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Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations., Competing Interests: The authors have declared that no competing interests exist.

Background: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias., Methods: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis., Results: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours., Conclusions: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

The aldehyde dehydrogenase 2 (ALDH2) polymorphism rs671 (Glu504Lys) causes ALDH2 inactivation and adverse acetaldehyde exposure among Asians, but little is known of the association between alcohol consumption and rs671 and ovarian cancer (OvCa) in Asians. We conducted a pooled analysis of Asian ancestry participants in the Ovarian Cancer Association Consortium. We included seven case-control studies and one cohort study comprising 460 invasive OvCa cases, 37 borderline mucinous OvCa and 1274 controls of Asian descent with information on recent alcohol consumption. Pooled odds ratios (OR) with 95% confidence intervals (CI) for OvCa risk associated with alcohol consumption, rs671 and their interaction were estimated using logistic regression models adjusted for potential confounders. No significant association was observed for daily alcohol intake with invasive OvCa (OR comparing any consumption to none = 0.83; 95% CI = 0.58-1.18) or with individual histotypes. A significant decreased risk was seen for carriers of one or both Lys alleles of rs671 for invasive mucinous OvCa (OR = 0.44; 95% CI = 0.20-0.97) and for invasive and borderline mucinous tumors combined (OR = 0.48; 95% CI = 0.26-0.89). No significant interaction was observed between alcohol consumption and rs671 genotypes. In conclusion, self-reported alcohol consumption at the quantities estimated was not associated with OvCa risk among Asians. Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse genetic association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype. This association will require replication in a larger sample., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Cigarette smoking is associated with an increased risk of developing mucinous ovarian tumors but whether it is associated with ovarian cancer survival overall or for the different histotypes is unestablished. Furthermore, it is unknown whether the association between cigarette smoking and survival differs according to strata of ovarian cancer stage at diagnosis. In a large pooled analysis, we evaluated the association between various measures of cigarette smoking and survival among women with epithelial ovarian cancer. We obtained data from 19 case-control studies in the Ovarian Cancer Association Consortium (OCAC), including 9,114 women diagnosed with ovarian cancer. Cox regression models were used to estimate adjusted study-specific hazard ratios (HRs), which were combined into pooled hazard ratios (pHR) with corresponding 95% confidence intervals (CIs) under random effects models. Overall, 5,149 (57%) women died during a median follow-up period of 7.0 years. Among women diagnosed with ovarian cancer, both current (pHR = 1.17, 95% CI: 1.08-1.28) and former smokers (pHR = 1.10, 95% CI: 1.02-1.18) had worse survival compared with never smoking women. In histotype-stratified analyses, associations were observed for mucinous (current smoking: pHR = 1.91, 95% CI: 1.01-3.65) and serous histotypes (current smoking: pHR = 1.11, 95% CI: 1.00-1.23; former smoking: pHR = 1.12, 95% CI: 1.04-1.20). Further, our results suggested that current smoking has a greater impact on survival among women with localized than disseminated disease. The identification of cigarette smoking as a modifiable factor associated with survival has potential clinical importance as a focus area to improve ovarian cancer prognosis., (© 2017 UICC.)

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with improved survival in some cancers, but evidence for ovarian cancer is limited., Methods: Pooling individual-level data from 12 Ovarian Cancer Association Consortium studies, we evaluated the association between self-reported, pre-diagnosis use of common analgesics and overall/progression-free/disease-specific survival among 7694 women with invasive epithelial ovarian cancer (4273 deaths)., Results: Regular analgesic use (at least once per week) was not associated with overall survival (pooled hazard ratios, pHRs (95% confidence intervals): aspirin 0.96 (0.88-1.04); non-aspirin NSAIDs 0.97 (0.89-1.05); acetaminophen 1.01 (0.93-1.10)), nor with progression-free/disease-specific survival. There was however a survival advantage for users of any NSAIDs in studies clearly defining non-use as less than once per week (pHR=0.89 (0.82-0.98))., Conclusions: Although this study did not show a clear association between analgesic use and ovarian cancer survival, further investigation with clearer definitions of use and information about post-diagnosis use is warranted.

Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer., Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients., Results: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively)., Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Previously developed models for predicting absolute risk of invasive epithelial ovarian cancer have included a limited number of risk factors and have had low discriminatory power (area under the receiver operating characteristic curve (AUC) < 0.60). Because of this, we developed and internally validated a relative risk prediction model that incorporates 17 established epidemiologic risk factors and 17 genome-wide significant single nucleotide polymorphisms (SNPs) using data from 11 case-control studies in the United States (5,793 cases; 9,512 controls) from the Ovarian Cancer Association Consortium (data accrued from 1992 to 2010). We developed a hierarchical logistic regression model for predicting case-control status that included imputation of missing data. We randomly divided the data into an 80% training sample and used the remaining 20% for model evaluation. The AUC for the full model was 0.664. A reduced model without SNPs performed similarly (AUC = 0.649). Both models performed better than a baseline model that included age and study site only (AUC = 0.563). The best predictive power was obtained in the full model among women younger than 50 years of age (AUC = 0.714); however, the addition of SNPs increased the AUC the most for women older than 50 years of age (AUC = 0.638 vs. 0.616). Adapting this improved model to estimate absolute risk and evaluating it in prospective data sets is warranted., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Despite a large body of literature evaluating the association between recreational physical activity and epithelial ovarian cancer (EOC) risk, the extant evidence is inconclusive, and little is known about the independent association between recreational physical inactivity and EOC risk. We conducted a pooled analysis of nine studies from the Ovarian Cancer Association Consortium to investigate the association between chronic recreational physical inactivity and EOC risk., Methods: In accordance with the 2008 Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. Multivariable logistic regression was utilized to estimate the ORs and 95% confidence intervals (CI) for the association between inactivity and EOC risk overall and by subgroups based upon histotype, menopausal status, race, and body mass index., Results: The current analysis included data from 8,309 EOC patients and 12,612 controls. We observed a significant positive association between inactivity and EOC risk (OR = 1.34; 95% CI, 1.14-1.57), and similar associations were observed for each histotype., Conclusions: In this large pooled analysis examining the association between recreational physical inactivity and EOC risk, we observed consistent evidence of an association between chronic inactivity and all EOC histotypes., Impact: These data add to the growing body of evidence suggesting that inactivity is an independent risk factor for cancer. If the apparent association between inactivity and EOC risk is substantiated, additional work via targeted interventions should be pursued to characterize the dose of activity required to mitigate the risk of this highly fatal disease. Cancer Epidemiol Biomarkers Prev; 25(7); 1114-24. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality., Methods: Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years., Results: In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18-1.52) and without (HR=1.22, 95% CI: 1.12-1.33) further adjustment for residual disease, respectively., Conclusion: In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC.

Background: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC., Methods: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis., Results: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81)., Conclusions: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence., (© The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objective: To describe the association between postmenopausal estrogen-only therapy use and risk of ovarian carcinoma, specifically with regard to disease histotype and duration and timing of use., Methods: We conducted a pooled analysis of 906 women with ovarian carcinoma and 1,220 women in a control group; all 2,126 women included reported having had a hysterectomy. Ten population-based case-control studies participating in the Ovarian Cancer Association Consortium, an international consortium whose goal is to combine data from many studies with similar methods so reliable assessments of risk factors can be determined, were included. Self-reported questionnaire data from each study were harmonized and conditional logistic regression was used to examine estrogen-only therapy's histotype-specific and duration and recency of use associations., Results: Forty-three and a half percent of the women in the control group reported previous use of estrogen-only therapy. Compared with them, current or recent estrogen-only therapy use was associated with an increased risk for the serous (51.4%, odds ratio [OR] 1.63, 95% confidence interval [CI] 1.27-2.09) and endometrioid (48.6%, OR 2.00, 95% CI 1.17-3.41) histotypes. In addition, statistically significant trends in risk according to duration of use were seen among current or recent postmenopausal estrogen-only therapy users for both ovarian carcinoma histotypes (Ptrend<.001 for serous and endometrioid). Compared with women in the control group, current or recent users for 10 years or more had increased risks of serous ovarian carcinoma (36.8%, OR 1.73, 95% CI 1.26-2.38) and endometrioid ovarian carcinoma (34.9%, OR 4.03, 95% CI 1.91-8.49)., Conclusion: We found evidence of an increased risk of serous and endometrioid ovarian carcinoma associated with postmenopausal estrogen-only therapy use, particularly of long duration. These findings emphasize that risk may be associated with extended estrogen-only therapy use.

