Immunohistochemical detection of sporadic and hereditary colorectal carcinomas with defective DNA mismatch repair

Background. Identification of colorectal carcinomas (CRCs) with defective DNA mismatch repair (MMR) is of great clinical relevance. Aim of the present study was to precisely determine the role of immunohistochemistry as a screening test for the detection of these tumors. Design. A consecutive series of 330 CRCs was included in the study. Expression of MMR proteins (MLH1, MSH2, MSH6 and PMS2) was evaluated by immunohistochemistry and microsatellite instability (MSI) by a fluorescence PCR method using mononucleotide (BAT26, BAT25 and BAT40) and dinucleotide markers. MLH1 promoter methylation was determined by methylation specific PCR. Results. Deficit of MMR was observed in 51 tumors (MMR-D, 15,5%), whereas the remaining 279 CRCs showed normal protein expression and microsatellite stability and were classified as MMR proficient (MMR-P, 84,5%). 50/51 MMR-D tumors showed high frequency MSI and 50/51 demonstrated loss of protein expression. In detail 39 tumors showed complete loss of MLH1 and PMS2 expression, 3 tumors loss of MSH2 and MSH6 expression, and 6 tumors selective loss of the MSH6 protein. A single carcinoma showed selective loss of PMS2 expression. The large majority (84,3%) of MMR-D tumors were localized in the proximal colon. MLH1 promoter methylation was observed in 34 MLH1/PMS2 negative carcinomas. On the basis of immunohistochemical data and MLH1 promoter methylation status, we can hypothesize that about 70% of MMR-D tumors were sporadic and 30% hereditary. Conclusion. Our results indicate that immunohistochemistry is a rapid and suitable method for the identification of MMR-D CRCs. Pathologic screening of colorectal tumors should include analysis of expression of MLH1, MSH2 and MSH6 proteins, as the observed frequency of cases with selective loss of MSH6 expression was much higher than expected