Development of an ovarian cancer screening decision model that incorporates disease heterogeneity: implications for potential mortality reduction.

Background: Pathologic and genetic data suggest that epithelial ovarian cancer may consist of indolent and aggressive phenotypes. The objective of the current study was to estimate the impact of a 2-phenotype paradigm of epithelial ovarian cancer on the mortality reduction achievable using available screening technologies.

Methods: The authors modified a Markov model of ovarian cancer natural history (the 1-phenotype model) to incorporate aggressive and indolent phenotypes (the 2-phenotype model) based on histopathologic criteria.

Dasatinib (BMS-35482) has synergistic activity with paclitaxel and carboplatin in ovarian cancer cells.

Purpose: To explore the activity of dasatinib alone and in combination with paclitaxel and carboplatin in ovarian cancer cells and to determine if dasatinib activity can be predicted based on evaluation of the SRC pathway.

Experimental Design: Microarray analysis was performed for IGROV1, OVCAR3, A2780 and SKOV3 ovarian cancer cells and the status of the genomic SRC signature pathway was determined. Cells were treated with carboplatin, paclitaxel and dasatinib individually and in combination.

Epigenetic suppression of the TGF-beta pathway revealed by transcriptome profiling in ovarian cancer.

Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Diagnosis usually occurs after metastatic spread, largely reflecting vague symptoms of early disease combined with lack of an effective screening strategy. Epigenetic mechanisms of gene regulation, including DNA methylation, are fundamental to normal cellular function and also play a major role in carcinogenesis.

Projecting the need for gynecologic oncologists for the next 40 years.

Objective: To estimate the ratio of gynecologic cancer cases to practicing gynecologic oncologists in the United States over the next 40 years.

Methods: Using population projections from the U.S.

Common variants at 19p13 are associated with susceptibility to ovarian cancer.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.

A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24.

Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2). Here, we report on nine additional candidate loci (defined as having P ≤ 10⁻⁴) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls.

Prophylactic and risk-reducing bilateral salpingo-oophorectomy: recommendations based on risk of ovarian cancer.

Women who do not have a documented germline mutation or who do not have a strong family history suspicious for a germline mutation are considered to be at average risk of ovarian cancer. Women who have confirmed deleterious BRCA1 and BRCA2 germline mutations are high risk of ovarian cancer. In addition, women who have a strong family history of either ovarian or breast cancer may carry a deleterious mutation and must be presumed to be at higher-than-average risk, even if they have not been tested, because there could be other mutations that are either untested or yet undiscovered that confirm higher-than-average risk of these diseases.

Progesterone receptor gene polymorphisms and risk of endometriosis: results from an international collaborative effort.

Objective: To investigate the association between self-reported endometriosis and the putative functional promoter +331C/T single nucleotide polymorphism and the PROGINS allele.

Design: Control subjects from ovarian cancer case-control studies participating in the international Ovarian Cancer Association Consortium. The majority of controls are drawn from population-based studies.

Microcell-mediated chromosome transfer identifies EPB41L3 as a functional suppressor of epithelial ovarian cancers.

We used a functional complementation approach to identify tumor-suppressor genes and putative therapeutic targets for ovarian cancer. Microcell-mediated transfer of chromosome 18 in the ovarian cancer cell line TOV21G induced in vitro and in vivo neoplastic suppression. Gene expression microarray profiling in TOV21G(+18) hybrids identified 14 candidate genes on chromosome 18 that were significantly overexpressed and therefore associated with neoplastic suppression.

Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer.

Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty-three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk.

Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay.

Genetic variation in TYMS in the one-carbon transfer pathway is associated with ovarian carcinoma types in the Ovarian Cancer Association Consortium.

Background: We previously reported the risks of ovarian carcinoma for common polymorphisms in one-carbon transfer genes. We sought to replicate associations for DPYD rs1801265, DNMT3A rs13420827, MTHFD1 rs1950902, MTHFS rs17284990, and TYMS rs495139 with risk of ovarian carcinoma overall and to use the large sample of assembled cases to investigate associations by histologic type.

Methods: Associations were evaluated in the Ovarian Cancer Association Consortium, including 16 studies of 5,593 epithelial ovarian carcinoma cases and 9,962 controls of white non-Hispanic origin.

Expression signatures of TP53 mutations in serous ovarian cancers.

Background: Mutations in the TP53 gene are extremely common and occur very early in the progression of serous ovarian cancers. Gene expression patterns that relate to mutational status may provide insight into the etiology and biology of the disease.

