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

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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 second‐degree 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 first‐degree 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.