After hMSH2 and hMLH1—what next? Analysis of three‐generational, population‐based, early‐onset colorectal cancer families

Abstract

The aim of our study was to examine the role of genetic factors on early-onset colorectal cancer after excluding the impact of germline mutations in the two major mismatch repair genes. A total of 131 incident probands, under 45 years at diagnosis of a first primary colorectal cancer selected from the Victorian Cancer Registry, and their first-and seconddegree relatives, were interviewed. Germline DNA from all 12 probands with a family history meeting the modified Amsterdam Criteria for Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and a random sample of 31 of the remaining probands was screened for mutations in hMSH2 and hMLH1 via manual sequencing. Germline mutations were identified in 6 of the 131 probands (5%), all from the "HNPCC" families. Of the remaining 125 probands, 51 (41%) reported at least one first-or second-degree relative with colorectal cancer with an excess of colorectal cancer in firstdegree relatives (SMR ‫؍‬ 2.7, 95% CI ‫؍‬ 1.7-4.1, p < 0.001). The lifetime risk to age 70 for first-degree relatives was 8.0% (5.0 -12.8%), compared to the Victorian population risk of 3.2% (p ‫؍‬ 0.01). The best fitting major gene model was a recessively-inherited risk of 98% to age 70 (95% CI ‫؍‬ 24 -100%) carried by 0.17% of the population and would explain 15% of all colorectal cancer in cases with a diagnosis before age 45. Early-onset colorectal cancer is strongly familial even after excluding families found to be segregating a mutation in either of the 2 major mismatch repair genes. There is evidence for a role of yet to be identified genes associated with a high recessively-inherited risk of colorectal cancer. © 2002 Wiley-Liss, Inc. Germline mutations in several mismatch repair genes have been identified that greatly increase the risk of colorectal cancer and, to a lesser extent, cancer of other sites including the endometrium and small bowel. 1 Mutations in 2 of the mismatch repair genes, hMSH2 and hMLH1, have been found to be segregating with disease in about 50% of multiple-case, multi-generational families meeting the Amsterdam Criteria for hereditary non-polyposis colorectal cancer (HNPCC). 2,3 These families have at least 3 relatives diagnosed with colorectal cancer, at least 1 affected member being a first-degree relative of at least 2 other affected relatives, at least 2 affected relatives in successive generations and at least 1 affected member diagnosed before age 50. 1 Few instances of germline mutations in hMSH2 or hMLH1 have been documented outside HNPCC families except in those diagnosed with colorectal cancer at a very young age 4 -6 and only a small proportion of HNPCC families appear to have segregating a mutation in other mismatch repair genes, such as hMSH6. 7 Family history is one of the strongest predictors of colorectal cancer. 8 -12 A recent meta-analysis found that having a first-degree relative with colorectal cancer approximately doubled the risk of colorectal cancer and if the affected relative was diagnosed before age 45 the risk was approximately 4-fold. 13 What is ...

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