Purpose: Socioeconomic status (SES) is a known predictor of survival for several cancers and it has been suggested that SES differences affecting tumour stage at diagnosis may be the most important explanatory factor for this. However, only a limited number of studies have investigated SES differences in tumour stage at diagnosis of ovarian cancer. In a pooled analysis, we investigated whether SES as represented by level of education is predictive for advanced tumour stage at diagnosis of ovarian cancer, overall and by histotype. The effect of cigarette smoking and body mass index (BMI) on the association was also evaluated., Methods: From 18 case-control studies, we obtained information on 10,601 women diagnosed with epithelial ovarian cancer. Study specific odds ratios (ORs) with corresponding 95% confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio (pOR) using a random effects model., Results: Overall, women who completed ≤high school had an increased risk of advanced tumour stage at diagnosis compared with women who completed >high school (pOR 1.15; 95% CI 1.03-1.28). The risk estimates for the different histotypes of ovarian cancer resembled that observed for ovarian cancers combined but did not reach statistical significance. Our results were unchanged when we included BMI and cigarette smoking., Conclusion: Lower level of education was associated with an increased risk of advanced tumour stage at diagnosis of ovarian cancer. The observed socioeconomic difference in stage at diagnosis of ovarian cancer calls for further studies on how to reduce this diagnostic delay., Competing Interests: None, (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC., (© 2015 WILEY PERIODICALS, INC.)

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations., Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls)., Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network., Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development., Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization., (©2015 American Association for Cancer Research.)

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

Background: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk., Methods: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons., Results: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4)., Conclusion: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

Objective: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted., Methods: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations., Results: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive)., Conclusions: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10 -4 ]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1 , may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.

Objectives: Animal evidence suggests that circadian disruption may be associated with ovarian cancer, though very little epidemiological work has been done to assess this potential association. We evaluated the association between self-reported nightshift work, a known circadian disruptor, and ovarian cancer in a population-based case-control study., Methods: The study included 1101 women with invasive epithelial ovarian cancer, 389 women with borderline epithelial ovarian tumours and 1832 controls and was conducted in western Washington state. Shift work data were collected as part of inperson interviews., Results: Working the nightshift was associated with an increased risk of invasive (OR=1.24, 95% CI 1.04 to 1.49) and borderline (OR=1.48, 95% CI 1.15 to 1.90) tumours; however, we observed little evidence that risks increased with increasing cumulative duration of nightshift work, and risks were not elevated in the highest duration category (>7 nightshift work-years). Increased risks were restricted to women who were 50 years of age and older and to serous and mucinous histologies of invasive and borderline tumours. There was suggestive evidence of a decreased risk of ovarian cancer among women reporting a preference for activity during evenings rather than mornings., Conclusions: We found evidence suggesting an association between shift work and ovarian cancer. This observation should be followed up in future studies incorporating detailed assessments of diurnal preference (ie, chronotype) in addition to detailed data on shift schedules.

Purpose: Associations between sun exposure (a primary source of vitamin D) and risk of ovarian cancer have been inconsistent. Furthermore, studies have not investigated whether sun exposure at different periods in the lifetime of a person results in differences in risk associations, and little is known about differences according to histological subtype., Methods: Using a population-based case-control study of 1,334 non-Hispanic white women diagnosed with epithelial ovarian cancer in western Washington State between 2002 and 2009 and 1,679 non-Hispanic white controls, we assessed the relation of epithelial ovarian cancer with constitutional pigmentation characteristics, sun exposure behaviors, and an index of ultraviolet (UV) exposure based on residential history. Information was collected through in-person interviews. Logistic regression was used to compute odds ratios, 95 % confidence intervals, and trend p values (P(trend))., Results: We noted no association with residence-based measures of UV exposure or self-reported sun exposure, either over the lifetime or within specific age intervals. Also, we observed little evidence of association between constitutional pigmentation characteristics and risk, save for a suggestion of increased risk among women who reported increased ability to suntan upon prolonged sun exposure (P(trend) = 0.03)., Conclusions: Results from this study suggest that sun exposure has little influence on the risk of epithelial ovarian cancer. Additional studies in populations with a wider gradient of sun exposure may yet be warranted.

