Testing for Defective DNA Mismatch Repair in Colorectal Carcinoma: A Practical Guide

Context.—Significant bench and clinical data have been generated during the last decade regarding DNA mismatch repair in colorectal carcinoma. Objectives.—To review clinically relevant aspects of defective DNA mismatch repair in colorectal carcinoma and to suggest testing algorithms for identification of these tumors in the sporadic and familial settings. Data Sources.—This article is based on literature review and clinical testing experience of more than 2000 patient samples. Conclusions.—Approximately 15% of colorectal carcinomas arise as a result of defective DNA mismatch repair. Ninety percent of these carcinomas are sporadic, arising as a result of methylation of the MLH1 gene promoter, silencing expression. These sporadic carcinomas have improved stage-specific prognosis and can be identified by demonstrating aberrant loss of expression with an MLH1 immunoperoxidase stain. Familial colorectal carcinomas with defective DNA mismatch repair (Lynch syndrome) are due to a germline defect in one of several DNA mismatch repair genes. The familial carcinomas are best identified with a combination of immunohistochemistry and molecular microsatellite analysis. This testing facilitates subsequent directed genetic testing of the proband and family members.