#114500
ICD+
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| COLORECTAL CANCER; CRC | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| COLON CANCER | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because mutations in several different genes have been identified in colorectal cancer. Mutations in a single gene result in a marked predisposition to colorectal cancer in 2 distinct syndromes: familial adenomatous polyposis (FAP; 175100) and hereditary nonpolyposis colorectal cancer (HNPCC; see 120435). FAP is caused by mutations in the APC gene (611731), whereas HNPCC is caused by mutations in several genes, including MSH2 (609309), MLH1 (120436), PMS1 (600258), PMS2 (600259), MSH6 (600678), TGFBR2 (190182), and MLH3 (604395). Epigenetic silencing of MSH2 results in a form of HNPCC (see HNPCC8, 613244). Other colorectal cancer syndromes include autosomal recessive adenomatous polyposis (608456), which is caused by mutations in the MUTYH gene (604933), and oligodontia-colorectal cancer syndrome (608615), which is caused by mutations in the AXIN2 gene (604025). The CHEK2 gene (604373) has been implicated in susceptibility to colorectal cancer in Finnish patients. A germline mutation in the PLA2G2A gene (172411) was identified in a patient with colorectal cancer. Susceptibility to colorectal cancer (CRCS1; 608812) can be conferred by germline mutation in the GALNT12 gene (610290). In addition, somatic mutations in many different genes, including KRAS (190070), PIK3CA (171834), BRAF (164757), CTNNB1 (116806), FGFR3 (134934), AXIN2 (604025), AKT1 (164730), MCC (159350), MYH11 (160745), and PARK2 (602544) have been identified in colorectal cancer. Genomewide association studies have shown that common alleles of SMAD7 (602932) influence colorectal cancer risk; see CRCS3, 612229. Additionally, susceptibility loci for colorectal cancer have been mapped to chromosomes 8q24 (CRCS2; 611469), 15q13.3 (CRCS4; 601228), 10p14 (CRCS5; 612230), 8q23.3 (CRCS6; 612231), 11q23 (CRCS7; 612232), 14q22 (CRCS8; 612589), 16q22 (CRCS9; 612590), 19q13 (CRCS10; 612591), and 20p12 (CRCS11; 612592). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Colon cancer is a well-known feature of familial polyposis coli. Cancer of the colon occurred in 7 members of 4 successive generations of the family reported by Kluge (1964), leading him to suggest a simple genetic basis for colonic cancer independent of polyposis. The combination of colonic and endometrial cancer has been observed in many families (e.g., Williams, 1978). Sivak et al. (1981) studied a kindred with the familial cancer syndrome in which every confirmed affected member had at least 1 primary carcinoma of the colon. The average age at which cancer appeared was 38 years. Multiple primary neoplasms occurred in 23% of cancer patients. Budd and Fink (1981) reported a family with a high frequency of mucoid colonic carcinoma. Since endometrial carcinoma, atypical endometrial hyperplasia, uterine leiomyosarcoma, bladder transitional carcinoma, and renal cell carcinoma also occurred in the family, this may be the same disorder as the Lynch cancer family syndrome type II (120435). Bamezai et al. (1984) reported an Indian Sikh kindred in which 8 persons suffered from cancer of the cecum, not associated with polyposis. Burt et al. (1985) studied a large Utah kindred called to attention because of occurrence of colorectal cancer in a brother, a sister, and a nephew. No clear inheritance pattern was discernible until systematic screening was undertaken for colonic polyps using flexible proctosigmoidoscopy. One or more adenomatous polyps were found in 41 of 191 family members (21%) and 12 of 132 controls (9%)--p less than 0.005. Pedigree analysis showed best fit with autosomal dominant inheritance. Cannon-Albright et al. (1988) extended the studies with investigations of 33 additional kindreds. The kindreds were selected through either a single person with an adenomatous polyp or a cluster of relatives with colonic cancer. The kindreds all had common colorectal cancers, not the rare inherited condition of familial polyposis coli or nonpolyposis inherited colorectal cancer. Likelihood analysis strongly supported dominant inheritance of a susceptibility to colorectal adenomas and cancers, with a gene frequency of 19%. According to the most likely genetic model, adenomatous polyps and colorectal cancers occur only in genetically susceptible persons; however, the 95% confidence interval for this proportion was 53 to 100%. Ponz de Leon et al. (1992) analyzed data on 605 families of probands with colorectal cancer in the province of Modena in Italy. Among the 577 presumed nonpolyposis cases, both parents had colorectal cancer in 11, one parent in 130, and neither parent in 436. Segregation was compatible with dominant transmission of susceptibility to cancer. Mecklin (1987) investigated the frequency of hereditary colorectal cancer among all colorectal cancer patients diagnosed in 1 Finnish county during the 1970s. The cancer family syndrome type of hereditary nonpolyposis colorectal carcinoma emerged as the most common verifiable risk factor, involving between 3.8 and 5.5% of all colorectal cancer patients. The frequencies of familial adenomatosis and ulcerative colitis were 0.2% and 0.6%, respectively. The observed frequency is probably an underestimate. The patients with cancer family syndrome were young, accounting for 29 to 39% of the patients under 50 years of age, and their tumors were located predominantly (65%) in the right hemicolon. