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  1. 1. Skip NavigationOxford Journals Contact Us My Basket My Account HUMAN MOLECULAR GENETICS About This Journal Contact This Journal Subscriptions View Current Issue (Volume 21 Issue 2 January 15, 2012) Archive Search Institution: Benghazi University Sign In as Personal Subscriber 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 geneticsof colorectal cancerNext SectionAbstractColorectal carcinoma (CRC) remains a frequent cause of cancer-associated mortality inthe 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 aparadigm for cancer genetics. Almost all the major-gene influences on CRC have beenidentified, and the identification of the remaining susceptibility alleles is provingtroublesome. Only a few low-penetrance alleles, such as methylene tetrahydrofolatereductase C677T, appear convincingly to be associated with CRC risk. To identify theremaining CRC genes, parallel approaches, including strategies based on linkage andassociation and complementary analyses such as searches for modifier genes, must be
  2. 2. employed. To gain sufficient evidence to prove that a gene is involved in CRCpredisposition, it is probably necessary for multiple, adequately-powered studies todemonstrate an association with the disease, especially if the allelic variants have only asmall differential effect on risk. It may also be possible to show how genes interact witheach other and the environment, although this will be even more difficult. Accuratequantitation of the allele-specific risks in different populations will be necessary, butproblematic, especially if those risks combine in a fashion which is not of astraightforward additive or multiplicative type. Without any good prior evidence of thenature of the remaining genetic influence on CRC, the possibility remains that this is atruly polygenic trait or that multiple, rare variants contribute to the increased risk; inthese cases, identification of the genes involved will be very difficult. Despite thesepotential 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 SectionColorectal cancer (CRC) is the third most common cause of cancer-related death in thewestern world. The annual incidence in the United Kingdom is 35 000, and worldwide ithas been estimated to be at least half a million. There exists a number of syndromes withMendelian dominant inheritance in which there is a primary predisposition to benign ormalignant tumours of the large bowel (Table 1). Familial adenomatous polyposis (FAP)patients inherit a mutated copy of the adenomatous polyposis gene ( APC), whereashereditary non-polyposis colon cancer (HNPCC) is caused by inheritance of defective DNAmismatch repair genes (MLH1, MSH2, PMS2 and MSH6). Germline mutations of theLKB1/STK11 gene have been shown to cause the Peutz–Jeghers syndrome (PJS), andmutation of SMAD4 or ALK3 underly juvenile polyposis (JPS). In contrast, the MYH-associated polyposis (MAP) syndrome has autosomal recessive inheritance and resultsfrom bi-allelic mutations in the MYH gene. View this table: In this window In a new windowTable 1.Genes responsible for known polyposis and CRC syndromesTaken together, these syndromes account only for ∼2–6% of CRC cases. The greatmajority of CRCs do not have a recognizable inherited cause, but a number of studieshave suggested a role for genetic factors in predisposition to a substantial minority ofcolorectal tumours. The relatives of patients with ‘sporadic’ CRC are themselves atincreased risk of the disease and segregation analysis has suggested dominantinheritance of the uncharacterized susceptibility genes (1–3). The relative risk in siblingsof affected individuals is 2–3-fold increased for both colorectal adenomas and CRC, therisk being higher in relatives of patients diagnosed young, and in those with two or moreaffected family members. In addition, an extensive analysis of twins has suggested that35% of CRCs arise through inherited factors (4). Although some high and moderatepenetrance genes are probably undiscovered, inherited predisposition to CRC in humansis more likely to be the result of low-penetrance alleles at several or many genetic loci. Insupport of this contention, experimental data from rodent models have demonstrated
