DNA mismatch repair and Lynch syndrome
- 187 Downloads
The evolutionary conserved mismatch repair proteins correct a wide range of DNA replication errors. Their importance as guardians of genetic integrity is reflected by the tremendous decrease of replication fidelity (two to three orders of magnitude) conferred by their loss. Germline mutations in mismatch repair genes, predominantly MSH2 and MLH1, have been found to underlie the Lynch syndrome (also called hereditary non-polyposis colorectal cancer, HNPCC), a hereditary predisposition for cancer. Lynch syndrome affects predominantly the colon and accounts for 2–5% of all colon cancer cases. During more than 30 years of biochemical, crystallographic and clinical research, deep insight has been achieved in the function of mismatch repair and the diseases that are associated with its loss. We review the biochemistry of mismatch repair and also introduce the clinical, diagnostic and genetic aspects of Lynch syndrome.
KeywordsMismatch repair Lynch syndrome HNPCC Hereditary non-polyposis colorectal cancer MSH2 MLH1
Unable to display preview. Download preview PDF.
We would like to apologize to all authors whose work could not be cited here due to space limitations. This work was supported by the HOMFOR Grant A/2004/13 to G.P. and by the Marianne and Klaus Paschke grant of the Freunde der Universität des Saarlandes to J.R.
- Alam NA, Gorman P, Jaeger EE, Kelsell D, Leigh IM, Ratnavel R, Murdoch ME, Houlston RS, Aaltonen LA, Roylance RR, Tomlinson IP (2003) Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability. Cancer Genet Cytogenet 147:121–127PubMedGoogle Scholar
- Ban C, Yang W (1998a) Crystal structure and ATPase activity of MutL: implications for DNA repair and mutagenesis. Cell 95:541–552Google Scholar
- Ban C, Yang W (1998b) Structural basis for MutH activation in E. coli mismatch repair and relationship of MutH to restriction endonucleases. EMBO J 17:1526–1534Google Scholar
- Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S (1998) A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248–5257PubMedGoogle Scholar
- Guarne A, Ramon-Maiques S, Wolff EM, Ghirlando R, Hu X, Miller JH, Yang W (2004) Structure of the MutL C-terminal domain: a model of intact MutL and its roles in mismatch repair. EMBO J 23:4134–4145Google Scholar
- Hendriks YM, Jagmohan-Changur S, Van Der Klift HM, Morreau H, Van Puijenbroek M, Tops C, Van Os T, Wagner A, Ausems MG, Gomez E, Breuning MH, Brocker-Vriends AH, Vasen HF, Wijnen JT (2006) Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch Syndrome). Gastroenterology 130:312–322PubMedGoogle Scholar
- Jagmohan-Changur S, Poikonen T, Vilkki S, Launonen V, Wikman F, Orntoft TF, Moller P, Vasen H, Tops C, Kolodner RD, Mecklin JP, Jarvinen H, Bevan S, Houlston RS, Aaltonen LA, Fodde R, Wijnen J, Karhu A (2003) EXO1 variants occur commonly in normal population: evidence against a role in hereditary nonpolyposis colorectal cancer. Cancer Res 63:154–158PubMedGoogle Scholar
- Lynch HT, Coronel SM, Okimoto R, Hampel H, Sweet K, Lynch JF, Barrows A, Wijnen J, Van Der Klift H, Franken P, Wagner A, Fodde R, De La Chapelle A (2004a) A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States. JAMA 291:718–724Google Scholar
- Lynch HT, Riley BD, Weissman SM, Coronel SM, Kinarsky Y, Lynch JF, Shaw TG, Rubinstein WS (2004b) Hereditary nonpolyposis colorectal carcinoma (HNPCC) and HNPCC-like families: problems in diagnosis, surveillance, and management. Cancer 100:53–64Google Scholar
- Nakagawa H, Lockman JC, Frankel WL, Hampel H, Steenblock K, Burgart LJ, Thibodeau SN, De La Chapelle A (2004) Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Res 64:4721–4727PubMedGoogle Scholar
- Umar A, Boland CR, Terdiman JP, Syngal S, De La Chapelle A, Ruschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HF, Hawk ET, Barrett JC, Freedman AN, Srivastava S (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268PubMedCrossRefGoogle Scholar
- Wu Y, Berends MJ, Post JG, Mensink RG, Verlind E, Van Der Sluis T, Kempinga C, Sijmons RH, Van Der Zee AG, Hollema H, Kleibeuker JH, Buys CH, Hofstra RM (2001) Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms. Gastroenterology 120:1580–1587PubMedGoogle Scholar