Bowel Cancer molecular biology and genetics

There are two major forms of colorectal cancer predisposition and both show autosomal dominant inheritance.

Bowel cancer molecular biology and genetics:

 
 

Familial adenomatous polyposis (FAP)

FAP accounts for approximately 1% of colorectal cancers in the west and is characterised by the presence of multiple (often thousands) of adenomas in the large bowel. FAP patients have an almost 100% risk of developing colorectal cancer by their 40s.

The gene for FAP is the APC tumour suppressor gene on chromosome 5q21. 1 The different mutation sites in the gene are associated with varying severities of the disease, though people with the same germline mutation may show different disease manifestations. This suggests that other factors, both genetic and/or environmental, may act as modifiers. Prophylactic surgery is offered to affected individuals, usually in their teens.

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Hereditary non-polyposis colorectal cancer (HNPCC)

HNPCC, or Lynch syndrome, is estimated to be responsible for 2-5% of colorectal cancers. HNPCC is caused by a fault in a DNA mismatch repair (MMR) gene; faults in the MMR genes hMSH2 and hMLH1 account for over 90% of detectable mutations. 2

HNPCC is characterised by early onset of bowel cancer and is associated with non-colorectal cancers, including cancers of the endometrium, ovaries, stomach, pancreatico-biliary system and urinary tract. Genetic testing for predisposing mutations in people with a strong family history of these cancers enables screening and prevention to be targeted to those most at risk. For people with a known mutation, especially young patients from HNPCC families, prophylactic surgery may be recommended. 3

Pilot studies in colorectal cancer patients under 30 years old have shown that 41% are carriers of MMR gene mutations. 4 The risk for people with these mutations of developing colorectal cancer by age 70 is approximately 91% for men and 69% for women. 5 A study in Scotland is screening all newly diagnosed colorectal cancer patients under the age of 55 years for MMR gene mutations.

Apart from FAP and HNPCC, hereditary factors are estimated to account for an additional 20% of colorectal cancer cases and a national collaborative study is underway to identify other genes involved in familial bowel cancer. In addition to the high-risk gene faults, polymorphisms with a moderate effect on risk have been described; these are variants in the APC, HRAS1-VNTR and MTHFR genes. 6

Other conditions that predispose to colorectal cancer include rare polyposis autosomal dominant conditions such as Peutz-Jeghers syndrome and familial juvenile polyposis. 7

Overall, only a minority of bowel cancers are linked to a strong inherited predisposition. Around 75% of colorectal cancers arise sporadically in people over the age of 50 years. Bowel cancer results from the accumulation of multiple mutations within a cell in the bowel lining allowing it to escape the normal growth control mechanisms. The step-wise accumulation of mutations drives the histological transition from normal tissue to adenoma to carcinoma. 7

The most common genetic alterations in sporadic bowel cancers are activating mutations in the oncogene KRAS and mutation or loss of the tumour suppressor genes APC, SMAD4 and TP53. There is good evidence that the occurrence of APC mutations represents the earliest step in colorectal carcinogenesis, and both copies of the APC gene are inactivated in up to 80% of sporadic cases. 8,9

The APC protein has many important roles including control of the Wnt developmental signalling pathway, cell adhesion, migration, apoptosis and chromosomal segregation. Loss of APC causes stabilisation of ß-catenin which binds the Tcf/LEF family of transcription factors, activating gene expression. 10

Better understanding of these pathways is helping researchers develop small molecule inhibitors of the Wnt cascade. There is some evidence that selected compounds can disrupt Tcf/ß-catenin complexes and screening for more refined targets is underway. 11

Other conditions linked to an increased risk include ulcerative colitis (UC) and Crohn’s disease. UC is estimated to be responsible for around 1% of cases. 12 Recent research suggests that environmental factors related to long-term inflammation of the bowel may contribute more to the increased cancer risk in UC than inherited susceptibility. 13

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References

  1.  Bodmer, W.F., et al., Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature, 1987. 328(6131): p. 614-6.
  2.  Liu, B., et al., Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med, 1996. 2(2): p. 169-74.
  3.  Burke, W., et al., Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA, 1997. 277(11): p. 915-9.
  4.  Farrington, S.M., et al., Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls. Am J Hum Genet, 1998. 63(3): p. 749-59.
  5.  Dunlop, M.G., et al., Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet, 1997. 6(1): p. 105-10.
  6.  Houlston, R.S. and I.P. Tomlinson, Polymorphisms and colorectal tumor risk. Gastroenterology, 2001. 121(2): p. 282-301.
  7.  Fearnhead, N.S., J.L. Wilding, and W.F. Bodmer, Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumorigenesis. Br Med Bull, 2002. 64: p. 27-43.
  8.  Powell, S.M., et al., APC mutations occur early during colorectal tumorigenesis. Nature, 1992. 359(6392): p. 235-7.
  9.  Miyoshi, Y., et al., Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet, 1992. 1(4): p. 229-33.
  10.  Fodde, R., R. Smits, and H. Clevers, APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer, 2001. 1(1): p. 55-67.
  11.  Lepourcelet, M., et al., Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell, 2004. 5(1): p. 91-102.
  12.  Winawer, S.J., Natural history of colorectal cancer. Am J Med, 1999. 106(1A): p. 3S-6S; discussion 50S-51S.
  13.  Wong, N.A. and D.J. Harrison, Colorectal neoplasia in ulcerative colitis-recent advances. Histopathology, 2001. 39(3): p. 221-34.