APC I1307K variant is present in about 6% of Ashkenazi Jews, but is much rarer in
those of other ethnic groups. I1307K creates an A8 tract that appears to be somatically
unstable, leading to frameshift mutations (52). Originally, I1307K was proposed to lead
to an AFAP-like phenotype, although extra-colonic disease does not appear to feature in
this group. Recent data have shown that APC I1307K only confers a small excess risk of
CRC (53), inconsistent prima facie with an AFAP-like phenotype. Moreover, only a
minority of colorectal tumours from I1307K carriers shows slippage of the A 8 tract. It may
be the case, therefore, that although the 1307K allele is somewhat unstable, this effect is
subtle in most carriers; only some individuals, perhaps with an unidentified, additional
germline factor, go on to develop an AFAP-like phenotype (54).
Previous SectionNext Section
6. RECENT DEVELOPMENTS THROUGH LINKAGE
ANALYSIS
Hereditary mixed polyposis syndrome
Hereditary mixed polyposis syndrome (HMPS) was described as a distinct syndrome of
colorectal adenomas, hyperplastic polyps, atypical ‘mixed’ polyps and carcinoma by
Whitelaw et al. (55) in a large Ashkenazi family. The extra-colonic features of FAP and the
typical features of PJS were absent. The phenotype had limited similarity to JPS. Linkage
of HMPS to chromosome 6q16–q21 was demonstrated by Thomas et al. (56). Tomlinson
et al. (57) showed linkage to chromosome 15q14–q15 (CRAC1 locus) in another
Ashkenazi family with multiple colorectal adenomas (including serrated lesions) and CRC.
The development of multiple adenomas in a HMPS individual without the disease-
associated haplotype led to the reassignment and stricter implementation of affection
status in that family in order to minimize the phenocopy rate. Subsequent linkage
analysis showed HMPS and CRAC1 to be one-and-the-same (58). Affected individuals in
these families and in several other Ashkenazi kindreds with a similar phenotype were
shown to share an ancestral haplotype between D15S1030 and D15S118. The gene itself
is, as yet, unidentified and its influence in other population groups, undetermined.
A CRC locus on chromosome 9q?
Wiesner et al. (59) undertook linkage analysis using the affected sibling pair method in
53 families with individuals affected at <65 years of age by CRC or adenomas (>1 cm or
displaying high-grade dysplasia). Six potential loci were identified with excess allele
sharing among concordantly affected sib-pairs (P<0.016). Of these, a region on
chromosome 9 gave a significant result when additionally examined for deficient allele
sharing among discordant sib pairs (P=0.014). The Haseman–Elston regression method
provided an overall probability of linkage of P=0.00045.
Previous SectionNext Section
EVIDENCE FOR LOW-PENETRANCE ALLELES
ASSOCIATED WITH AN INCREASED RISK OF CRC
Some high- or moderate-penetrance CRC predisposition genes remain to be detected
and their pursuit is of great importance. It is generally believed, nevertheless, that low-
penetrance variants, such as common alleles at SNPs, are responsible for much of the
uncharacterized inherited influence on CRC. Many different SNPs and other common
polymorphisms have been evaluated for their effects on CRC risk, and space precludes
detailed descriptions or analysis here. Case–control (association) analysis has been used
most frequently. Such studies have often been criticized, some of the reasons being the
following:
sample sizes produce insufficient statistical power;
cases and controls are inappropriately chosen;
statistical thresholds are chosen with insufficient rigour, so that most
reported associations are inevitably false (60);
the ‘multiple testing’ problem and tendency to inappropriate sub-group
analyses are endemic;
7. publication bias remains problematic, even though methods have been
developed to assess this (61,62);
studies rarely attempt to replicate their findings in the same population;
findings which are not replicated in different populations may be
inappropriately dismissed;
the functional effects of variants have often not been clearly shown;
some methods, such as PCR–RFLP analysis, are prone to systematic error
unless control measures are carefully applied.
