Hereditary cancer due to pathological mutations in the mismatch repair gene family is now known as Lynch syndrome and affects at least 1 in 1,000 people, resulting in a 30–50% cancer risk most often involving the colorectum and endometrium. Annual or biennial colonoscopy reduces cancer deaths and many offer gynaecological surveillance, but most other associated cancers are not amenable to early detection. As microsatellite instability testing and tumour immunohistochemistry become routine, case finding will improve. Our recent demonstration that 600 mg aspirin per day for at least 2 years reduces the cancer burden by 63% after a 3-year lag period reinforces the need to identify gene carriers and introduce them to chemoprevention. CaPP3 will test different doses of aspirin in at least 3,000 gene carriers to determine whether low-dose aspirin is as effective.

Lynch HT, Krush AJ: Cancer family ‘G’ revisited: 1895–1970. Cancer 1971;27:1505–1511.
Vasen HF, Moslein G, Alonso A, Bernstein I, Bertario L, Blanco I, Burn J, Capella G, Engel C, Frayling I, Friedl W, Hes FJ, Hodgson S, Mecklin JP, Moller P, Nagengast F, Parc Y, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Wijnen J: Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 2007;44:353–362.
Peltomaki P, Aaltonen LA, Sistonen P, Pylkkanen L, Mecklin J-P, Jarvinen H, Green JS, Jass JR, Weber JL, Leach FS, Petersen GM, Hamilton SR, De la Chapelle A, Vogelstein B: Genetic mapping of a locus predisposing to human colorectal cancer. Science 1993;260:810–819.
Fishel R, Lescoe MK, Rao MRS, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993;75:1027–1038.
Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Clendenning M, Sotamaa K, Prior T, Westman JA, Panescu J, Fix D, Lockman J, LaJeunesse J, Comeras I, de la Chapelle A: Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008;26:5783–5788.
Wheeler JMD, Loukola A, Aaltonen LA, Mortensen NJM, Bodmer WF: The role of hypermethylation of the hMLH1 promoter region in HNPCC versus MSI+ sporadic colorectal cancers. J Med Genet 2000;37:588–592.
Ligtenberg MJ, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, Lee TY, Bodmer D, Hoenselaar E, Hendriks-Cornelissen SJ, Tsui WY, Kong CK, Brunner HG, van Kessel AG, Yuen ST, van Krieken JH, Leung SY, Hoogerbrugge N: Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet 2009;41:112–117.
Clendenning M, Senter L, Hampel H, Robinson KL, Sun S, Buchanan D, Walsh MD, Nilbert M, Green J, Potter J, Lindblom A, de la Chapelle A: A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome. J Med Genet 2008;45:340–345.
Domingo E, Laiho P, Ollikainen M, Pinto M, Wang L, French AJ, Westra J, Frebourg T, Espin E, Armengol M, Hamelin R, Yamamoto H, Hofstra RMW, Seruca R, Lindblom A, Peltomaki P, Thibodeau SN, Aaltonen LA, Schwartz S Jr: BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet 2004;41:664–668.
Dinh TA, Rosner BI, Atwood JC, Boland CR, Syngal S, Vasen HF, Gruber SB, Burt RW: Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population. Cancer Prev Res (Phila) 2011;4:9–22.
Schwitalle Y, Kloor M, Eiermann S, Linnebacher M, Kienle P, Knaebel HP, Tariverdian M, Benner A, von Knebel Doeberitz M: Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 2008;134:988–997.
Kloor M, Michel S, Buckowitz B, Ruschoff J, Buttner R, Holinski-Feder E, Dippold W, Wagner R, Tariverdian M, Benner A, Schwitalle Y, Kuchenbuch B, von Knebel Doeberitz M: Beta2-microglobulin mutations in microsatellite unstable colorectal tumors. Int J Cancer 2007;121:454–458.
Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, Tu D, Redston M, Gallinger, S: Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349:247–257.
Burn J, Bishop DT, Chapman PD, Elliott F, Bertario L, Dunlop MG, Eccles D, Ellis A, Evans DG, Fodde R, Maher ER, Moslein G, Vasen HF, Coaker J, Phillips RK, Bulow S, Mathers JC: A randomized placebo-controlled prevention trial of aspirin and/or resistant starch in young people with familial adenomatous polyposis. Cancer Prev Res (Phila) 2011;4:655–665.
Kune GA, Kune S, Watson LF: Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer Study. Cancer Res 1988;48:4399–4404.
Cuzick J, Otto F, Baron JA, Brown PH, Burn J, Greenwald P, Jankowski J, La Vecchia C, Meyskens F, Senn HJ, Thun M: Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol 2009;10:501–507.
Burn J, Bishop DT, Mecklin JP, Macrae F, Moslein G, Olschwang S, Bisgaard ML, Ramesar R, Eccles D, Maher ER, Bertario L, Jarvinen HJ, Lindblom A, Evans DG, Lubinski J, Morrison PJ, Ho JW, Vasen HF, Side L, Thomas HJ, Scott RJ, Dunlop M, Barker G, Elliott F, Jass JR, Fodde R, Lynch HT, Mathers JC: Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med 2008;359:2567–2578.
Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, Eccles D, Evans DG, Maher ER, Bertario L, Bisgaard ML, Dunlop MG, Ho JW, Hodgson SV, Lindblom A, Lubinski J, Morrison PJ, Murday V, Ramesar R, Side L, Scott RJ, Thomas HJ, Vasen HF, Barker G, Crawford G, Elliott F, Movahedi M, Pylvanainen K, Wijnen JT, Fodde R, Lynch HT, Mathers JC, Bishop DT: Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2011;378:2081–2087.
Flossmann E, Rothwell PM: Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 2007;369:1603–1613.
Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, Meade TW: Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010;376:1741–1750.
Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z: Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012;379:1591–1601.
Chan AT, Ogino S, Fuchs CS: Aspirin use and survival after diagnosis of colorectal cancer. JAMA 2009;302:649–658.
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