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pathogenesis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The state of DNA methylation appears to play a role in genetic instability in colorectal cancer cells. Lengauer et al. (1997) noted that DNA methylation is essential in prokaryotes, dispensable in lower eukaryotes (such as Saccharomyces cerevisiae) yet present and presumably important in mammals. Many cancers have been shown to have a global hypomethylation of DNA compared with normal tissues. Treatment of cells or animals with 5-azacytidine (5-aza-C), a demethylating agent that irreversibly inactivates methyltransferase (see 156569), is oncogenic in vitro and in vivo. Conversely, other studies showed that hypermethylation of specific sequences found in some tumors can be associated with the inactivation of tumor suppressor gene expression. Mice genetically deficient in methyltransferase are resistant to colorectal tumorigenesis initiated by mutation of the APC tumor suppressor gene, and treatment of these mice with 5-aza-C enhances the resistance (Laird et al., 1995). Lengauer et al. (1997) reported a striking difference in the expression of exogenously introduced retroviral genes in various colorectal cancer cell lines. Extinguished expression was associated with DNA methylation and could be reversed by treatment with the demethylating agent 5-aza-C. A striking correlation between genetic instability and methylation capacity suggested that methylation abnormalities may play a role in the chromosome segregation processes in cancer cells. It has been speculated that genetic instability is necessary for a tumor to accumulate the numerous genetic alterations that accompany carcinogenesis. There appeared to exist 2 pathways of genetic instability in colorectal cancer. The first is found in about 15% of tumors and involves point mutations, microdeletions, and microinsertions associated with deficiency of mismatch repair (MMR). The second is found in MMR-proficient cells and involves gains and losses of whole chromosomes. Lengauer et al. (1997) suggested that methylation abnormalities are intrinsically and directly involved in the generation of the second type of instability, thus allowing for the selection of methylation-negative cells during the clonal evolution of tumors. The hypothesis was supported by the observation that demethylation is associated with chromosomal aberrations, including mitotic dysfunction and translocation, and was consistent with the hypothesis relating methylation and aneuploidy put forward by Thomas (1995). Jones and Gonzalgo (1997) commented on altered DNA methylation and genome instability as a new pathway to cancer. In a second report, Lengauer et al. (1997) showed that tumors without microsatellite instability exhibit a striking defect in chromosome segregation, resulting in gains or losses in excess of 10(-2) per chromosome per generation. This form of chromosomal instability reflected a continuing cellular defect that persisted throughout the lifetime of the tumor cell and was not simply related to chromosome number. While microsatellite instability is a recessive trait, chromosomal instability appeared to be dominant. The data indicated that persistent genetic instability may be critical for the development of all colorectal cancers, and that this instability can arise through 2 distinct pathways. Adenocarcinoma of the small intestine is rare in the general population, but its histologic features are similar to those of the much more common colorectal adenocarcinoma, and it is seen as part of the HNPCC tumor predisposition spectrum. Wheeler et al. (2002) examined the possible role of mismatch repair defects in the pathogenesis of sporadic small intestinal adenocarcinoma. The replication error status was determined in a total of 21 nonfamilial, nonampullary small intestinal adenocarcinomas: only 1 tumor was scored as replication error-positive. This tumor showed normal immunostaining for MLH1 (see 120436) and MSH2. The authors commented that this result may reflect an epigenetic change in the tumor rather than germline mutation in a mismatch repair gene, and concluded that mismatch repair defects were unlikely to contribute significantly to the genetic pathway leading to sporadic small intestinal adenocarcinoma. Vilar and Gruber (2010) reviewed the role of microsatellite instability (MSI) in the development of CRC. They stated that approximately 15% of CRCs display MSI owing either to epigenetic silencing of MLH1 or to a germline mutation in