The recognition of these problems has arguably led to too pessimistic an attitude to
studies of low-penetrance variants as CRC susceptibility alleles. Most recent studies have
used larger, better defined populations of cases and controls, together with genotyping
methods with greater accuracy and throughput. Formal assessments of the roles of
several polymorphisms in CRC predisposition were made by Houlston and Tomlinson (63)
and by de Jong et al. (64). In summary, there is already good evidence to show that a
small number of polymorphisms is associated with a differential risk of CRC (Table 2).
These include methylene tetrahydrofolate reductase MTHFRC677T, H-ras VNTR rare
alleles and NAT2 alleles which cause a rapid acetylator phenotype. Other polymorphisms
have been tested (Table 2) and many are unproven, although in a small number of cases,
loci continue to be cited as being associated with CRC risk despite the evidence in their
favour being minimal.
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Table 2.
Summary of polymorphisms tested for association with differential CRC risk
Recent data have suggested that loss of imprinting (LOI) of the insulin-like growth factor
II (IGF2) in normal colonic mucosa and/or lymphocytes is indicative of increased CRC risk
(89–92). It has been suggested that IGF2 LOI is a genetically determined trait. It is not
clear whether the association between IGF2 LOI and CRC might be a direct effect of
increased IGF2 levels, or a marker of a general tendency to, for example,
hypomethylation or aberrant gene silencing.
Studies are increasingly testing risks associated with combinations of putative CRC
genes, or of genes and specific environments, although inherent problems of statistical
power mean that most of the reported associations of this type must currently be taken
as no more than suggestive. Even for the MTHFR polymorphisms, advice on dietary
modification so that folate intake is increased cannot yet be given reliably or with
confidence. A further question is whether or not a true CRC risk factor should affect the
risk of both rectal and colonic cancers, conditions that are usually treated as essentially
the same disease (albeit with some different molecular and clinical features) by
geneticists, but as different conditions by epidemiologists. Further studies are beginning
to test the influence of germline variation on factors other than disease susceptibility,
8. including the presenting features of CRCs, response to therapy and toxicity (including
pharmacogenetic analyses), and recurrence/survival.
In general, acceptance of a polymorphism as a CRC risk factor can only come through
repeated analysis by different studies and by consequent slow progress to a consensus
judgement. Accurate quantitation of the associated risk will be just as important as its
identification in the first place, and this will require multiple studies in individual
populations which may differ in genetic background, environment and availability of
screening and medical care. Quantitation of risks associated with variants at multiple
predisposition loci will be even more difficult, especially if risks do not combine in a
simple additive or multiplicative manner, yet if testing for low-penetrance alleles is to
come into routine clinical practice, such risks must be determined.
Without any good prior evidence of the nature of the remaining genetic influence on CRC,
the possibility remains that it is a truly polygenic trait in which risks associated with any
single polymorphism are so low that identification of the genes involved (and their
testing in clinical practice) will be very difficult. This is, perhaps, the worst case scenario.
An alternative is that multiple, rare variants may contribute to the increased familial risk
of CRC: in this case, identification of the variants will be possible through mutation
screening methods, although evaluation of their functional importance will be time-
consuming. The case of the sub-polymorphic variant APCE1317Q provides a case in point
(93–97); it currently seems likely that this variant, which was discovered by mutation
screening, has little functional effect, although ‘closing the door’ on such a variant is not
easy. Nevertheless, the modestly increased risk of breast cancer associated with the
CHEK2del1100C sub-polymorphic variant (98) shows that important alleles of this type
do exist. (Any association between CHEK2del1100C and CRC remains controversial.)
Should many of the remaining CRC alleles prove to be of the low-frequency/low-risk
type, genetic testing in the clinical setting may not be worthwhile. Despite these potential
problems, however, the effectiveness of preventive measures for CRC, especially in high-
risk individuals, means that the search for new predisposition genes is justified.
Previous SectionNext Section
FUTURE STRATEGIES FOR IDENTIFYING CRC
PREDISPOSITION GENES
The successful detection of predisposition genes for cancer has largely been limited to
high-penetrance genes such as APC, BRCA1/2 and CDNK2A. Although the search for
low-penetrance genes has been informative in some other complex diseases, for
example, APOE-4 in Alzheimer's disease, those underlying cancer remain largely elusive.