Background: Endometriosis is a risk factor for epithelial ovarian cancer; however, whether this risk extends to all invasive histological subtypes or borderline tumours is not clear. We undertook an international collaborative study to assess the association between endometriosis and histological subtypes of ovarian cancer., Methods: Data from 13 ovarian cancer case-control studies, which were part of the Ovarian Cancer Association Consortium, were pooled and logistic regression analyses were undertaken to assess the association between self-reported endometriosis and risk of ovarian cancer. Analyses of invasive cases were done with respect to histological subtypes, grade, and stage, and analyses of borderline tumours by histological subtype. Age, ethnic origin, study site, parity, and duration of oral contraceptive use were included in all analytical models., Findings: 13 226 controls and 7911 women with invasive ovarian cancer were included in this analysis. 818 and 738, respectively, reported a history of endometriosis. 1907 women with borderline ovarian cancer were also included in the analysis, and 168 of these reported a history of endometriosis. Self-reported endometriosis was associated with a significantly increased risk of clear-cell (136 [20·2%] of 674 cases vs 818 [6·2%] of 13 226 controls, odds ratio 3·05, 95% CI 2·43-3·84, p<0·0001), low-grade serous (31 [9·2%] of 336 cases, 2·11, 1·39-3·20, p<0·0001), and endometrioid invasive ovarian cancers (169 [13·9%] of 1220 cases, 2·04, 1·67-2·48, p<0·0001). No association was noted between endometriosis and risk of mucinous (31 [6·0%] of 516 cases, 1·02, 0·69-1·50, p=0·93) or high-grade serous invasive ovarian cancer (261 [7·1%] of 3659 cases, 1·13, 0·97-1·32, p=0·13), or borderline tumours of either subtype (serous 103 [9·0%] of 1140 cases, 1·20, 0·95-1·52, p=0·12, and mucinous 65 [8·5%] of 767 cases, 1·12, 0·84-1·48, p=0·45)., Interpretation: Clinicians should be aware of the increased risk of specific subtypes of ovarian cancer in women with endometriosis. Future efforts should focus on understanding the mechanisms that might lead to malignant transformation of endometriosis so as to help identify subsets of women at increased risk of ovarian cancer., Funding: Ovarian Cancer Research Fund, National Institutes of Health, California Cancer Research Program, California Department of Health Services, Lon V Smith Foundation, European Community's Seventh Framework Programme, German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research, German Cancer Research Centre, Eve Appeal, Oak Foundation, UK National Institute of Health Research, National Health and Medical Research Council of Australia, US Army Medical Research and Materiel Command, Cancer Council Tasmania, Cancer Foundation of Western Australia, Mermaid 1, Danish Cancer Society, and Roswell Park Alliance Foundation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: We conducted a population-based, case-control study to examine the association between the use of genital powder and ovarian cancer risk, including measures of extent and timing of exposure. We also assessed the relationship of powder use with risk of disease subtypes according to histology and degree of malignancy., Methods: Information was collected during in-person interviews with 812 women with epithelial ovarian cancer diagnosed in western Washington State from 2002 to 2005 and 1,313 controls. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Overall, the perineal use of powder after bathing was associated with a slightly increased ovarian cancer risk (OR = 1.27, 95% CI: 0.97-1.66), which was most evident among women with borderline tumors (OR = 1.55, 95% CI: 1.02-2.37). We noted no clear pattern of risk increase on the basis of the extent of use, assessed as years in which powder was used, or as lifetime number of applications for invasive or borderline tumors, or their histologic subtypes. There was no alteration in the risk of ovarian cancer associated with other types of powder exposure (e.g., on sanitary napkins or diaphragms)., Conclusions: The International Agency for Research on Cancer has designated perineal exposure to talc (via the application of genital powders) as a possible carcinogen in women. A modest association of ovarian cancer with this exposure was seen in our study and in some previous ones, but that association generally has not been consistent within or among studies. Therefore, no stronger adjective than "possible" appears warranted at this time.