one of the mismatch repair genes MLH1, MSH2, MSH6, or PMS2. They noted that MSI tumors have a better prognosis than microsatellite stable CRCs, but that MSI cancers do not necessarily have the same response to the chemotherapeutic strategies used to treat microsatellite stable tumors. Batlle et al. (2005) showed that although Wnt (see 164820) signaling remains constitutively active, most human colorectal cancers lose expression of EphB (see 600600) at the adenoma-carcinoma transition. They found that loss of EphB expression strongly correlated with degree of malignancy. Furthermore, reduction of EphB activity accelerated tumorigenesis in the colon and rectum of Apc(Min/+) mice (see 611731), and resulted in formation of aggressive adenocarcinomas. Batlle et al. (2005) concluded that loss of EphB expression represents a critical step in colorectal cancer progression. By microdissection of bifurcating colonic crypts and sequencing of the entire mitochondrial genome in all of the cells, Greaves et al. (2006) demonstrated that stochastic mutations in mtDNA resulting in phenotypic cytochrome c oxidase (COX) deficiency of were identical in both arms of a crypt that was bifurcating. Furthermore, they showed that patches of neighboring crypts deficient in COX also shared identical mitochondrial mutations, and that these patches increased in size with age, indicating that crypt fission is a mechanism by which mutations can spread within the colon. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Management | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Various laboratory, clinical, and epidemiologic evidence suggested that calcium may help prevent colorectal adenomas. Baron et al. (1999) conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. They found a significant, though moderate, reduction in the risk of recurrent colorectal adenomas in the supplemented group. In randomized trials of aspirin to determine its efficacy in prevention of colorectal adenomas, Sandler et al. (2003) and Baron et al. (2003) studied patients with either previous colorectal cancer or recent histologically documented adenomas, respectively. Both studies found that aspirin was associated with a significant reduction in the incidence of colorectal adenomas. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Diagnosis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prediction of Colorectal Cancer Risk Loss of imprinting, an epigenetic alteration affecting the insulin-like growth factor II gene (IGF2; 147470), is found in normal colonic mucosa of about 30% of colorectal cancer patients, but it is found in only 10% of healthy individuals. In a pilot study to investigate the utility of loss of imprinting as a marker of colorectal cancer risk, Cui et al. (2003) evaluated 172 patients at a colonoscopy clinic. The adjusted odds ratio for loss of imprinting in lymphocytes was 5.15 for patients with a positive family history (95% CI, 1.70-16.96; p = 0.002), 3.46 for patients with adenomas (95% CI, 1.14-11.37; p = 0.026), and 21.7 for patients with colorectal cancer (95% CI, 3.48-153.6; p = 0.0005). Loss of imprinting can be assayed with a DNA-based blood test, and Cui et al. (2003) concluded that it may be a valuable predictive marker of an individual's risk for colorectal cancer. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| To identify susceptibility genes for familial colorectal neoplasia, Daley et al. (2008) conducted a comprehensive, genomewide linkage scan of 194 kindreds. Clinical information (histopathology, size and number of polyps, and other primary cancers) was used in conjunction with age at onset and family history for classification of the families into 5 phenotypic subgroups (severe histopathology, oligopolyposis, young colon/breast and multiple cancer) before analysis. By expanding the traditional affected sib pair design to include unaffected and discordant sib pairs, analytical power and robustness to type I error were increased. Linkage peaks of interest were identified at several sites. At marker D1S1665 (1p31.1), there was strong evidence for linkage in the multiple cancer subgroup (p = 0.00007). For 15q14-q22, a linkage peak was identified in the full sample, oligopolyposis, and young phenotypes. This region includes the locus associated with hereditary mixed polyposis syndrome (HMPS; 601228) in families of Ashkenazi descent. Daley et al. (2008) provided compelling evidence linking this region in families of European descent with oligopolyposis and/or young age at onset (51 years or younger) phenotypes. They found linkage to BRCA2 (600185) in the colon/breast phenotypic subgroup and identified a second locus in the region of D21S1437 segregating with, but distinct from, BRCA2. Linkage to 17p13.3 at marker D17S1308 in the breast/colon subgroup identified HIC1 (603825) as a candidate gene. The study demonstrated that using clinical information, unaffected sibs, and family history can increase the analytic power of a linkage study. Associations Pending Confirmation In a large