Differential gene expression identifies a transcriptional regulatory network involving ER-alpha and PITX1 in invasive epithelial ovarian cancer.

Background: The heterogeneous subtypes and stages of epithelial ovarian cancer (EOC) differ in their biological features, invasiveness, and response to chemotherapy, but the transcriptional regulators causing their differences remain nebulous.

Methods: In this study, we compared high-grade serous ovarian cancers (HGSOCs) to low malignant potential or serous borderline tumors (SBTs). Our aim was to discover new regulatory factors causing distinct biological properties of HGSOCs and SBTs.

Recurrent patterns of DNA methylation in the ZNF154, CASP8, and VHL promoters across a wide spectrum of human solid epithelial tumors and cancer cell lines.

The study of aberrant DNA methylation in cancer holds the key to the discovery of novel biological markers for diagnostics and can help to delineate important mechanisms of disease. We have identified 12 loci that are differentially methylated in serous ovarian cancers and endometrioid ovarian and endometrial cancers with respect to normal control samples. The strongest signal showed hypermethylation in tumors at a CpG island within the ZNF154 promoter.

BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study.

Background: Breast cancer 1, early onset (BRCA1) is a tumour-suppressor gene associated with familial epithelial ovarian cancer (EOC). Reduced BRCA1 expression is associated with enhanced sensitivity to platinum-based chemotherapy. We sought to examine the prognostic relevance of BRCA1 expression in EOC patients treated with intraperitoneal platinum/taxane.

Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.

Background: Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH).

Methods: Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated.

Comparison of ERCC1/XPF genetic variation, mRNA and protein levels in women with advanced stage ovarian cancer treated with intraperitoneal platinum.

Objective: Approximately 20% of patients receiving platinum-based chemotherapy for epithelial ovarian cancer (EOC) are refractory or develop early recurrence. Identifying these patients early could reduce treatment-associated morbidity and allow quicker transfer to more effective therapies. Much attention has focused on ERCC1 as a potential predictor of response to therapy because of its essential role in the repair of platinum-induced DNA damage.

BRCA1/2 mutations and expression: response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer.

Objective: Our objective was to determine the rate of BRCA1/2 deficiency in platinum-sensitive and platinum-resistant tumors from a cohort of unselect patients with advanced epithelial ovarian cancer (EOH).

Methods: BRCA1/2 mutation analysis was performed in 29 patients with platinum-sensitive EOC and 24 patients with platinum-resistant disease. Germline DNA was analyzed in mutation carriers when normal tissue was available.

Differential analysis of ovarian and endometrial cancers identifies a methylator phenotype.

Despite improved outcomes in the past 30 years, less than half of all women diagnosed with epithelial ovarian cancer live five years beyond their diagnosis. Although typically treated as a single disease, epithelial ovarian cancer includes several distinct histological subtypes, such as papillary serous and endometrioid carcinomas. To address whether the morphological differences seen in these carcinomas represent distinct characteristics at the molecular level we analyzed DNA methylation patterns in 11 papillary serous tumors, 9 endometrioid ovarian tumors, 4 normal fallopian tube samples and 6 normal endometrial tissues, plus 8 normal fallopian tube and 4 serous samples from TCGA.

Pre-treatment tumor expression of ERCC1 in women with advanced stage epithelial ovarian cancer is not predictive of clinical outcomes: a Gynecologic Oncology Group study.

Objective: Excision repair cross-complementation group 1 (ERCC1) is required for the repair of platinum-induced DNA damage. This study sought to assess the prognostic value of ERCC1 expression, measured by immunohistochemistry (IHC) using a highly specific antibody, in advanced epithelial ovarian cancer (EOC) patients treated with platinum-based chemotherapy.

Methods: Formalin-fixed, paraffin-embedded tumors were collected from two GOG phase III trials (GOG-172 and GOG-182) of patients with stage III/IV EOC treated with platinum-based chemotherapy.

Common variants in ABCB1, ABCC2 and ABCG2 genes and clinical outcomes among women with advanced stage ovarian cancer treated with platinum and taxane-based chemotherapy: a Gynecologic Oncology Group study.

Purpose: Efflux transporters of the ATP-binding cassette (ABC) family are major determinants of chemoresistance in tumor cells. This study examined associations between functional variants in ABCB1, ABCC2 and ABCG2 genes and clinical outcomes in patients with epithelial ovarian/primary peritoneal cancer (EOC/PPC) following platinum and taxane-based chemotherapy.

