title: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, Canada. fangilu@interchange.ubc.ca
authors.forename: Fang-I
authors.initials: FI
authors.lastname: Lu
authors.forename: Cyril Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: Anna-Marie
authors.initials: AM
authors.lastname: Mulligan
authors.forename: Paul
authors.initials: P
authors.lastname: Ryan
authors.forename: Ghassan
authors.initials: G
authors.lastname: Allo
authors.forename: Keiyan
authors.initials: K
authors.lastname: Sy
authors.forename: Particia A
authors.initials: PA
authors.lastname: Shaw
authors.forename: Aaron
authors.initials: A
authors.lastname: Pollett
authors.forename: Blaise A
authors.initials: BA
authors.lastname: Clarke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D000251:Adenosine Triphosphatases / Q000032:analysis; D000328:Adult; D000077216:Carcinoma, Ovarian Epithelial; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000032:analysis; D005260:Female; D006801:Humans; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000032:analysis; D009375:Neoplasms, Glandular and Epithelial / Q000737:chemistry* / Q000235:genetics*; D009687:Nuclear Proteins / Q000032:analysis; D010051:Ovarian Neoplasms / Q000737:chemistry* / Q000235:genetics*; D046888:Tissue Array Analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes