Germ-line mutations in MLH1 and MSH2 genes predispose to hereditary non-polyposis colorectal cancer (HNPCC) syndrome, but they do not predict a specific phenotype of the disease. We speculated that the ataxia-telangiectasia mutated gene (ATM) was a candidate gene to modulate the phenotypic expression of HNPCC, as heterozygous individuals for germ-line ATM mutations have been considered at higher risk of developing epithelial malignancies. The frequency of the ATM D1853N polymorphism was evaluated in 167 individuals from 20 HNPCC families in which MLH1 or MSH2 germ-line mutations co-segregated with the disease. Among the 67 MLH1 or MSH2 mutation carriers, the ATM 1853N variant was associated with a significantly higher incidence of colorectal and other HNPCC-related cancers, when compared with individuals carrying the ATM 1853D variant [12/13 (92%) vs. 31/54 (57.5%); p = 0.02]. MLH1 and MSH2 mutation carriers who concomitantly carried the ATM 1853N variant, had an 8 times increased risk of developing colorectal and other HNPCC-related cancers (OR: 8.9; p = 0.02), when compared with MLH1 or MSH2 mutation carriers with the ATM 1853D variant. Our results suggest that the ATM D1853N polymorphism modulates the penetrance of MLH1 and MSH2 germ-line mutations.
Copyright 2000 Wiley-Liss, Inc.