Mutated Genes and Abnormal Protein Expression (53)
Recurrent Chromosome Abnormalities (4)
Overview of Colorectal Cancer Genetics
Hereditary NonPolyposis Colorectal Cancer
Genetic Counselling for Hereditary Colorectal Cancers
DNA Testing for Colorectal Cancer Screening
de(1p) in Colorectal Cancer
del(8p) in Colorectal Cancers [incl del(8q21)]
LOH 17p
18q Loss in Colorectal Cancer
ColoRectal Cancers: Clinical and Epidemiological Resources

de(1p) in Colorectal Cancer
del(8p) in Colorectal Cancers [incl del(8q21)]
LOH 17p
18q Loss in Colorectal Cancer

Between 15-20% of all colorectal cancers are thought to be familial. Some colon cancers and pre-disposing conditions are known to have an inherited element:

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

HNPCCMSH2, MSH6, MLH1, PMS1 and PMS2. These highly penetrant mutations result in microsatellite instability in the tumour (referred to as the replication error phenotype, RER+). These tumours are predominantly diploid and occur more frequently in the right colon, and often have characteristic mutations including TGFBR2 and/or BAX.

Familial Adenomatous Polyposis (FAP)

FAP is an autosomal dominant disorder causing extensive adenomatous polyps in the colon and early onset colorectal cancer.FAP accounts for about 1% of all colorectal cancers. The disorder is characterised by APC gene mutation. FAP is also assciated with elevated risk of extracolonic tumours (previously refered to as Gardner syndrome) including hepatoblastoma and thyroid carcinoma.

Approximately 15% of sporadic colorectal cancers are of the RER+ phenotype (though not necessarily having the same genetic basis as HNPCC).

Genomic Instability: Using inter-(simple sequence repeat) PCR, Stoler (1999) found a mean of 11,000 genomic alterations per colorectal carcinoma cell. A similar number of genetic events were detected in colonic polyps. Since colonic polyps are early in the tumor progression pathway this suggests that genomic destabilization is an early step in sporadic tumor development. Stoler and colleauges state that this supports a model in which genomic instability is a cause rather than an effect of colorectal carcinogenesis.

The CpG island methylator phenotype (CIMP) is characterized by the simultaneous methylation of multiple CpG islands. Toyota (2000) found that CIMP identifies 2 groups of colorectal cancers: CIMP+ tumours which have a significanly higher proportion of K-RAS mutations (68% vs. 30%) and CIMP- tumours which have a significantly higher proportion of TP53 mutations (60% vs. 24%).

Jass JR Towards a molecular classification of colorectal cancer. [Review] Int J Colorectal Dis 1999;14(4-5):194-200    Related articles (PubMed)

Stoler DL, et al. The onset and extent of genomic instability in sporadic colorectal tumor progression Proc Natl Acad Sci USA. 1999; 96(26):15121-26

Breivik J, Gaudernack G. Genomic instability, DNA methylation, and natural selection in colorectal carcinogenesis [Review] Semin Cancer Biol. 1999;9(4):245-54    Related articles

Potter JD Colorectal cancer: molecules and populations. J Natl Cancer Inst 1999; 91(11):916-32    Related articles

Lynch HT, de La Chapelle A Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet 1999; 36(11):801-18    Related articles (PubMed)

Gertig DM, Hunter DJ Genes and environment in the etiology of colorectal cancer. Semin Cancer Biol 1998; 8(4):285-98    Related articles (PubMed)

Ionov Y, et al. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993; 363(6429):558-61    Related articles (PubMed)

Toyota M, et al. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype Proc Natl Acad Sci USA. 2000; 97(2): 710-5

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ColoRectal Cancers Genetics
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Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, is an autosomal dominant disease characterised by early onset of colorectal cancer and increased risk of other malignancies including endometrial and renal cell carcinomas. HNPCC is associated with germline mutations of DNA mismatch repair genes, individuals who inherit HNPCC have an 80% lifetime risk of developing colorectal cancer.

