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The utility of immunohistochemical detection of DNA mismatch repair proteins in screening colorectal cancer for hereditary nonpolyposis colorectal cancer (HNPCC) is being widely investigated. Currently, in both research and clinical settings, a 4-antibody panel that includes the 4 most commonly affected proteins (MLH1, MSH2, MSH6, and PMS2) is being used generally. On the basis of the biochemical properties of these proteins, we hypothesized that a 2-antibody panel, comprising MSH6 and PMS2, would be sufficient to detect abnormalities in all 4 proteins. We tested this hypothesis on a series of 232 colorectal carcinoma samples derived from 2 patient cohorts: (1) a prospectively accrued series of patients who were judged to carry a higher-than-average risk for HNPCC based on the revised Bethesda guidelines (n=190); and (2) a retrospective series of patients who were 40 years of age or younger (n=42). Immunohistochemical stains were regarded as negative (protein lost), when there was no nuclear labeling in tumor cells (with positive internal control). Overall, 70 of the 232 tumors demonstrated loss of at least one protein. The most common abnormality was concurrent loss of MLH1 and PMS2 (observed in 17% of the cases), followed by concurrent loss of MSH2 and MSH6 (6%). All MLH1 and MSH2-abnormal cases were also abnormal for PMS2 and MSH6, respectively, whereas 9 of 50 (18%) PMS2 and 6 of 20 (30%) MSH6-abnormal cases showed only isolated loss of PMS2 or MSH6 (with normal staining for MLH1 and MSH2). As such, our findings provide evidence that a 2-antibody panel (PMS2 and MSH6) is as effective as the current 4-antibody panel in detecting DNA mismatch repair protein abnormalities. Such a cost-effective approach carries significant implication, as immunohistochemistry is being widely used as first-line screening for HNPCC.