Microsatellite instability and mismatch repair protein defects in ovarian epithelial neoplasms in patients 50 years of age and younger

Ovarian malignancies occurring in the setting of hereditary nonpolyposis colorectal carcinoma syndrome typically present in young women, often as the first or "sentinel" cancer, but the frequency of microsatellite instability (MSI) and mismatch repair (MMR) defects in ovarian surface epithelial malignancies in women :! 50 years of age is neither well known nor well tested. Fifty-two ovarian surface epithelia] carcinomas, including 4 with synchronous endometrial carcinomas, were identified in patients 50 years of age or younger and evaluated for evidence of NISI and MMR protein deficiency. Each case was tested for NISI by multiplex polymerase chain reaction amplification of the National Cancer Institute reference panel (BAT25, BAT26, D2S123, D5S346, and D17S250) and deficiency of MMR protein expression by immunohistochemistry (MLH1, MSH2, MSH6, and PMS2). MMR protein expression and NISI (in a subset of cases) were also evaluated in 50 unselected ovarian serous tumors of low malignant potential, a tumor common in younger women. Defects in MMR were detected in 5 of 52 (10%) ovarian carcinomas by at least I testing method, including 2 of 4 (50%) ovarian cancers presenting with synchronous endometrial cancer. Three of the 5 (60%) ovarian carcinomas were clear cell carcinomas (17% of all pure clear cell carcinomas) and the remaining 2 were high-grade carcinomas with endometrioid and mixed histology. Loss of MSH2 and MSH6 was detected in all of the affected clear cell carcinomas and a synchronous endometrial cancer with endometrioid histology. Loss of I or more MMR proteins was initially noted in 10150 ovarian serous tumors of low malignant potential on tissue microarray, but further testing on full tissue sections showed intact protein expression and microsatellite stability in all informative cases. This study demonstrates a 10% rate of MMR-deficient ovarian cancer in women :! 50 years of age. MMR-deficient ovarian cancer is frequently associated with loss of expression of MSH2 and MSH6 proteins and clear cell histology. The occurrence of MMR inactivation in a significant proportion of ovarian clear cell carcinomas (17% in this study) suggests that this tumor may warrant targeted testing in women <= 50 years of age.