Methods: Sequenom iPLEXTMGOLD Assay and MALDI-TOF platform were used to genotype the non-synonymous G2677T/A (rs2032582; encoding Ala893Ser/Thr) and synonymous C3435T (rs1045642; encoding Ile1145Ile) variants in ABCB1, the non-synonymous G1249A variant in ABCC2 (rs2273697; encoding Val417Ile), and the non-synonymous C421A variant in ABCG2 (rs2231142; encoding Q141K, Gln141Lys) in normal DNA from up to 511 women in Gynecologic Oncology Group (GOG) phase III trials, GOG-172 or GOG-182.

Noninvasive assessment of cell proliferation in ovarian cancer using [18F] 3'deoxy-3-fluorothymidine positron emission tomography/computed tomography imaging.

Introduction: Positron emission tomography (PET)/computed tomography (CT) imaging of suspected new and recurrent ovarian carcinoma was performed to assess the relationship between [(18)F] 3'deoxy-3'fluorothymidine ((18)FLT) uptake and histopathological tissue markers of cellular proliferation (Ki67) and thymidine kinase-1 (TK-1) expression.

Methods: Six subjects were included in this pilot study. Subjects were injected with 5 mCi of (18)FLT prior to a planned surgery and then scanned on a GE Discovery-ST PET/CT scanner within an hour of injection.

Single nucleotide polypmorphisms in ERCC1 are associated with disease progression, and survival in patients with advanced stage ovarian and primary peritoneal carcinoma; a Gynecologic Oncology Group study.

Objective: This study evaluated common polymorphisms in excision repair cross-complementation group 1 (ERCC1) involved in repair of platinum-induced DNA damage in advanced-stage, epithelial ovarian/peritoneal/tubal cancer (EOC/PPC/FTC) patients treated with intravenous carboplatin- and paclitaxel-based chemotherapy.

Methods: Pyrosequencing was performed to examine single nucleotide polymorphisms (SNPs) in codon 118 and C8092A in ERCC1 in leukocyte DNA from the Gynecologic Oncology Group phase III protocol, GOG-182. Kaplan-Meier method and adjusted Cox regression modeling were used to examine associations between ERCC1 polymorphisms and progression-free survival (PFS) and overall survival (OS).

Pharmacologic and phenotypic study of docetaxel in patients with ovarian or primary peritoneal cancer.

Purpose: The objectives of this study were to determine whether the midazolam clearance predicted docetaxel pharmacokinetics, CA-125 change, and response and to assess the impact of cytochrome P450 (CYP) 3A5 and ATP-binding cassette, subfamily B, member 1 (ABCB1) genotypes on docetaxel pharmacokinetics and pharmacodynamics in ovarian or primary peritoneal cancer patients.

Methods: Thirty-four patients with advanced ovarian and primary peritoneal cancer were administered docetaxel at 75 mg/m(2) as a 1-h infusion in combination with carboplatin IV over 30 min at a target AUC of 5 mg/ml min. Cycles were repeated every 21 days for 6 cycles.

Cigarette exposure induces changes in maternal vascular function in a pregnant mouse model.

Smoking is associated with multiple adverse pregnancy outcomes, including fetal growth restriction. The objective of this study was to determine whether cigarette smoke exposure during pregnancy in a mouse model affects the functional properties of maternal uterine, mesenteric, and renal arteries as a possible mechanism for growth restriction. C57Bl/CJ mice were exposed to whole body sidestream smoke for 4 h/day.

Relationship between ERCC1 polymorphisms, disease progression, and survival in the Gynecologic Oncology Group Phase III Trial of intraperitoneal versus intravenous cisplatin and paclitaxel for stage III epithelial ovarian cancer.

Purpose: We hypothesized that common polymorphisms in excision repair cross-complementation group 1 (ERCC1), involved in nucleotide excision repair of platinum-induced damage, would be associated with progression-free survival (PFS) and overall survival (OS) in women with optimally resected, stage III epithelial ovarian cancer (EOC) treated with cisplatin and paclitaxel (C+P).

Patients And Methods: Single nucleotide polymorphism analysis was carried out by direct pyrosequencing at two sites (codon 118 and C8092A) in ERCC1 in leukocyte DNA from women who participated in the Gynecologic Oncology Group (GOG) phase III protocol-172 and were randomly assigned to intraperitoneal or intravenous C+P.

Results: ERCC1 genotyping was performed in 233 of the 429 women who participated in GOG-172.

Comparison of cell cycle regulatory gene mRNA in three different types of human trophoblasts and effect of transforming growth factor.