  3. 3. that numerous genes with relatively small effects control susceptibility to cancerincluding CRC (reviewed in 5). Furthermore, hereditary factors may influence the severityof the disease in the Mendelian CRC syndromes, as exemplified by the number ofcolorectal polyps presenting within FAP families or in individuals with identical germlineAPC mutations (6).There are two factors that, in combination, make the search for additional CRCpredisposition genes so important. First, identification and removal of colorectaladenomas (and possibly other types of bowel polyp) almost certainly greatly reducecancer incidence; identification of cancers before they present clinically may have similarbenefits. Second, regular, frequent and effective screening for colorectal tumours is notcurrently available at the population level. The identification of controlling genetic factorstherefore allows individual cancer risk assessment and the targeting of screening tothose at highest risk; there may also be spin-offs in terms of effective chemopreventionand the development of new therapies. The challenge, therefore, is to identify all therelevant genes, and to specify their contribution in controlling CRC predisposition andseverity in human populations. A major part of this challenge is to choose the mostappropriate methods to locate and identify novel susceptibility genes.In this short review, we shall detail some of the recent developments in the study ofinherited susceptibility to CRC. Progress has been made in the understanding of theMendelian syndromes and towards the identification of the small number of remaininghigh-penetrance CRC genes. We shall also present recent evidence for low-penetranceCRC alleles and for modifier genes of the Mendelian syndromes phenotypes. Wecomplete our review by outlining future strategies for use in the continued search forgenes predisposing to CRC.Previous SectionNext SectionPROGRESS IN UNDERSTANDING THE HEREDITARYCOLORECTAL TUMOUR SYNDROMESMYH-associated polyposisMYH is a DNA glycosylase involved in the response to oxidative damage of DNA by baseexcision repair (BER). MYH was identified as a recessive CRC and adenoma predispositiongene 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 thepathogenic effects of the APC missense variant E1317Q. The MAP phenotype generallyresembles attenuated (<100 adenomas) or mild, classical (100–1000 adenomas) FAP (8),although MAP tumours seem to be confined to the gastrointestinal tract. MAP individualswith early-onset CRC but no detected colorectal adenomas have been reported (9),although small adenomas can be missed using colonoscopy without dye-spray. MAPaccounts for about 1% of all CRCs and one-third of patients with 15–100 colorectaladenomas (8,10). MYH screening should be considered in patients with multiplecolorectal adenomas, although APC remains as a much stronger candidate in familieswith vertical transmission of disease. Testing MYH in patients with early-onset CRC andno adenomas would be justified if further data support those of Wang et al. (9). Mutationtesting should be tailored to the ethnic group, with mutations Y165C and G382D morecommon in Caucasians, Y90X in Pakistanis, E466X in Indians and nt1395delGGA in thoseof Mediterranean origin (10–13). The site-specific nature of MAP tumours remains
  4. 4. puzzling. BER deficiency does not specifically target APC and many MAP tumours harbourspecific G→T changes in K-ras (14). The few MAP cancers studied so far aremicrosatellite-stable and near-diploid (14).AXIN2Apart from APC, studies have generally failed to find germline mutations in othercomponents of the Wnt pathway (such as beta-catenin, APC2, axin, conductin (axin2) andglycogen synthase kinase 3-beta) in patients with multiple or early-onset colorectaltumours (15). Recently, however, a Finnish family with dominantly-transmittedoligodontia and colorectal polyps was shown to carry a germline R656X mutation inAXIN2 (16). The colorectal phenotype in the family was highly variable, ranging from 68adenomas through 10 hyperplastic polyps to no disease. Loss of the wild-type AXIN2allele was not tested in the polyps.Peutz–Jeghers syndromeGermline mutations of the serine/threonine kinase gene LKB1(STK11) cause PJS. PJSpatients develop harmatomatous polyps of the gastrointestinal tract, and characteristicfreckling, and are at increased risk of colorectal and other cancers. LKB1 has beenreported 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). Itremains to be seen whether mutations in such genes play a role in PJS. From a strictlygenetic perspective, there is ongoing controversy as to the existence of a second PJSlocus, primarily because LKB1 mutations cannot be found in 30–80% of PJS patients. PJSkindreds unlinked to LKB1 (26) and some linked to 