Methods: The TP53 coding region was sequenced in 89 frozen serous ovarian cancers, 40 early stage (I/II) and 49 advanced stage (III/IV).

Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer.

Background: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study.

Methods/principal Findings: The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen.

Robotic-assisted laparoscopic gynecologic procedures in a fellowship training program.

Background And Objective: The robotic surgical platform is an alternative technique to traditional laparoscopy and requires the development of new surgical skills for both the experienced surgeon and trainee. Our goal was to perform an early evaluation of the feasibility of training fellows in robotic-assisted gynecologic procedures at the outset of our incorporation of this technology into clinical practice.

Methods: A systematic approach to fellow training included (1) didactic and hands-on training with the robotic system, (2) instructional videos, (3) assistance at the operating table, and (4) performance of segments of gynecologic procedures in tandem with the attending physician.

Variation at 8q24 and 9p24 and risk of epithelial ovarian cancer.

The chromosome 8q24 region (specifically, 8q24.21.a) is known to harbor variants associated with risk of breast, colorectal, prostate, and bladder cancers.

Polymorphism in the GALNT1 gene and epithelial ovarian cancer in non-Hispanic white women: the Ovarian Cancer Association Consortium.

Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk.

Risk of ovarian cancer and inherited variants in relapse-associated genes.

Background: We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk.

Methods And Findings: Women with and without invasive ovarian cancer (749 cases, 1,041 controls) were genotyped at 136 single nucleotide polymorphisms (SNPs) within 13 candidate genes.

ESR1/SYNE1 polymorphism and invasive epithelial ovarian cancer risk: an Ovarian Cancer Association Consortium study.

We genotyped 13 single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) region in three population-based case-control studies of epithelial ovarian cancer conducted in the United States, comprising a total of 1,128 and 1,866 non-Hispanic white invasive cases and controls, respectively. A SNP 19 kb downstream of ESR1 (rs2295190, G-to-T change) was associated with invasive ovarian cancer risk, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.

High poly(adenosine diphosphate-ribose) polymerase expression and poor survival in advanced-stage serous ovarian cancer.

Objective: To estimate the range of poly(adenosine diphosphate [ADP]-ribose) polymerase expression in serous ovarian cancers and to determine whether expression is associated with response to therapy and outcome.

Methods: Immunostaining for poly(ADP-ribose) polymerase was performed in 186 paraffin-embedded, serous ovarian cancers. Nuclear poly(ADP-ribose) polymerase expression was quantified using a scoring system that assesses both staining intensity and percentage of cells staining.

Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype.

Objective: The objective of this study was to examine the clinicopathologic correlates of T-regulatory (T(reg)) cell infiltration in serous ovarian cancers and to define gene signatures associated with high T(reg)s.

Methods: Tumor infiltrating T(reg) and cytotoxic T-cells (CTLs) were quantitated in 232 primary serous ovarian cancers by immunostaining for FOXP3 and CD8. Expression microarray analysis was performed in a subset of 48 advanced cancers with the highest and lowest numbers of infiltrating T(reg)s and a genomic signature was developed using binary regression.

Targeting slow-proliferating ovarian cancer cells.

Advanced ovarian cancer has a high rate of recurrence and mortality despite relative chemosensitivity at the time of initial treatment. Conventional chemotherapeutic agents typically target rapidly dividing cells. Disease relapse may therefore result from the survival and later emergence of latent slow-proliferating and/or quiescent cancer cells.

Association between the N-terminally truncated (DeltaN) p63alpha (DeltaNp63alpha) isoform and debulking status, VEGF expression and progression-free survival in previously untreated, advanced stage epithelial ovarian cancer: A Gynecologic Oncology Group study.

Objectives: The Gynecologic Oncology Group (GOG) examined the association between the relative expression of the DeltaNp63alpha isoform and clinicopathologic variables, p53 status, angiogenic markers, progression-free survival (PFS) and overall survival (OS) in epithelial ovarian cancer (EOC).

Methods: Immunoblot analysis was used to determine the relative expression of DeltaNp63alpha to beta-actin in lysates of frozen primary tumor from women with previously untreated, advanced stage EOC who participated in a GOG specimen banking protocol and a randomized phase III treatment protocol.

Results: DeltaNp63alpha was detected in 49/56 (87.

Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis.

Background: Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide.

Methods: We examined single nucleotide polymorphisms (SNPs) (n=288) from 39 cell cycle regulation genes, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors, in a two-stage study. White, non-Hispanic cases (n=829) and ovarian cancer-free controls (n=941) were genotyped using an Illumina assay.