Prevalence of Loss of Expression of DNA Mismatch Repair Proteins in Primary Epithelial Ovarian Tumors

Abstract

Although different histologic subtypes of epithelial ovarian tumors have long been recognized, their molecular abnormalities have not been fully defined. We examined the prevalence of DNA mismatch repair (MMR) protein loss in these tumors. Tissue microarrays (TMA) of suspected ovarian carcinomas were stained for hMLH1, hMSH2, hMSH6, and hPMS2 and scored separately by 2 groups of investigators. Loss of staining (negative) or discrepant staining results on TMA were verified on whole-section slides. Intact (positive) staining results were also verified for an additional 25 randomly selected cases. Clinical data for cases demonstrating MMR protein loss were collected. A second set of TMA composed purely of mucinous tumors was also stained for antibodies to MMR proteins and scored by 1 group of investigators. TMA was an effective method for screening a large number of ovarian tumors for MMR protein expression, with a sensitivity of 100% for all 4 MMR proteins, and a specificity of 22.2%-53.8% for different MMR proteins. Of the primary epithelial tumors of the ovary, loss of expression of MMR proteins was significantly more common in the endometriosis-associated carcinomas (7/69; 10.1%) than in high-grade serous carcinomas (2/182; 1.1%): P=0.0021. The former group also showed more frequent loss of MMR proteins compared with mucinous intestinal-type carcinomas (0/32; P=0.0940). Cases within the group of endometriosis-associated carcinomas were endometrioid (2/29 cases), clear cell (1/27 cases), undifferentiated (1/8 cases), and mixed carcinomas with an endometrioid, clear cell, and/or undifferentiated component (3/5 cases). No loss of MMR protein expression was identified in epithelial tumors of other histologic subtypes. Our study demonstrated the loss of MMR protein expression in 10.1% of endometriosis-associated ovarian carcinomas. These results raise the possibility of selective screening for Lynch syndrome in patients with these types of ovarian carcinoma.

The Prevalence and Associated Factors of Microsatellite Instability in Ovarian Epithelial Cancers Detected by Molecular Genetic Studies in a Sample of Iranian Women

“…The wide range was due to differences in study design, number, and type of detector markers and the criteria for the definition of MSI-H (14, 15). However, in the studies using Bethesda panel markers or MSI analysis system, the rate of MMR system defects has been reported at about 10% (CI95% = 6 -14) in ovarian epithelial cancers (16)(17)(18). Therefore, our results are consistent with previous findings regarding the overall rate of MSI in all histological types.…”

Ovarian Cancer: A Heterogeneous Disease

“…Sporadic cases showing microsatellite instability have been reported [37]. EC harbor some somatic mutations of CTNNB1, PI3KCA, PPP2R1A, PTEN, and ARID1A [38].…”

The molecular background of mucinous carcinoma beyond MUC2

“…BRAF mutations are rare in ovarian carcinoma, with only 0-9% of MC and 0-4% of NMC showing this mutation [112,117,118]. There seems to be no significant role for MSI in the mucinous differentiation, with MSI in 0-55% of MC and in 2-62% of NMC (supplementary material, Figure S4) [120][121][122][123][124]. For PIK3CA and PTEN, literature is limited.…”