Hereditary nonpolyposis cancer

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

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

Without regard to therapy, potentially valuable diagnostic tests are available for presymptomatic evaluation of risk of breast cancer due to predisposition from BRCA 1 or BRCA 2 and of colon cancer related to familial adenomatous polyposis (APC gene) or hereditary nonpolyposis mismatch repair genes (MSH 2). Genetic predisposition to Alzheimer disease associated with ApoE4 is neither sufficient nor necessary to lead to the clinical condition, and no definitive therapy is available. 

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. 

Lynch, H. T., and Smyrk, T. 1996. Hereditary nonpolyposis colorectal cancer (Lynch Syndrome) An updated review. Cancer 78 1149-1167. 

Raedle, J., Brieger, A., Trojan, J., Hardt, T., Herrmann, G., and Zeuzem, S. 1999. Evaluation of rapid microsatellite analysis of paraffin embedded specimens in screening for hereditary nonpolyposis colorectal cancer. Mod. Pathol. 72 485-491. 

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. 

PMSl). The DNA located between the nick and the mismatch is removed by 3 to 5 or 5 to 3 exonucleases depending on whether the nick is 3 or 5 to the mismatch. The gap is then filled by DNA Pol III in E. coli (Fig. 10) by DNA Pol 5 in humans and is ligated. Mismatch repair increases the spontaneous mutation rate in E. coli and yeast. Humans defective in mismatch repair exhibit a cancer-prone syndrome called hereditary nonpolyposis colon cancer (HNPCC), and sporadic mutations of mismatch repair genes are also associated with up to 50% of all human cancers (42 4). 

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)... 

R. Fishel, M.K. Lescoe, M.R.S. Rao, N.G Copeland, N.A. Jenkins, J. Garber, M. Kane, and R. Kolodner. 1993. The human mutator gene homologTV75772 and its association with hereditary nonpolyposis colon cancer Cell 75 1027-1038. (PubMed)... 

Microsatellite instability is found to be a common feature of nearly all tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) (4,16). The majority of HNPCC cases arise through germline mutations in two genes, hMSH2 and hMLHl on chromosomes 2 and 3, which encode the human homologs of bacterial mismatch repair genes, MutS and MutL (17,18). Cells which display microsatellite instability are termed as having an RER+ phenotype, which stands for replication error (5). Such RER+ tumor cells have been shown to have defects in mismatch repair and possess a mutator phenotype (19). 

Inherited CRC syndromes initiate as a result of an inherited mutation in one of the genes involved in the CIN or MSI pathway. Although several CRC syndromes exist, the two most common are famUial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), Most interestingly, tumors in FAP kindreds and tumors displaying CIN more frequently are found in the distal part of the colon, whereas tumors in HNPCC families and tumors displaying MSI more commonly occur in the proximal part of the colon. ... 

Aaltonen LA, Salovaara R, Kristo P, Caiizian F, Hemminki A, Peltomald P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 1998 338 1481-7. 

Akiyama Y, Iwanaga R, Saitoh K, Shiba K, Ushio K, Ikeda E, et ai. Transforming growth factor B type II receptor gene mutations in adenomas from hereditary nonpolyposis colorectal cancer. Gastroenterology 1997 112 33-9. 

Burke W, Peterson G, Lynch P, Botkin J, Daly M, Garber J, et al. Recommendations for follow-up care of individuals with inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 1997 277 915-9. 

Jenkins NA, Garber J, et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. CeU 1993 75 1027-38. 

Leach FS, Nicolaides NC, Papadopoulos N> Liu B, Jen J, Parsons R, et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993 75 1215-25. 

Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 1997 17 271-2. 

Peltomaki P, Vasen HF, and the ICG-HNPCC. Mutations predisposing to hereditary nonpolyposis colorectal cancer database and results of a collaborative study. Gastroenterology 1997 113 1146-58. 

Vasen HFA, Watson P, Mecklin JP, Lynch HT and The International Collaborative Group on HNPCC. New clinical criteria for Hereditary Nonpolyposis Colorectal Cancer (Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 1999 116 1453-6. 

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