19q13 (27) have been reported, butno second locus has been identified. In this regard, it should be noted that, although PJSpolyps are probably pathognomic, several conditions have pigmented lesions that maymimic PJS (28).Hereditary non-polyposis CRCHereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant disordercharacterized by early-onset CRC (often right-sided), few adenomas and specific extra-colonic cancers, including those of the ovary, stomach, small bowel and uroepithelialtract. HNPCC accounts for 1–5% of CRCs and results from germline mutations in MLH1and MSH2 in about 90% of cases and more rarely in PMS2 and MSH6 (remaining 10% ofcases). HNPCC cancers are characterized by microsatellite instability (MSI). The MMRgenes are not mutated in sporadic CRCs, although MLH1 is silenced by promotermethylation in 10–15% of these tumours, most of which are right-sided and tend to occurin older females. In the light of these data, Suter et al. (29) hypothesized that methylationof the MLH1 promoter could occur in the germline and act as an alternative to mutationin predisposing to HNPCC. They found evidence of such a MLH1 ‘epimutation’ in twopatients 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 theindividuals, indicating a germline defect and the potential for transmission to offspring. Itwas not clear whether an uncharacterized, primary genetic defect had led to theepimutation. Other workers have focussed on the role of additional MMR genes in theHNPCC families, with evidence that MLH3 (30–32) and EXO1 (33–36) might be involved ina small number of cases, although data are inconsistent. There is also accumulatingevidence to show that the genetic pathways of sporadic, MSI+ CRCs and HNPCC CRCs arenon-identical. Johnson et al. (37), for example, showed that beta-catenin mutations were
  5. 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) andwhether or not MMR loss initiates tumorigenesis in HNPCC, remain under close scrutiny.Familial adenomatous polyposis and APC modifier genesFAP is caused by germline APC mutations. Affected individuals develop hundreds tothousands of adenomatous colorectal polyps during the second and third decades,progressing to cancer in nearly 100% of cases without treatment. Specific extra-colonicfeatures exist (39). We shall focus on three aspects of recent FAP research. First, it isclear, 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 optimallevel of Wnt signalling, varies among tissues (40,43). The ‘first hit–second hit’ associationat APC has also provided a new mechanism for determining disease severity (40), giventhat certain ‘second hits’ such as allelic loss probably occur spontaneously at a relativelyhigh frequency and are only selected in certain FAP patients (with mutations close tocodon 1300), who consequently have severe disease. Second, clues have emerged as tothe cause of attenuated disease (AFAP, AAPC) in individuals with germline APC mutationsin exons 1–4, 9 and the latter half of exon 15, owing to the discovery of ‘third hits’ in thetumours of some of these patients (44). In order to explain the paradox that arequirement for ‘third hits’ should in theory cause AFAP patients to have no moretumours than the general population, Su et al. (45) suggested that a broader spectrum ofsomatic mutations was selected in AFAP individuals than in those with no germline APCmutation (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 cannotexplain all the phenotypic variation which is seen in FAP and AFAP. It is likely thatmodifier genes distinct from APC influence features such as the number of tumours ineach region of the gastrointestinal tract (46), the development of desmoids (47) andprogression to cancer. In ApcMin mice, a modifier gene, Mom1/Pla2g2a, influences polypnumber (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 hassuggested effects of polymorphisms in the N-acetyltransferases (NAT1 and NAT2) onpolyp numbers in FAP (51).APC I1307KThe APC I1307K variant is present in about 6% of Ashkenazi Jews, but is much rarer inthose of other ethnic groups. I1307K creates an A8 tract that appears to be somaticallyunstable, leading to frameshift mutations (52). Originally, I1307K was proposed to leadto an AFAP-like phenotype, although extra-colonic disease does not appear to feature inthis group. Recent data have shown that APC I1307K only confers a small excess risk ofCRC (53), inconsistent prima facie with an AFAP-like phenotype. Moreover, only aminority of colorectal tumours from I1307K carriers shows slippage of the A 8 tract. It maybe the case, therefore, that although the 1307K allele is somewhat unstable, this effect issubtle in most carriers; only some individuals, perhaps with an unidentified, additionalgermline factor, go on to develop an AFAP-like phenotype (54).Previous SectionNext Section