Background: Physical activity may influence ovarian cancer risk through hormonal, inflammatory, or immune-mediated processes or by suppressing ovulation. In a population-based case-control study of epithelial ovarian cancer, we assessed risk associated with recreational physical activity with a focus on characterizing risk within histologic subtypes., Methods: Information was collected during in-person interviews with 812 women with ovarian cancer diagnosed in western Washington State from 2002-2005 and 1,313 controls. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Exercise was assessed according to the average hours and metabolic equivalent (MET)-hours per week and the number of years in which regular recreational activity occurred., Results: Relative to women who reported no regular exercise throughout adulthood, the overall risk of invasive, but not borderline, ovarian cancer was reduced among more active women. Reductions in risk of invasive disease were most evident among women with the greatest frequency of high-intensity activity during adulthood. For serous invasive cancer, women in the uppermost category of MET-hours per week of recreational activity in adulthood had 60% the risk of inactive women (95% CI 0.4-0.9), whereas this level of activity was associated with more than a doubling in risk of endometrioid and clear cell invasive tumors., Conclusions: Our findings are compatible with an overall reduction in risk of invasive epithelial ovarian cancer associated with recreational activity but suggest that this association may differ in women with different histologic types of disease. Inconsistent findings across studies that have considered histologic type indicate that this issue is not yet resolved.

Background: A recent consensus statement encouraged use of certain symptoms to diagnose ovarian cancer earlier. We assessed the sensitivity, specificity, and positive predictive value of a proposed symptom index and of symptoms included in the consensus recommendation., Methods: In-person interviews were conducted with 812 case patients, aged 35-74 years, who had epithelial ovarian cancer that was diagnosed from January 1, 2002, through December 31, 2005, and with 1313 population-based control subjects. The symptom index was considered positive when pelvic or abdominal pain or bloating or feeling full was reported at least daily for at least 1 week, with an onset of less than 12 months before diagnosis or a reference date (for control subjects). The consensus criteria were considered fulfilled when any symptom above or urinary urgency or frequency was reported for at least 1 month, with an onset of less than 12 months before diagnosis or a reference date. Positive predictive value was calculated by use of external estimates of cancer prevalence., Results: Most case patients who had a positive index or met consensus criteria did so only within 5 months before diagnosis. Symptoms (except nausea) were somewhat less likely to have occurred among women diagnosed with early-stage than late-stage ovarian cancer. The estimated positive predictive value of the symptom index or symptoms meeting the consensus criteria was 0.6%-1.1% overall and less than 0.5% for early-stage disease., Conclusion: Use of symptoms to trigger medical evaluation for ovarian cancer is likely to result in diagnosis of the disease in only one of 100 women in the general population with such symptoms.

Objective: Some forms of ovarian neoplasms may be preventable through the removal of precursor lesions. We assessed the risk associated with a prior diagnosis of, and ovarian surgery following, ovarian cysts and endometriosis, with a focus on characterizing risk among tumor subgroups., Methods: Information was collected during in-person interviews with 812 women with ovarian cancer diagnosed in western Washington State from 2002 to 2005 and 1,313 population-based controls. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: The risk of a borderline mucinous ovarian tumor associated with a history of an ovarian cyst was increased (OR=1.7, 95% CI: 1.0-2.8), but did not vary notably according to receipt of subsequent ovarian surgery. While risk of invasive epithelial ovarian cancer was slightly increased among women with a cyst who had no subsequent ovarian surgery, it was reduced when a cyst diagnosis was followed by surgery (OR = 0.6, 95% CI: 0.4-0.9). This reduction in risk was most evident for serous invasive tumors. Women with a history of endometriosis had a threefold increased risk of endometrioid and clear cell invasive tumors, with a lesser risk increase among women who underwent subsequent ovarian surgery., Conclusions: Our results suggest differences in the relation of ovarian cysts and endometriosis with risk of specific subtypes of ovarian cancer as well as the possibility that ovarian surgery in women with these conditions may lower the risk of invasive disease.