kindred with excess colorectal cancer, Neklason et al. (2010) performed 2 separate genomewide scans and additional fine mapping and identified a single major locus on chromosome 13q22.1-q31.3 that segregated with adenomatous polyps and colon cancer, for which they obtained a nonparametric linkage score of 24 (lod score of 2.99; p = 0.001) at D13S251. Haplotype analysis identified a 21-Mb interval encompassing a nonrecombinant region bounded by rs2077779 and rs2351871 and containing 27 genes. Sequencing of 8 candidate genes failed to identify a clearly deleterious mutation. Neklason et al. (2010) noted that chromosome 13q is commonly gained and overexpressed in colon cancers and correlates with metastasis, suggesting the presence of an important cancer progression gene, and stated that evaluation of tumors from the kindred revealed a gain of chromosome 13q as well. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In the DNA from 1 colon and 2 lung carcinoma cell lines, Perucho et al. (1981) demonstrated the same or closely related transforming elements. By DNA-mediated gene transfer, mouse fibroblasts could be morphologically transformed and rendered tumorigenic in nude mice. In preliminary observations, Pathak and Goodacre (1986) found deletion of 12p in colorectal cancer specimens. Fearon et al. (1987) studied the clonal composition of human colorectal tumors. Using X-linked RFLPs, they showed that all 50 tumors from females showed a monoclonal pattern of X-chromosome inactivation; these tumors included 20 carcinomas and 30 adenomas of either familial or spontaneous type. In over 75% of carcinomas examined, somatic loss of chromosome 17p sequences was found; such loss was rare in adenomas. Fearon et al. (1987) suggested that a gene on the short arm of chromosome 17 may be associated with progression from the benign to the malignant state. By a combination of DNA hybridization analyses and tissue sectioning techniques, Bos et al. (1987) demonstrated that RAS gene mutations occur in over a third of colorectal cancers, that most of the mutations are at codon 12 of the KRAS gene (190070), and that the mutations usually precede the development of malignancy. In 38 tumors from 25 patients with familial polyposis coli, and in 20 sporadic colon carcinomas, Okamoto et al. (1988) found frequent occurrence of allele loss on chromosome 22, with some additional losses on chromosomes 5, 6, 12q, and 15. The DNA probe C11p11, which has been found to be linked to familial polyposis coli, also detected frequent allele loss in both familial and sporadic colon carcinomas but not in benign adenomas. In a more extensive study, Vogelstein et al. (1988) studied the interrelationships of the 4 alterations demonstrated in colorectal cancer (RAS gene mutations and deletions of chromosome 5, 17 and 18 sequences) and determined their occurrence with respect to different stages of colorectal tumorigenesis. They found RAS gene mutations frequently in adenomas, this being the first demonstration of such in benign human tumors. In adenomas greater than 1 cm in size, the prevalence was similar to that observed in carcinomas (58% and 47%, respectively). Sequences on chromosome 5 that are linked to familial adenomatous polyposis were seldom lost in adenomas from such patients. Therefore, the Knudson model is unlikely to be applicable to the adenoma/carcinoma sequence in this disorder. Chromosome 18 sequences were lost frequently in colon carcinomas (73%) and in advanced adenomas (47%), but only occasionally in earlier stage adenomas (11-13%); see 120470. Chromosome 17 sequences were usually lost only in carcinomas (75%). The results suggested a model wherein the steps required for malignancy involve the activation of a dominantly acting oncogene coupled with the loss of several genes that normally suppress tumorigenesis. Wildrick and Boman (1988) found deletion of the glucocorticoid receptor locus (138040), located on 5q, in colorectal cancers. Law et al. (1988) examined the question of whether the gene for familial polyposis coli on chromosome 5 may be the site of changes leading to colorectal cancer in the general population, analogous to recessive tumor genes in retinoblastoma and Wilms tumor. To avoid error in interpretation of allelic loss from a study of nonhomogeneous samples, tumor cell populations were first microdissected from 24 colorectal carcinomas, an additional 9 cancers were engrafted in nude mice, and nuclei were flow-sorted in an additional 2. Of 31 cancers informative for chromosome 5 markers, only 6 (19%) showed loss of heterozygosity of chromosome 5 alleles, compared to 19 of 34 (56%) on chromosome 17, and 17 of 33 (52%) on chromosome 18. Law et al. (1988) concluded that FPC is a true dominant for adenomatosis but not a common recessive gene for colon cancer, and that simple mendelian models involving loss of alleles at a single locus may be inappropriate for understanding common human solid tumors. Vogelstein et al. (1989) examined the extent and variation of allelic loss for polymorphic