In a study of 48 HNPCC kindreds (Liu et al, 1996) identified mutations in known mismatch repair genes;

31%: had mutations in the MSH2 gene

33%, had mutations in the MLH1 gene

2%, had mutations in the PMS1 gene

4% had mutations in the PMS2 gene

Lynch HT, et al. Hereditary nonpolyposis colorectal cancer. Semin Surg Oncol 2000 Jun;18(4):305-13    Related articles (PubMed)

Lynch HT, de La Chapelle A Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet 1999; 36(11):801-18    Related articles (PubMed)

Wang Q et al. Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, nonpolyposis colorectal cancer. Hum Genet 1999; 105:79-85    Related articles (PubMed)

Liu B, et al. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med 1996; 2(2):169-74    Related articles (PubMed)

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Petersen GM, et al. Genetic testing and counseling for hereditary forms of colorectal cancer. Cancer 1999; 86(8 Suppl):1720-30    Related articles (PubMed)

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Genetic Counselling Resources

 

Standard faecal occult blood testing for colorectal cancer has the benefit of being non-invasive, however, there are problems with sensitivity (tumours may bleed intermittently or not at all) and specificity. Since DNA is continuously released into the faecal stream there is potential for developing new screening tests to detect mutations in tumour DNA. Detecting mutations in single genes such as KRAS or TP53 may be limited as colorectal cancers have a heterogeneous range of DNA alterations and some mutations occur in non-malignant conditions eg. KRAS abnormalities in pancreatic hyperplasia. However, research into developing tests for multiple DNA alterations may offer great potential for new non-invasive screening for colorectal cancer with high levels of sensitivity and specificity.

Ahlquist DA Molecular stool screening for colorectal cancer. Using dna markers may be beneficial, but large scale evaluation is needed. [Editorial] BMJ 2000 Jul 29;321(7256):254-255

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KRAS Mutations and Colorectal Cancer Screening

Cancer Screening and Cancer Prevention

 

Matsuzaki M, et al. Detailed deletion mapping on chromosome 1p32-p36 in human colorectal cancer: identification of three distinct regions of common allelic loss. Int J Oncol 1998 Dec;13(6):1229-33    Related articles (PubMed)

Di Vinci A, et al. Intratumor distribution of 1p deletions in human colorectal adenocarcinoma is commonly homogeneous: indirect evidence of early involvement in colorectal tumorigenesis. Cancer 1998 Aug 1;83(3):415-22    Related articles (PubMed)

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Chromosme 1

 

Lerebours F, et al. Deletion mapping of the tumor suppressor locus involved in colorectal cancer on chromosome band 8p21. Genes Chromosomes Cancer 1999 Jun;25(2):147-53    Related articles (PubMed)

Fujiwara Y, et al. Evidence for the presence of two tumor suppressor genes on chromosome 8p for colorectal carcinoma. Cancer Res 1993 Mar 1;53(5):1172-4    Related articles (PubMed)

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Chromosme 8

 

Lindforss U, et al. Allelic loss is heterogeneous throughout the tumor in colorectal carcinoma. Cancer 2000 Jun 15;88(12):2661-7    Related articles (PubMed)

Takanishi DM Jr, et al. Chromosome 17p allelic loss in colorectal carcinoma. Clinical significance. Arch Surg 1995 Jun;130(6):585-8; discussion 588-9    Related articles (PubMed)

Khine K, et al. High frequency of allelic deletion on chromosome 17p in advanced colorectal cancer. Cancer 1994 Jan 1;73(1):28-35    Related articles (PubMed)

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Chromosme 17

 

Lindforss U, et al. Allelic loss is heterogeneous throughout the tumor in colorectal carcinoma. Cancer 2000 Jun 15;88(12):2661-7    Related articles (PubMed)

Lanza G, et al. Chromosome 18q allelic loss and prognosis in stage II and III colon cancer. Int J Cancer 1998 Aug 21;79(4):390-5    Related articles (PubMed)

Ogunbiyi OA, et al. Confirmation that chromosome 18q allelic loss in colon cancer is a prognostic indicator. J Clin Oncol 1998 Feb;16(2):427-33    Related articles (PubMed)

Jen J, et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 1994 Jul 28;331(4):213-21    Related articles (PubMed)

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ColoRectal Cancers Genetics
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Chromosme 18