Microsatellite instability as a predictor of a mutation in a DNA mismatch repair gene in familial colorectal cancer

Germline alterations in human DNA mismatch repair genes are associated with hereditary nonpolyposis colorectal cancer (HNPCC). Mutation analysis of th e genes reveals carriers with a high risk of colorectal cancer, who will be nefit from surveillance. We wanted to find the best predictive parameter of a germline mutation in those genes among patients with familial colorectal cancer. Affected members from a total of 83 unrelated colorectal cancer fa milies previously analyzed for mutations in MSH2 and MLH1 were used to eval uate different parameters' ability to predict a germline mutation. We studi ed various clinical criteria such as family structure, age of onset, and pr evalence of endometrial cancer, as well as microsatellite instability in th e tumors from the families. In total, 124 tumors from 59 of the families we re tested for microsatellite instability (MSI) using PCR-based mono- and di nucleotide markers to establish whether the families could be scored as MSI -positive or -negative. The finding of MSI-positive tumors in a family was the best predictor of a germline mutation, and was found in 73% of the MSI- positive, but in less than 3% of the MSI-negative families (P < 0.0001). In contrast, MSI in unselected colorectal cancer is not as useful, since most of these MSI-positive tumors are sporadic. The finding of microsatellite i nstability in colorectal tumors seems efficient enough even to select those with germline mutations among families fulfilling HNPCC Amsterdam criteria , once used in identification of the DNA mismatch repair genes. Genes Chrom osomes Cancer 27:17-25, 2000. (C) 2000 Wiley-Liss, Inc.