DNA markers in every nonacrocentric autosomal arm in 56 paired colorectal carcinoma and adjacent normal colonic mucosa specimens. They referred to the analysis as an allelotype, in analogy with a karyotype. Three major conclusions were drawn from the study: (1) Allelic deletions are remarkably common; 1 of the alleles of each polymorphic marker tested was lost in at least some tumors, and some tumors lost more than half of their parental alleles. (2) In addition to allelic deletions, new DNA fragments not present in normal tissue were identified in 5 carcinomas; these new fragments contained repeated sequences (of the variable-number-of-tandem-repeat type). (3) Patients with more than the median percentage of allelic deletions had a considerably worse prognosis than did the other patients, although the stage and size of the primary tumors were very similar in the 2 groups. Delattre et al. (1989) reviewed the 3 general types of genetic alterations in colorectal cancer: (1) change in DNA content of the malignant cells as monitored by flow cytometry; (2) specific loss of genetic material, i.e., a complete loss of chromosome 18 and a structural rearrangement of chromosome 17 leading most often to the loss of 1 short arm, and loss of part of 5q as demonstrated by loss of heterozygosity; and (3) in nearly 40% of tumors, activation by point mutation of RAS oncogenes (never HRAS, rarely NRAS, and most frequently KRAS). In KRAS, with 1 exception, the activation has always occurred by a change in the coding properties of the twelfth or thirteenth codon. In studies of the multiple genetic alterations in colorectal cancer, Delattre et al. (1989) found that deletions and mitotic abnormalities occurred more frequently in distal than in proximal tumors. The frequency of KRAS mutations did not differ between proximal and distal cancers. In studies of 15 colorectal tumors, Konstantinova et al. (1991) found rearrangements of the short arm of chromosome 17, leading to deletion of this arm or part of it in 12; in 2 others, one of the homologs of pair 17 was lost. One chromosome 18 was lost in 12 out of 13 cases with fully identified numerical abnormalities; chromosome 5, in 6 tumors; and other chromosomes in lesser numbers of cases. See 120470 for a discussion of a gene on chromosome 18 called DCC ('deleted in colorectal cancer') that shows mutations, including point mutations, in colorectal tumor tissue; also see 164790 for a discussion of a mutation in the NRAS oncogene in colorectal cancer. On the basis of complex segregation analysis of a published series of consecutive pedigrees ascertained through patients undergoing treatment for colorectal cancer, Houlston et al. (1992) concluded that a dominant gene (or genes) with a frequency of 0.006 with a lifetime penetrance of 0.63 is likely. The gene was thought to account for 81% of colorectal cancer in patients under 35 years of age; however, by age 65, about 85% appeared to be phenocopies. Fearon and Vogelstein (1990) reviewed the evidence supporting their multistep genetic model for colorectal tumorigenesis. They suggested that multiple mutations lead to a progression from normal epithelium to metastatic carcinoma through hyperplastic epithelium--early adenoma--intermediate adenoma--late adenoma--and carcinoma. The genes in which mutations occur at steps in this process include APC on chromosome 5, KRAS on chromosome 12, TP53 (191170) on 17p, and DCC on chromosome 18. Other genes that have been demonstrated or suspected of involvement in colorectal cancer include MSH2 (609309) on chromosome 2 and the DRA candidate colon tumor-suppressor gene (126650) on chromosome 7. Sarraf et al. (1999) presented evidence that colon cancer in humans is associated with loss-of-function mutations in the PPARG gene (601487). Kikuchi-Yanoshita et al. (1992) presented evidence that genetic changes in both alleles of the TP53 gene through mutation and LOH, which result in abnormal protein accumulation, are involved in the conversion of adenoma to early carcinoma in both familial adenomatous polyposis and in nonfamilial polyposis cases. Kinzler and Vogelstein (1996) gave a review of hereditary colorectal cancer and the multistep process of carcinogenesis that typically develops over decades and appears to require at least 7 genetic events for completion. They stated that the genetic defect in FAP involves the rate of tumor initiation by targeting the gatekeeper function of the APC gene. In contrast, the defect in HNPCC largely affects tumor aggression by targeting the genome guardian function of DNA repair. Rajagopalan et al. (2002) systematically evaluated mutation in BRAF (164757) and KRAS (190070) in 330 colorectal tumors. There were 32 mutations in BRAF, 28 with a V600E mutation (164757.0001) and 1 each with the R462I (164757.0002), I463S (164757.0003), G464E (164757.0004), or K601E (164757.0005) mutations. All but 2 mutations seemed to be heterozygous, and in all 20 cases for which normal tissue was available, the mutations were shown to be somatic. In the