FOUNDING MUTATIONS AND ALU-MEDIATED RECOMBINATION IN HEREDITARY COLON-CANCER

By screening members of Finnish families displaying hereditary nonpoly posis colorectal cancer (HNPCC) for predisposing germline mutations in MSH2 and MLH1, we show that two mutations in MLH1 together account fo r 63% (19/30) of kindreds meeting international diagnostic criteria. M utation 1, originally detected as a 165-base pair deletion in MLH1 cDN A comprising exon 16, was shown to consist of a 3.5-kilobase genomic d eletion most likely resulting from Alu-mediated recombination. Mutatio n 2 destroys the splice acceptor site of exon 6. A simple diagnostic t est based on polymerase chain reaction was designed for both mutations . Our results show that these two ancestral founding mutations account for a majority of Finnish HNPCC kindreds and represent the first repo rt of Alu-mediated recombination causing a prevalent, dominantly inher ited predisposition to cancer.