The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas

A comprehensive analysis of somatic and germline mutations related to DNA m ismatch-repair (MMR) genes can clarify the prevalence and mechanism of inac tivation in colorectal carcinoma (CRC). In the present study, 257 unselecte d patients referred for CRC resection were examined for evidence of defecti ve DNA MMR. In particular, we sought to determine the frequency of heredita ry defects in DNA MMR in this cohort of patients. MMR status was assessed b y testing of tumors for the presence or absence of hMLH1, hMSH2, and hMSH6 protein expression and for microsatellite instability (MSI). Of the 257 pat ients, 51 (20%) had evidence of defective MMR, demonstrating high levels of MSI (MSI-H) and an absence of either hMLH1 (n=48) or hMSH2 (n=3). All thre e patients lacking hMSH2, as well as one patient lacking hMLH1, also demons trated an absence of hMSH6. DNA sequence analysis of the 51 patients with d efective MMR revealed seven germline mutations-four in hMLH1 (two truncatin g and two missense) and three in hMSH2 (all truncating). A detailed family history was available for 225 of the 257 patients. Of the seven patients wi th germline mutations, only three had family histories consistent with here ditary nonpolyposis colorectal cancer. Of the remaining patients who had tu mors with defective MMR, eight had somatic mutations in hMLH1. In addition, hypermethylation of the hMLH1 gene promoter was present in 37 (88%) of the 42 hMLH1-negative cases available for study and in all MSI-H tumors that s howed loss of hMLH1 expression but no detectable hMLH1 mutations. Our resul ts suggest that, although defective DNA MMR occurs in 20% of unselected pat ients presenting for CRC resection, hereditary CRC due to mutations in the MMR pathway account for only a small proportion of patients. Of the 257 pat ients, only 5 (1.9%) appear to have unequivocal evidence of hereditary defe cts in MMR. The epigenetic (nonhereditary) mechanism of hMLH1 promoter hype rmethylation appears to be responsible for the majority of the remaining pa tients whose tumors are characterized by defective DNA MMR.