Molecular Diagnosis of Hereditary Nonpolyposis Colorectal Cancer

When a new strand of DNA is synthesized during the process of replication, errors that are not immediately corrected by the 3′ to 5′ exonuclease activity of DNA polymerase are corrected by a DNA mismatch repair (MR) system. Mutations in gene coding for proteins that participate in the MR system allow persistence of replication errors that would otherwise be repaired. Some of these errors take the form of a phenomenon called microsatellite instability—insertions or deletions of simple repetitive elements within microsatellite sequences that occur throughout the genome. Approximately 0.1% to 0.5% of the population carries a germline mutation in 1 of 6 MR genes, hMSH2, hMSH6, hMLH1, hPMS1, hPMS2, or hTGFBR2 (and perhaps others), that results in a substantial increase in the probability of developing cancer of the colon and rectum, endometrium, kidney, and other sites.¹ Up to 80% of people who harbor a mutation in 1 of the MR genes will develop colorectal cancer (accounting for approximately 5000 new colorectal cancers in the United States yearly)¹; up to 60% of women will develop endometrial cancer.²