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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.

The PI3K/PTEN pathway plays a major role in carcinogenesis. Dysregulation of this pathway occurs frequently in breast cancer, and loss of PTEN expression is emerging as a potentially important mechanism of resistance to the widely used anti-HER2 therapy, trastuzumab. However, assays for loss of PTEN expression have suffered from lack of consistency. Here, we describe an automated and reliable protocol for PTEN protein expression by immunohistochemistry in formalin-fixed paraffin-embedded tissue that can be easily incorporated into clinical trials.

Background: The high mortality rate associated with epithelial ovarian carcinoma (EOC) reflects diagnosis commonly at an advanced stage, but improved early detection is hindered by uncertainty as to the histologic origin and early natural history of this malignancy., Methodology/principal Findings: Here we report combined molecular genetic and morphologic analyses of normal human ovarian tissues and early stage cancers, from both BRCA mutation carriers and the general population, indicating that EOCs frequently arise from dysplastic precursor lesions within epithelial inclusion cysts. In pathologically normal ovaries, molecular evidence of oncogenic stress was observed specifically within epithelial inclusion cysts. To further explore potential very early events in ovarian tumorigenesis, ovarian tissues from women not known to be at high risk for ovarian cancer were subjected to laser catapult microdissection and gene expression profiling. These studies revealed a quasi-neoplastic expression signature in benign ovarian cystic inclusion epithelium compared to surface epithelium, specifically with respect to genes affecting signal transduction, cell cycle control, and mitotic spindle formation. Consistent with this gene expression profile, a significantly higher cell proliferation index (increased cell proliferation and decreased apoptosis) was observed in histopathologically normal ovarian cystic compared to surface epithelium. Furthermore, aneuploidy was frequently identified in normal ovarian cystic epithelium but not in surface epithelium., Conclusions/significance: Together, these data indicate that EOC frequently arises in ovarian cystic inclusions, is preceded by an identifiable dysplastic precursor lesion, and that increased cell proliferation, decreased apoptosis, and aneuploidy are likely to represent very early aberrations in ovarian tumorigenesis.

The reported experience with early-stage (FIGO stage I/II) ovarian carcinoma (OC) is limited given that the majority of women with OC are diagnosed at an advanced stage. There has not been an extensive review of these tumors, and since the pathologic criteria differentiating invasive and borderline tumors have evolved over time, the issue of whether a proportion of these tumors should be reclassified has not been addressed. We identified patients with stage I/II invasive OC who underwent primary surgical management at Memorial Sloan-Kettering Cancer Center from 1980 to 2000. Patients known to have a BRCA mutation or a family history of breast/ovarian cancer were excluded. Hematoxylin and eosin slide review, blinded to clinical outcomes, using current diagnostic criteria for ovarian carcinomas and borderline ovarian tumors, was performed. Progression-free survival (PFS) and disease-specific survival (DSS) were estimated and compared. Hematoxylin and eosin slides were reviewed for 140 of the 145 patients identified. The diagnosis was changed to borderline (low malignant potential) in 41 cases (29.3%). Twenty-nine (70.7%) of 41 changes in diagnosis involved endometrioid and mucinous tumors. This was attributable to the application of recently revised criteria for distinguishing borderline tumors from carcinomas. None of the originally diagnosed clear cell carcinomas was reclassified as borderline. The distribution of histologic subtypes among the 94 carcinomas included 26 serous (27.7%), 25 clear cell (26.6%), 22 endometrioid (23.4%), 10 mixed (10.6%), 6 mucinous (6.4%), 2 malignant Brenner (2.1%), and 3 adenocarcinomas, not otherwise specified (3.2%). Adjuvant therapy was given to 84 (89.4%) of the 94 patients with carcinomas. The 5-year PFS and DSS were significantly greater for the group of cases that was reclassified as borderline (4.5% vs. 26.2% progressed [P = 0.006]; 4.5% vs. 25.6% died [P = 0.003]). The 5-year PFS and DSS were significantly worse for carcinomas with a TP53 mutation (22.6% vs. 41.2% progressed [P = 0.04]; 21.7% vs. 24.7% died [P = 0.04]). There were no statistically significant differences in outcome between stages I versus II, tumor grades, clear cell histology versus other, and stage IC preoperative versus intraoperative rupture. We concluded that a large number of cases originally diagnosed as early-stage sporadic OC were borderline tumors. Clear cell histology does not confer a worse prognosis compared with other histologies. The presence of a TP53 mutation was an adverse prognostic indicator.

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.