same set of tumors there were 169 mutations in KRAS. No tumor exhibited mutations in both BRAF and KRAS. There was also a striking difference in the frequency of BRAF mutations between cancers with and without mismatch repair deficiency. All but 1 of the 15 BRAF mutations identified in mismatch repair deficient cases resulted in a V600E substitution. Rajagopalan et al. (2002) concluded their results provide strong support for the hypothesis that BRAF and KRAS mutations are equivalent in their tumorigenic effects. Both genes seem to be mutated at a similar phase of tumorigenesis, after initiation but before malignant conversion. Moreover, no tumor concurrently contained both BRAF and KRAS mutations. To determine whether carriers of BLM (604610) mutations are at increased risk of colorectal cancer, Gruber et al. (2002) genotyped 1,244 cases of colorectal cancer and 1,839 controls, both of Ashkenazi Jewish ancestry, to estimate the relative risk of colorectal cancer among carriers of the BLM(Ash) founder mutation. Ashkenazi Jews with colorectal cancer were more than twice as likely to carry the BLM(Ash) (604610.0001) mutation than Ashkenazi Jewish controls without colorectal cancer (odds ratio = 2.45, 95% confidence interval 1.3 to 4.8; p = 0.0065). Gruber et al. (2002) verified that the APC I1307K mutation (611731.0029) did not confound their results. Lynch and de la Chapelle (2003) provided a general discussion of hereditary colorectal cancer. They presented a flow diagram of the breakdown of 1,044 unselected consecutive patients with colorectal cancer. Tumors from 129 patients (12%) were positive for microsatellite instability; 28 of these patients were positive for germline mutations in MLH1 or MSH2, giving HNPCC a 2.7% frequency among the 1,044 patients. In the 88% of the patients whose tumors had no microsatellite instability, no mutations were found in MLH1 or MSH2. Bardelli et al. (2003) used high-throughput sequencing technologies and bioinformatics to investigate how many or how often members of the tyrosine kinase family were altered in any particular cancer type. The protein kinase complement of the human genome (the 'kinome') can be organized into a dendrogram containing 9 broad groups of genes. Bardelli et al. (2003) selected 1 major branch of this dendrogram, containing 3 of the 9 groups, including the 90 tyrosine kinase genes (TK group), the 43 tyrosine kinase-like genes (TKL group), and the 5 receptor guanylate cyclase genes (RGC group), for mutation analysis. The 819 exons containing the kinase domains from the annotated TK, TKL, and RGC genes were screened from 35 colorectal cancer cell lines and were directly sequenced. Fourteen genes had somatic mutations within their kinase domains. Bardelli et al. (2003) analyzed these 14 genes for mutations in another 147 colorectal cancers and identified 46 mutations, 2 of which were synonymous; the remainder were either nonsynonymous or splice site alterations. All of these mutations were found to be somatic in the cancers that could be assessed by sequencing DNA from matched normal tissue. Seven genes were mutated in more than 1 tumor in the cohort: NTRK3 (191316), FES (190030), KDR (191306), EPHA3 (179611), NTRK2 (600456), MLK4, and GUCY2F (300041). Samuels et al. (2004) examined the sequences of 117 exons that encode the predicted kinase domains of 8 phosphatidylinositol-3 kinase genes and 8 PI3K-like genes in 35 colorectal cancers. PIK3CA (171834) was the only gene with somatic mutations. Subsequent sequence analysis of all coding exons of PIK3CA in 199 additional colorectal cancers revealed mutations in a total of 74 tumors (32%). Samuels et al. (2004) also evaluated 76 premalignant colorectal tumors; only 2 mutations were found, both in very advanced tubulovillous adenomas greater than 5 cm in diameter. Thus, Samuels et al. (2004) concluded that PIK3CA mutations generally arise late in tumorigenesis, just before or coincident with invasion. Mutations in PIK3CA were also identified in 4 of 15 glioblastomas (27%), 3 of 12 gastric cancers (25%), 1 of 12 breast cancers (8%), and 1 of 24 lung cancers (4%). No mutations were observed in 11 pancreatic cancers or 12 medulloblastomas. In total, 92 mutations were observed, all of which were determined to be somatic in the cancers that could be assessed. Samuels et al. (2004) concluded that the sheer number of mutations observed in this gene strongly suggests that they are functionally important. Furthermore, most of the mutations were nonsynonymous and occurred in the PI3K helical and kinase domains, suggesting functional significance. Clear-cut inherited mendelian traits, such as FAP or HNPCC, account for less than 4% of colorectal cancers. Another 20% of all colorectal cancers are thought to occur in individuals with a significant inherited multifactorial susceptibility to colorectal cancer that is not obviously familial. Incompletely penetrant, comparatively rare missense variants in the APC gene (611731) have been described in patients with multiple colorectal adenomas. For example, the I1307K mutation in the APC gene, which is found in Ashkenazi Jewish populations with an incidence of approximately 6%, confers a significantly increased risk of developing multiple adenomas and colorectal cancer. The glu1317-to-gln mutation in the APC gene (E1317Q; 611731.0036), which is found in non-Jewish Caucasian populations at a low frequency, similarly appears to confer a significantly increased risk of multiple adenomatous polyps. These variants represent a category of variation that has been suggested, generally, to account for a substantial fraction of such multifactorial inherited susceptibility to colorectal cancer. Fearnhead et al. (2004) explored this rare variant hypothesis for multifactorial inheritance using multiple colorectal adenomas as the model. Patients with multiple adenomas were screened for germline variants in a panel of candidate genes. Germline DNA was obtained from 124 patients with 3 to 100 histologically proven synchronous or metachronous adenomatous polyps. All patients were tested for the APC gene variants I1307K and E1317Q and for variants in the AXIN1 (603816), CTNNB1, MLH1, and MSH2 genes. The control group consisted of 483 randomly selected individuals. Potentially pathogenic germline variants were found in 30 of 124 patients (24.9%), compared with 55 of 483 controls (approximately 12%). This overall difference was highly significant, suggesting that many rare variants collectively contribute to inherited susceptibility to colorectal adenomas. Parsons et al. (2005) selected 340 genes encoding serine/threonine kinases from the human genome and analyzed them for mutations in the kinase domain in tumors from colorectal cancer patients. A total of 23 changes, including 20 nonsynonymous point mutations, 1 insertion, and 1 splice site alteration, were identified. The gene mutations affected 8 different proteins: 6 were in mitogen-activated protein kinase kinase-4 (MKK4/JNKK1; 601335), 6 in myosin light-chain kinase-2 (MYLK2; 606566), 3 in phosphoinositide-dependent protein kinase-1 (PDK1; 605213, of which 2 mutations affected the same residue in the kinase domain), 2 in p21-activated kinase-4 (PAK4; 605451), 2 in v-akt murine thymoma viral oncogene homolog-2 kinase (AKT2; 164731), and 2 in MAP/microtubule affinity-regulating kinase-3 (MARK3; 602678); there was 1 alteration in cell-division cycle-7 kinase (CDC7; 603311) and another in a hypothetical casein kinase (PDIK1L). Eighteen of the 23 somatic mutations occurred at evolutionarily conserved residues. MKK4/JNKK1 is altered in a variety of tumor types, but no mutations in any of the other genes had theretofore been found in colorectal cancers. Three of the altered genes, PDK1, AKT2, and PAK4, encode proteins involved in the phosphatidylinositol-3-hydroxykinase pathway, and 2 of these (AKT2 and PAK4) are overexpressed in human cancers. Overall, nearly 40% of colorectal tumors had alterations in 1 of 8 PI(3)K-pathway genes. Boraska Jelavic et al. (2006) studied genotype and allele frequencies of the GT microsatellite repeat polymorphism in intron 2 of the TLR2 gene (603028.0002) in 89 Croatian patients with sporadic colorectal cancer and 88 Croatian sex- and age-matched controls. The frequency of TLR2 alleles with 20 and 21 GT repeats was decreased (p = 0.0044 and p = 0.001, respectively) and the frequency of the allele with 31 GT repeats was increased (p = 0.0147) in patients versus controls. The authors also found that the gly299 allele of the TLR4 gene (603030.0001) was more frequent in colorectal cancer patients than controls (p = 0.0269). Sjoblom et al. (2006) determined the sequence of well-annotated human protein-coding genes in 2 common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of about 90 mutant genes, but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, Sjoblom et al. (2006) identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these were not known to be genetically altered in tumors and were predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. Sjoblom et al. (2006) concluded that their data defined the genetic landscape of 2 human cancer types, provided new targets for diagnostic and therapeutic intervention, and opened fertile avenues for basic research in tumor biology. Forrest and Cavet (2007), Getz et al. (2007), and Rubin and Green (2007) commented on the article by Sjoblom et al. (2006), citing statistical problems that, if addressed, would result in the identification of far fewer genes with significantly elevated mutation rates. Parmigiani et al. (2007) responded that the conclusions of the above authors were inaccurate because they were based on analyses that did not fully take into account the experimental design and other critical features of the Sjoblom et al. (2006) study. To catalog the genetic changes that occur during tumorigenesis, Wood et al. (2007) isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, Wood et al. (2007) concluded that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene 'mountains' and a much larger