The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer

Background & Aims: Estimates of the frequency of hereditary nonpolyposis co lon cancer (HNPCC) based on clinical criteria have varied widely. Recent st udies of germline mismatch repair gene mutations have suggested that HNPCC accounts for close to 3% of all colon cancer, but this estimate may have be en inflated by inclusion of founder effects peculiar to Finland. We therefo re determined by genetic criteria the colon cancer burden associated with H NPCC in a population-based study of 1066 individuals from Utah and Californ ia. Methods: The coding regions of mismatch repair genes hMSH2 and hMLH1 we re sequenced from the germline of those individuals whose tumors exhibited microsatellite instability. Results: Microsatellite instability was present in 16% (171/1066) of tumors. Pathogenic germline mismatch repair gene muta tions were identified in 7 individuals, and missense amino acid changes of uncertain significance were identified in another 6 individuals. After adju sting for the availability of sufficient germline DNA for sequencing, the 7 clearly pathogenic mutations accounted for 0.86% of colon cancer at the po pulation level. Individuals with these mutations were significantly younger , more likely to have a family history of colon and endometrial cancer, and more likely to have first-degree relatives with a young-age onset of colon cancer than individuals with unstable tumors but without germline mutation s (P < 0.01). Conclusions: We conclude that genetically defined HNPCC accou nts for a very small percentage of colon cancer at the population level, a percentage less than that estimated by most previous clinical studies.