Microsatellite Instability and Mismatch Repair Protein Defects in Ovarian Epithelial Neoplasms in Patients 50 Years of Age and Younger

Abstract

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 <or=50 years of age is neither well known nor well tested. Fifty-two ovarian surface epithelial carcinomas, including 4 with synchronous endometrial carcinomas, were identified in patients 50 years of age or younger and evaluated for evidence of MSI and MMR protein deficiency. Each case was tested for MSI 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 MSI (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 1 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 1 or more MMR proteins was initially noted in 10/50 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 <or=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 <or=50 years of age.

Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma

“…An association between clear cell carcinoma of the ovary and MSI has been reported 46 – 49. In our series, there were two patients (one with a known MSH6 germline mutation) with EC and synchronous clear cell carcinoma of the ovary in the abnormal IHC group.…”

Genetic Testing by Cancer Site

“…75 In an analysis of 52 ovarian carcinomas in a population who received a diagnosis at younger than 50 years, defects in MMR expression were identified in 10% of cases using MSI and IHC. 88 Domanska and colleagues 89 evaluated ovarian carcinomas in a population who received a diagnosis at younger than 40 years and found MMR deficiency with IHC in È6% of cases. If tumor studies are indicative of Lynch syndrome (results show the tumor to be MSI-high and/or loss of Q1 MMR proteins), germline genetic testing should be offered and will identify a deleterious mutation anywhere from 20% to 70% of the time.…”

Endometrial Carcinoma in Women Aged 40 Years and Younger

“…Clear cell carcinomas of the ovary in young patients appear to be particularly associated with Lynch syndrome. [76][77][78] SUMMARY Endometrial carcinomas in patients 40 years of age and younger are uncommon. Most of these tumors are associated with estrogen excess; they are usually low-grade endometrioid carcinomas that present at low stages with excellent prognosis.…”