Testing for defective DNA mismatch repair in colorectal carcinoma: a practical guide

Abstract

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.