The characteristics of cancer create obstacles. The usual late onset of CRC means parents
may be deceased and the disease is often fatal, making sample collection difficult. In
addition, the requirement of random somatic mutations for the progression to carcinoma
may cloud the picture. However, some of these problems can be circumvented by the
selection of early-onset cases to increase the genetic component and to reduce the
environmental component, and by the study of benign, precursor lesions.
The question therefore arises of which methods to use to detect novel cancer genes. In
our view, given that there are undoubtedly still high and moderate penetrance CRC genes
yet to be discovered, linkage analysis should certainly not be abandoned. The latter
would require the use of non-parametric methodology in view of genetic heterogeneity
9. and the existence of phenocopies. However, even for moderate penetrance genes, the
numbers of multi-case families required to yield results are large. For example, under a
dominant model with a gene frequency of 0.1 and a risk ratio of 6, about 500 affected sib
pairs or 20 affected sib trios would be needed to give a LOD score of 3.3 (99).
The increasing attention being given to association studies to identify CRC genes is
therefore justified. For CRC, these have previously been limited to examining the
frequency of alleles at candidate loci in cases and controls. However, the advent of SNP
maps has created the potential for genome-wide association (100). The power of these
studies, especially for rare alleles can be increased by using cases with a family history of
CRC (101) and by selecting in other ways for ‘genetic’ disease (for example, multiple
tumours, cancers of more than one site or early age of presentation). The detection of a
dominant gene with a frequency of 0.1 and a relative risk of 4 would require 200 cases
and 200 controls in an association study, but over 1000 affected sib pairs in a traditional
linkage analysis (99).
A more controversial area in the optimal design of association studies revolves around
the question of how many SNPs to use and whether the approach should be haplotype-
map or sequence based. Public and private SNP discovery projects report the
identification of 1.4 and 2.1 million SNPs, respectively, although the total is estimated
(102) to be about 15 million in reality. Obviously only a small proportion of these could
currently be genotyped in any association study. A map-based approach depends on
linkage disequilibrium occurring between blocks of haplotypes within which only a few
common haplotypes are observed and there is little evidence of historical recombination.
This allows the genome to be represented by a carefully chosen group of haplotype tag
SNPs (htSNPs) (103). The number of SNPs required will increase with the genetic diversity
of a population because of shorter haplotype blocks. For example, the International
HapMap Project has recently decided to add 2.25 million SNPs to the original 600 000 for
each of three population maps, owing to the longer evolutionary history of the Yuroban
(Nigerian) population (88). This approach will mainly detect alleles with a frequency of
≥5%. Advocates of a sequence-based approach argue that SNPs should be chosen on the
basis of their probable contribution to the phenotype. The focus of this approach is
therefore on coding regions and SNPs resulting in amino acid changes and/or SNPs found
in evolutionarily conserved areas. This would require far fewer SNPs (50 000–100 000) for
a genome-wide screen and would potentially detect lower frequency alleles (1–20%).
Botstein and Risch (102) have suggested that, at least initially, a ‘sequence-based’
approach on a selected 5% of the genome might provide the power to detect some of the
CRC-associated variants.
For identifying sub-polymorphic variants associated with disease, a mutation screening
strategy based on candidate genes (and followed if possible by a suitable association
study) is probably the only practical method for the short term. It remains to be seen
whether or not new technologies such as re-sequencing microarrays prove cost-effective
for research and diagnosis here. The requirement for functional studies will be
particularly important for sub-polymorphic variants, especially those which lead to
conserved amino acid changes, or affect splice sites, promoters or control regions.
Although it is hoped that linkage, association and mutation screening studies will yield
answers, the concurrent use of more indirect methods is prudent and may contribute to
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1. Hum. Mol. Genet. (2004) 13 (suppl 2): R177-R185. doi: 10.1093/hmg/ddh247
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3. PROGRESS IN UNDERSTANDING THE HEREDITARY COLORECTAL TUMOUR SYNDROMES
4. RECENT DEVELOPMENTS THROUGH LINKAGE ANALYSIS
5. EVIDENCE FOR LOW-PENETRANCE ALLELES ASSOCIATED WITH AN INCREASED RISK OF CRC
6. FUTURE STRATEGIES FOR IDENTIFYING CRC PREDISPOSITION GENES
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