  6. 6. RECENT DEVELOPMENTS THROUGH LINKAGEANALYSISHereditary mixed polyposis syndromeHereditary mixed polyposis syndrome (HMPS) was described as a distinct syndrome ofcolorectal adenomas, hyperplastic polyps, atypical ‘mixed’ polyps and carcinoma byWhitelaw et al. (55) in a large Ashkenazi family. The extra-colonic features of FAP and thetypical features of PJS were absent. The phenotype had limited similarity to JPS. Linkageof HMPS to chromosome 6q16–q21 was demonstrated by Thomas et al. (56). Tomlinsonet al. (57) showed linkage to chromosome 15q14–q15 (CRAC1 locus) in anotherAshkenazi 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 affectionstatus in that family in order to minimize the phenocopy rate. Subsequent linkageanalysis showed HMPS and CRAC1 to be one-and-the-same (58). Affected individuals inthese families and in several other Ashkenazi kindreds with a similar phenotype wereshown to share an ancestral haplotype between D15S1030 and D15S118. The gene itselfis, 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 in53 families with individuals affected at <65 years of age by CRC or adenomas (>1 cm ordisplaying high-grade dysplasia). Six potential loci were identified with excess allelesharing among concordantly affected sib-pairs (P<0.016). Of these, a region onchromosome 9 gave a significant result when additionally examined for deficient allelesharing among discordant sib pairs (P=0.014). The Haseman–Elston regression methodprovided an overall probability of linkage of P=0.00045.Previous SectionNext SectionEVIDENCE FOR LOW-PENETRANCE ALLELESASSOCIATED WITH AN INCREASED RISK OF CRCSome high- or moderate-penetrance CRC predisposition genes remain to be detectedand 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 theuncharacterized inherited influence on CRC. Many different SNPs and other commonpolymorphisms have been evaluated for their effects on CRC risk, and space precludesdetailed descriptions or analysis here. Case–control (association) analysis has been usedmost frequently. Such studies have often been criticized, some of the reasons being thefollowing: 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. 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 tostudies of low-penetrance variants as CRC susceptibility alleles. Most recent studies haveused larger, better defined populations of cases and controls, together with genotypingmethods with greater accuracy and throughput. Formal assessments of the roles ofseveral 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 asmall number of polymorphisms is associated with a differential risk of CRC (Table 2).These include methylene tetrahydrofolate reductase MTHFRC677T, H-ras VNTR rarealleles and NAT2 alleles which cause a rapid acetylator phenotype. Other polymorphismshave 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 theirfavour being minimal. View this table: In this window In a new windowTable 2.Summary of polymorphisms tested for association with differential CRC riskRecent data have suggested that loss of imprinting (LOI) of the insulin-like growth factorII (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 notclear whether the association between IGF2 LOI and CRC might be a direct effect ofincreased 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 CRCgenes, or of genes and specific environments, although inherent problems of statisticalpower mean that most of the reported associations of this type must currently be takenas no more than suggestive. Even for the MTHFR polymorphisms, advice on dietarymodification so that folate intake is increased cannot yet be given reliably or withconfidence. A further question is whether or not a true CRC risk factor should affect therisk of both rectal and colonic cancers, conditions that are usually treated as essentiallythe same disease (albeit with some different molecular and clinical features) bygeneticists, but as different conditions by epidemiologists. Further studies are beginningto test the influence of germline variation on factors other than disease susceptibility,