Aim: Identifying the factors responsible for reducing the proliferation, syncytialization, and invasiveness of trophoblast tissues, as seen with preeclampsia, intrauterine growth restriction, and spontaneous miscarriage, is a current challenge in reproductive biology. These factors, transforming growth factor (TGF)-beta as an example, can work by altering trophoblast differentiation or proliferation. We therefore investigated and compared specific markers of trophoblast proliferation and differentiation in three commonly used trophoblast tissue cell models, and also investigated the influence of TGF-beta on these markers.

Use of gene expression profiles to stage concurrent endometrioid tumors of the endometrium and ovary.

Objective: The objectives of this study were to determine whether there are distinct gene expression profiles for endometrial and ovarian endometrioid carcinomas and to create a statistical model using these profiles to predict their organ of origin.

Methods: Expression profiles of seven stage I, grades 1 and 2, endometrioid endometrial carcinomas and seven stage I ovarian endometrioid carcinomas were analyzed as the training set. The test set included seven advanced endometrial carcinomas and nine dual primary endometrial and ovarian primary tumors of endometrioid histology.

Enzymatic removal of asparagine-linked carbohydrate chains from heterodimer human chorionic gonadotrophin and effect on bioactivity.

The native form of human chorionic gonadotropin (hCG) is a heterodimer protein with two asparagine (Asn)-linked carbohydrate chains on each subunit. Removal of the Asn-linked carbohydrate chains from hCG has resulted in hCG variants with consistent antagonistic properties on isolated murine cells. Specific and direct enzymatic removal of these carbohydrate chains from native hCG with resultant antagonistic properties has not been reported.

Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer.

Background: Ovarian cancer (OvCa) most often derives from ovarian surface epithelial (OSE) cells. Several lines of evidence strongly suggest that increased exposure to progesterone (P4) protects women against developing OvCa. However, the underlying mechanisms of this protection are incompletely understood.

Expression and activity of taxane-metabolizing enzymes in ovarian tumors.

Objective: Current firstline chemotherapy for ovarian cancer consists of carboplatin combined with either paclitaxel or docetaxel. Disposition of carboplatin is determined by renal clearance, while the taxanes are metabolized by cytochrome P450 (CYP450) enzymes. Although the majority of taxane metabolism occurs in the liver, recent data have shown that some solid tumors express CYP450 enzymes in the tumors themselves.

Tumorigenic epithelial stem cells and their normal counterparts.

ABC transporters are highly conserved and represent a major protective mechanism for barrier tissues as well as adult tissue stem cells. Emerging data support the existence of a cancer stem cell that shares features of tissue stem cells, including the ability to self-renew and undergo dysregulated differentiation. Here we show that a rare population of cells coexpressing MDR transporters and stem cell markers is a common feature across therapy-naive epithelial cancers as well as normal epithelial tissue.

Clinical use of combined positron emission tomography and computed tomography (FDG-PET/CT) in recurrent ovarian cancer.

Objective: The aim of this study was to evaluate the use of co-registered PET/CT using F-18 fluorodeoxyglucose (FDG) for surveillance and follow-up of ovarian cancer patients to detect recurrent disease.

Material And Methods: A retrospective chart review was performed on 39 ovarian cancer patients who underwent a total of 59 FDG-PET/CT scans. The following information was obtained: clinical indication for FDG-PET/CT, the results of FDG-PET/CT particularly with regard to the additional diagnostic information, the localization of disease and subsequent clinical patient management.

The effects of cigarette smoking on circulating maternal leukocytes during pregnancy.

During pregnancy, cigarette smoke exposure, a common environmental insult, is damaging to both mother and fetus and is associated with pregnancy loss. The mechanism underlying the pathophysiology of injury is not understood. We hypothesized that smoking during pregnancy interferes with the normal physiological adaptation of the maternal immune system.

Preeclampsia activates circulating immune cells with engagement of the NF-kappaB pathway.

Problem: Compelling evidence implicates peripheral immune activation in the pathophysiology of preeclampsia. Polymorphonuclear neutrophils appear to be the cells most strongly affected, with changes in expression of surface markers and release of granule enzymes. Here, we investigated activation in additional leukocyte populations among women with preeclampsia.

BRCA1 expression in a large series of sporadic ovarian carcinomas: a Gynecologic Oncology Group study.

BRCA1 is a tumor suppressor gene that, when mutated, is associated with the development of hereditary ovarian cancer. A role for BRCA1 in the pathoetiology of sporadic ovarian epithelial cancer (OEC) development has been suggested, although spontaneous mutations of the BRCA1 gene in this disease are uncommon. Loss of gene function by epigenetic alteration is observed more commonly, while other means of gene inactivation have not been intensively investigated.