number of gene 'hills' that are mutated at low frequency. Wood et al. (2007) described statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. The gene mountains are comprised of well-known cancer genes such as APC (611731), KRAS (190070), and TP53 (191170). Furthermore, Wood et al. (2007) observed that most tumors accumulated approximately 80 mutations, and that the majority of these were harmless. Fewer than 15 mutations are likely to be responsible for driving the initiation, progression, or maintenance of the tumor. Alhopuro et al. (2008) identified somatic mutations in the MYH11 gene in 56 (56%) of 101 samples of colorectal cancer tissue showing microsatellite instability. All 56 mutations were within a mononucleotide repeat of 8 cytosines (C8) in the last exon of the MYH11 SM2 isoform, which is susceptible to mutations under microsatellite instability, and were predicted to lead to a frameshift and elongation of the protein. All mutations were found within epithelial cells. Analysis of microsatellite stable tumors identified 2 somatic mutations in the same tumor that were not in the C8 repeat. Functional expression studies of the mutant proteins showed unregulated actin-activated motor activity. McMurray et al. (2008) showed that a large proportion of genes controlled synergistically by loss-of-function p53 and Ras activation are critical to the malignant state of murine and human colon cells. Notably, 14 of 24 'cooperation response genes' were found to contribute to tumor formation in gene perturbation experiments. In contrast, only 1 of 14 perturbations of the genes responding in a nonsynergistic manner had a similar effect. McMurray et al. (2008) concluded that synergistic control of gene expression by oncogenic mutations thus emerges as an underlying key to malignancy, and provides an attractive rationale for identifying intervention targets in gene networks downstream of oncogenic gain- and loss-of-function mutations. To help distinguish between driver and passenger mutations in colorectal cancer, Starr et al. (2009) used a transposon-based genetic screen in mice to identify candidate genes. Mice harboring mutagenic 'Sleeping Beauty' (SB) transposons were crossed with mice expressing SB transposase in gastrointestinal tract epithelium. Most of the offspring developed intestinal lesions including intraepithelial neoplasia, adenomas, and adenocarcinomas. Analysis of over 16,000 transposon insertions identified 77 candidate CRC genes, 60 of which are mutated and/or dysregulated in human CRC and thus are most likely to drive tumorigenesis. The genes included APC, PTEN (601728), and SMAD4 (600993). The screen also identified 17 candidate genes that had not been implicated in CRC, including POLI (605252), PTPRK (602545), and RSPO2 (610575). In colonocytes from COX-deficient crypts from 2 patients with colon cancer, Greaves et al. (2006) identified 2 missense mutations in the MTCO1 gene (see 516030.0010 and 516030.0011, respectively). Using high-throughput screening of 14,662 human protein coding transcripts, Sjoblom et al. (2006) found that the PKHD1 gene (606702) was the seventh most common somatically mutated gene in colorectal cancer. Germline mutations in the PKHD1 gene cause autosomal recessive polycystic kidney disease (263200). Ward et al. (2011) observed an association between the common T36M PKHD1 allele (606702.0001) and protection against colorectal cancer. Germline heterozygosity for the mutant allele was found in 0.42% of 3,603 healthy European controls and in 0.027% of 3,767 patients with colorectal cancer (p = 0.0002; odds ratio of 0.072). The authors postulated that reduced PKHD1 activity may enhance mitotic instability, which may inhibit carcinogenesis. Dorard et al. (2011) identified a mutant of HSP110 (see 610703), which they called HSP110-delta-E9, in colorectal cancer showing microsatellite instability (MSI CRC), generated from an aberrantly spliced mRNA and lacking the HSP110 substrate-binding domain. This mutant was expressed at variable levels in almost all MSI CRC cell lines and primary tumors tested. HSP110-delta-E9 impaired both the normal cellular localization of HSP110 and its interaction with other HSPs, thus abrogating the chaperone activity and antiapoptotic function of HSP110 in a dominant-negative manner. HSP110-delta-E9 overexpression caused the sensitization of cells to anticancer agents such as oxaliplatin and 5-fluorouracil, which are routinely prescribed in the adjuvant treatment of people with colorectal cancer. The survival and response to chemotherapy of subjects with colorectal cancer showing microsatellite instability was associated with the tumor expression level of HSP110-delta-E9. Dorard et al. (2011) concluded that HSP110 may thus constitute a major determinant for both prognosis and treatment response in colorectal cancer. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Lovett (1976); Lovett (1976); Mathis (1962) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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