MSH6 Knockout Cell Lysate

Background: Immunohistochemistry for loss of expression of one or more of the mismatch repair proteins is performed on colorectal cancer tissue as a screening test for Lynch syndrome; however, its role in pre-malignant polyps remains controversial. Aim: To determine the effectiveness of mismatch repair immunohistochemistry performed on pre-malignant colorectal polyps in identifying Lynch syndrome, focusing on clinical utility and value. Methods: A retrospective audit was conducted of mismatch repair immunohistochemistry performed on non-malignant polyps in patients who attended the Family Cancer Clinic at the Royal Melbourne Hospital. Two hundred and six patient records over a 10-year period (2006-2016) were reviewed. Personal and family history data were collected, including genetic testing results. Results: Of the 57 patients who underwent polyp testing, the family histories comprised Amsterdam II Criteria (12.3%), Lynch syndrome-associated malignancies (42.1%), Lynch syndrome-associated malignancies and polyps (35.1%) and polyps only (8.8%); 10.5% of patients had no significant family history. Normal expression of the mismatch repair proteins was observed in 94.7% of patients; loss of expression was observed in three individuals with concordant germline variants in two patients (one PMS2 variant of unknown significance and one MSH6 mutation). Additional genetic testing in 21 patients with normal immunohistochemistry did not identify any additional Lynch syndrome cases. Conclusion: The clinical utility of mismatch repair immunohistochemistry on polyp tissue was low. No additional cases of Lynch syndrome were identified, and a large proportion of patients proceeded to germline testing despite normal polyp immunohistochemistry. We suggest there is no value in this approach.

Screening for Lynch syndrome (LS) is routinely performed in patients with endometrial carcinoma. Currently, no screening recommendations exist for LS in precancerous lesions. The study goal was to determine the incidence of abnormal protein expression in endometrioid intraepithelial neoplasia/atypical hyperplasia (EIN/AH). We analyzed mismatch repair (MMR) protein expression by immunohistochemistry in EIN/AH concurrent with MMR-deficient endometrial carcinomas, and in endometrial biopsy/curettage specimens with EIN/AH from an unselected group of patients. Of 63 patients with MMR-deficient endometrial carcinoma, 34 demonstrated loss of MLH1/PMS2 expression; 1 showed loss of PMS2 alone; 12 showed loss of MSH2/MSH6, and 15 had loss of MSH6 alone. Genetic testing identified deleterious mutations in 14 cases (LS). 15 tumors demonstrated MLH1 promoter hypermethylation. Abnormal MMR expression in EIN/AH and adjacent carcinoma was concordant in 100% of LS cases and 71% of MLH1 promoter hypermethylation cases. Of 118 patients from the unselected group with EIN/AH, 4 (3%) cases demonstrated absent expression of one or more MMR proteins. Of these, 2 patients were later confirmed to have deleterious mutations in subsequent specimens with endometrial carcinoma. The prevalence of abnormal MMR expression in EIN/AH adjacent to carcinoma and in the unselected group of patients with EIN/AH is similar to the reported prevalence of LS in endometrial carcinoma. Identifying patients at high risk for LS through abnormal MMR expression in EIN/AH provides the benefit of early surveillance, treatment and timely diagnosis for the patient and affected family members.