title: Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma.
abstract: This study was undertaken with the hypothesis that certain common morphologic features of ovarian carcinomas are predictably associated with BRCA1 and BRCA2 deficiencies. We selected 43 high-grade serous carcinomas diagnosed at Memorial Sloan-Kettering Cancer Center that were studied as part of The Cancer Genome Atlas pilot project. In addition to 12 randomly selected nonfamilial BRCA-unassociated cases, all 31 Memorial Sloan-Kettering Cancer Center cases with BRCA1 or BRCA2 abnormality were included (n=43). Slides were examined to assess tumor architecture, mitotic index, tumor-infiltrating lymphocytes (TILs), nuclear pleomorphism, necrosis, and involvement of fallopian tube epithelium. Comparing BRCA1-associated cases (BRCA1 germline mutation, n=4, BRCA1 somatic mutation, n=6, BRCA1 promoter methylation, n=13) with unassociated cases (n=12) identified statistically significant differences in morphology. BRCA1-associated high-grade serous carcinomas had more frequent Solid, pseudoEndometrioid, and Transitional cell carcinoma-like morphology (SET features) (P=0.0045), higher mitotic indexes (P=0.012), more TILs (P=0.034), and either geographic or comedo necrosis (P=0.034). BRCA2-associated cases (germline mutation, n=4 and somatic mutation, n=4) tended to show SET features, but they were relatively deficient in TILs and necrosis. Two algorithms incorporating tumor architecture, necrosis, and either mitotic indexes or TILs separated cases that showed 2 of 3 features (BRCA1 associated) from those with 0 of 3 features (BRCA unassociated; P=0.0016 and P=0.0033). A test set comprising 9 BRCA1 germline mutants and 14 high-grade serous carcinoma controls lacking BRCA1 and BRCA2 germline mutation was used to validate the algorithms, with specific emphasis on the ability to detect cases with BRCA1 germline mutation. Best results were obtained with the algorithm that incorporated SET features, necrosis, and mitotic index (P=0.0072; sensitivity of 1.0 (95% CI, 0.66-1.0); specificity of 0.57 (95% CI, 0.29-0.82); positive predictive value of 0.60 (95% CI, 0.32-0.84) and a negative predictive value of 1.0 (95% CI, 0.63-1.0)). These preliminary data indicate potential strong associations between morphology and genotype in high-grade serous carcinomas.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. gynbreast@mskcc.org
authors.forename: Robert A
authors.initials: RA
authors.lastname: Soslow
authors.forename: Guangming
authors.initials: G
authors.lastname: Han
authors.forename: Kay J
authors.initials: KJ
authors.lastname: Park
authors.forename: Karuna
authors.initials: K
authors.lastname: Garg
authors.forename: Narciso
authors.initials: N
authors.lastname: Olvera
authors.forename: David R
authors.initials: DR
authors.lastname: Spriggs
authors.forename: Noah D
authors.initials: ND
authors.lastname: Kauff
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
mesh_terms: D000465:Algorithms; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000473:pathology; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005187:Fallopian Tubes / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008940:Mitotic Index; D009154:Mutation; D009336:Necrosis; D060787:Neoplasm Grading; D009519:New York City; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D011401:Promoter Regions, Genetic
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human