  8. 8. including the presenting features of CRCs, response to therapy and toxicity (includingpharmacogenetic analyses), and recurrence/survival.In general, acceptance of a polymorphism as a CRC risk factor can only come throughrepeated analysis by different studies and by consequent slow progress to a consensusjudgement. Accurate quantitation of the associated risk will be just as important as itsidentification in the first place, and this will require multiple studies in individualpopulations which may differ in genetic background, environment and availability ofscreening and medical care. Quantitation of risks associated with variants at multiplepredisposition loci will be even more difficult, especially if risks do not combine in asimple additive or multiplicative manner, yet if testing for low-penetrance alleles is tocome 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 anysingle polymorphism are so low that identification of the genes involved (and theirtesting 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 riskof CRC: in this case, identification of the variants will be possible through mutationscreening 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 mutationscreening, has little functional effect, although ‘closing the door’ on such a variant is noteasy. Nevertheless, the modestly increased risk of breast cancer associated with theCHEK2del1100C sub-polymorphic variant (98) shows that important alleles of this typedo exist. (Any association between CHEK2del1100C and CRC remains controversial.)Should many of the remaining CRC alleles prove to be of the low-frequency/low-risktype, genetic testing in the clinical setting may not be worthwhile. Despite these potentialproblems, 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 SectionFUTURE STRATEGIES FOR IDENTIFYING CRCPREDISPOSITION GENESThe successful detection of predisposition genes for cancer has largely been limited tohigh-penetrance genes such as APC, BRCA1/2 and CDNK2A. Although the search forlow-penetrance genes has been informative in some other complex diseases, forexample, APOE-4 in Alzheimers disease, those underlying cancer remain largely elusive.The characteristics of cancer create obstacles. The usual late onset of CRC means parentsmay be deceased and the disease is often fatal, making sample collection difficult. Inaddition, the requirement of random somatic mutations for the progression to carcinomamay cloud the picture. However, some of these problems can be circumvented by theselection of early-onset cases to increase the genetic component and to reduce theenvironmental component, and by the study of benign, precursor lesions.The question therefore arises of which methods to use to detect novel cancer genes. Inour view, given that there are undoubtedly still high and moderate penetrance CRC genesyet to be discovered, linkage analysis should certainly not be abandoned. The latterwould require the use of non-parametric methodology in view of genetic heterogeneity
  9. 9. and the existence of phenocopies. However, even for moderate penetrance genes, thenumbers of multi-case families required to yield results are large. For example, under adominant model with a gene frequency of 0.1 and a risk ratio of 6, about 500 affected sibpairs 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 istherefore justified. For CRC, these have previously been limited to examining thefrequency of alleles at candidate loci in cases and controls. However, the advent of SNPmaps has created the potential for genome-wide association (100). The power of thesestudies, especially for rare alleles can be increased by using cases with a family history ofCRC (101) and by selecting in other ways for ‘genetic’ disease (for example, multipletumours, cancers of more than one site or early age of presentation). The detection of adominant gene with a frequency of 0.1 and a relative risk of 4 would require 200 casesand 200 controls in an association study, but over 1000 affected sib pairs in a traditionallinkage analysis (99).A more controversial area in the optimal design of association studies revolves aroundthe 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 theidentification 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 couldcurrently be genotyped in any association study. A map-based approach depends onlinkage disequilibrium occurring between blocks of haplotypes within which only a fewcommon 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 tagSNPs (htSNPs) (103). The number of SNPs required will increase with the genetic diversityof a population because of shorter haplotype blocks. For example, the InternationalHapMap Project has recently decided to add 2.25 million SNPs to the original 600 000 foreach 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 thebasis of their probable contribution to the phenotype. The focus of this approach istherefore on coding regions and SNPs resulting in amino acid changes and/or SNPs foundin evolutionarily conserved areas. This would require far fewer SNPs (50 000–100 000) fora 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 theCRC-associated variants.For identifying sub-polymorphic variants associated with disease, a mutation screeningstrategy based on candidate genes (and followed if possible by a suitable associationstudy) is probably the only practical method for the short term. It remains to be seenwhether or not new technologies such as re-sequencing microarrays prove cost-effectivefor research and diagnosis here. The requirement for functional studies will beparticularly important for sub-polymorphic variants, especially those which lead toconserved amino acid changes, or affect splice sites, promoters or control regions.Although it is hoped that linkage, association and mutation screening studies will yieldanswers, the concurrent use of more indirect methods is prudent and may contribute to
  10. 10. the fine mapping of an identified region of interest. As with SMAD4 and more recently,MYH, the search for somatic mutations may also identify the site of germline mutations,as their effects in the cell are functionally similar. Other approaches include the study ofcancer-associated phenotypes including normal variation (for example in hormonelevels). Inflammatory bowel disease, which we have not discussed in detail earlier, isassociated with an increase risk of CRC yet has a higher sibling relative risk (104), andsome of the predisposition genes might be the same for the two conditions. The searchfor modifier genes is also potentially important, as a gene which influences the severityof a Mendelian syndrome should also, in principle, act as a low-penetrancepredisposition gene.Intensive, effective population-based screening for CRC and its precursor lesions is likelyin the foreseeable future to be expensive and/or to have a relatively low take-up rate.Even if this screening for CRC becomes more acceptable, it will optimally be targeted tothose at highest risk. The identification of CRC risk genes will permit targeted screening,and will open up possibilities for other preventive measures and, perhaps, therapies. It ishighly likely that at least some CRC genes can be identified and will provide usefultargets for routine genetic testing and preventive intervention.Previous SectionNext SectionACKNOWLEDGEMENTSWe are grateful to colleagues, particularly Richard Houlston and Walter Bodmer, fordiscussion and help. 1. Zoe Kemp1, 2. Cristina Thirlwell1, 3. Oliver Sieber1, 4. Andrew Silver2 and 5. Ian Tomlinson1,2,*+ Author Affiliations 1. Molecular and Population Genetics Laboratory, London Research Institute, 1 Cancer Research UK, 44 Lincolns Inn Fields, London WC2A 3PX, UK and 2. 2Colorectal Cancer Unit, Cancer Research UK, St Marks Hospital, Watford Road, Harrow HA1 3UJ, UK 1. To whom correspondence should be addressed. Tel: +44 1712692884; Fax: +44 * 1712692885; Email: Received July 23, 2004. Accepted July 27, 2004. Human Molecular Genetics, Vol. 13, Review Issue 2 © Oxford University Press 2004; all rights reservedPrevious SectionReferences
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  25. 25. o Full Text (HTML) o Full Text (PDF) Association of the ARLTS1 Cys148Arg variant with sporadic and familial colorectal cancer Carcinogenesis (2007) 28(8): 1687-1691 o Abstract o Full Text (HTML) o Full Text (PDF) TGF-{beta} signaling alterations and susceptibility to colorectal cancer Hum Mol Genet (2007) 16(R1): R14-R20 o Abstract o Full Text (HTML) o Full Text (PDF) « Previous | Next Article »Table of ContentsThis Article 1. Hum. Mol. Genet. (2004) 13 (suppl 2): R177-R185. doi: 10.1093/hmg/ddh247 1. Abstract 2. » Full Text (HTML) 3. Full Text (PDF)- Classifications 1. o Review o Review- Services 1. Alert me when cited 2. Alert me if corrected 3. Find similar articles 5. Similar articles in PubMed 6. Add to my archive 7. Download citation 8. Request Permissions+ Citing Articles+ Google Scholar+ PubMed+ Related Content+ Share o o o o o o oNavigate This Article 1. Top 2. Abstract 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 7. ACKNOWLEDGEMENTS 8. References- People also read [Beta]
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