Cancer, hereditary colorectal

An important example of how a progression of somatic mutations leads to cancer is in hereditary colorectal cancer (Figure l4-6). 

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MSH2, MLH1, PM SI, DNA mismatch repair enzymes Hereditary nonpolyposis colorectal cancer... 

Familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC)... 

Mismatched base (Gj) DNA replication errors A mutation on one of two genes, hMSH2 or hMLHl, initiates defective repair of DNA mismatches, resulting in a condition known as hereditary nonpolyposis colorectal cancer— HNPCC. DNA polymerase DNA ligase... 

Hereditary nonpolyposis colorectal cancer results from a deficiency in the ability to repair mismatched base pairs in DNA that are accidentally introduced during replication. 

A second group of inherited colon cancers are termed hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC may account for 5% of all colon cancer cases and can be caused by mutations in any of five different genes. All of these genes encode proteins involved in DNA mismatch repair (Fig II-5-3). As with inherited breast cancer, fiiulty DNA repair leads to mutated cells capable of producing tumors. 

There are two major forms of hereditary susceptibility to colon cancer.00 Familial adenomatous polyposis is caused by defects in the APC gene (see Chapter 32). The more common hereditary nonpolyposis colorectal cancer (HNPCC), which includes many endometrial, stomach, and urinary tract tumors, results from defects in DNA mismatch repair. -)) The proteins hMSH2 and hMSLl are homologs of the E.coli MutS and MutL (main text). 

The MSI is used as a diagnostic criterion of replication errors caused by various mutations in at least five mismatch repair genes (Lynch and Smyrk, 1996). Therefore, MSI analysis is useful in clinical practice to identify patients with hereditary nonpolyposis colorectal cancer. Raedle et al. (1999) have presented a rapid DNA extraction method (rapid microsatellite analysis) for analyzing replication errors in paraffin-embedded tissues. 

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Kong S, Amos Cl, Luthra R, Lynch PM, Levin B, Frazier ML. Effects of cyclin D1 polymorphism on age of onset of hereditary nonpolyposis colorectal cancer. Cancer Res 2000 60 249-252. 

Charbonnier F, Raux G, Wang Q, Drouot N, Cordier F, Limacher JM, Saurin JC, Puisieux A, Olschwang S, Frebourg T. Detection of exon deletions and duplications of the mismatch repair genes in hereditary nonpolyposis colorectal cancer families using multiplex polymerase chain reaction of short fluorescent fragments. Cancer Res 2000 60(ll) 2760-2763. 

H. T. Lynch, T.C. Smyrk, P. Watson, S.J. Lanspa, J.F. Lynch, P.M. Lynch, R.J. Cavalieri, and C.R. Boland. 1993. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer An updated review Gastroenterology 104 1535-1549. (PubMed)... 

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