Analgesic use may reduce ovarian cancer risk, possibly through antiinflammatory or antigonadotropic effects. The authors conducted a population-based, case-control study in Washington State that included 812 women aged 35-74 years who were diagnosed with epithelial ovarian cancer between 2002 and 2005 and 1,313 controls. Use of analgesics, excluding use within the previous year, was assessed via in-person interviews. Logistic regression was used to calculate odds ratios and 95% confidence intervals. Overall, acetaminophen and aspirin were associated with weakly increased risks of ovarian cancer. These associations were stronger after more than 10 years of use (acetaminophen: odds ratio (OR) = 1.8, 95% confidence interval (CI): 1.3, 2.6; aspirin: OR = 1.6, 95% CI: 1.1, 2.2) and were present for indications of headache, menstrual pain, and other pain/injury. Reduced risk was observed among aspirin users who began regular use within the previous 5 years (OR = 0.6, 95% CI: 0.4, 1.0) or used this drug for prevention of heart disease (OR = 0.7, 95% CI: 0.5, 1.0). These results, in the context of prior findings, do not provide compelling evidence of a true increase in risk of ovarian cancer among women who use these drugs. However, they add to the weight of evidence that, in the aggregate, provides little support for the use of analgesic drugs as chemoprevention for this disease.

Purpose: In contrast to other hormonally mediated cancers such as those of the breast, prostate, and testes, almost no data are available regarding the relation of prenatal characteristics and exposures to subsequent ovarian carcinogenesis. In a population-based study of 812 women ages 35-74 years with epithelial ovarian cancer diagnosed in Washington State from 2002 to 2005 and 1313 controls, we assessed the relation of such factors to disease risk., Methods: Information was collected through in-person interviews and logistic regression was used to calculate odds ratios and 95% confidence intervals., Results: Overall, we noted little evidence that prenatal or birth characteristics including birth weight, birth order, maternal age, or in utero exposure to cigarette smoking were associated with risk of epithelial ovarian cancer in adulthood. Among women younger than 55 years of age, risk was reduced among those whose weight at birth was < 5.5 pounds (odds ratio and 95% confidence interval 0.54, 0.31-0.94) relative to those with birth weight 5.5-9 pounds., Conclusions: In this study, birth weight was associated with risk of epithelial ovarian cancer only among women younger than 55 years of age. Prenatal influences might be expected to more substantially influence cancer risk at younger ages. Other reports examining associations of ovarian cancer risk with birth weight or other prenatal characteristics are few and have not examined risk separately according to age at diagnosis, suggesting that additional studies may prove useful.

Background: An increased risk of mucinous ovarian tumors among cigarette smokers has been observed in multiple studies. The association of smoking with other histologic types of ovarian cancer is less clear, but potentially holds greater importance for prevention of disease incidence and mortality., Methods: In a population-based study of 812 women with ovarian cancer diagnosed in western Washington State from 2002-2005 and 1,313 controls, we assessed the risk associated with cigarette smoking, with a particular focus on tumor subgroups jointly classified according to the degree of invasiveness and histology. Information was collected through in-person interviews, and logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: The incidence of both borderline and invasive mucinous ovarian tumors was increased among women with a history of cigarette smoking (ORs and 95% CIs = 1.8, 1.2-2.9, and 1.8, 0.8-4.3, respectively). Increases in risk of these tumor types were most evident among women with greater smoking duration and pack-years of exposure, and among those who had smoked within the prior 15 years. We noted no clear patterns of risk of serous tumors with duration or pack-years of smoking; however, risk of these tumor types was somewhat elevated among women who had smoked within the previous 15 years (for borderline serous tumors, OR and 95% CI = 1.5, 0.9-2.3; for invasive serous tumors, OR and 95% CI = 1.4, 1.1-1.9). The risk of endometrioid, clear cell, and the remaining histologic types of invasive ovarian cancer was not increased among smokers., Conclusion: In the aggregate, evidence is insufficient to determine whether smoking is linked with risk of serous or other non-mucinous histologic types of ovarian cancer. Studies that employ additional histopathologic and molecular techniques to more accurately delineate subsets of tumors may improve our understanding of the impact of smoking on ovarian cancer risk.

Associations of coffee, tea, and other caffeinated beverages with ovarian cancer risk remain uncertain. In a population-based study in Washington State, 781 women with epithelial ovarian cancer diagnosed in 2002 to 2005 and 1,263 controls completed self-administered questionnaires detailing consumption of caffeinated and noncaffeinated coffee, teas, and colas and in-person interviews regarding reproductive and hormonal exposures. We assessed risk associated with coffee, tea, and cola drinking and with total caffeine consumption using logistic regression to calculate odds ratios and 95% confidence intervals. Neither caffeinated nor decaffeinated coffees were associated with ovarian cancer risk; also, we observed no association of total caffeine with risk using a combined index that summed intake from coffee, tea, and carbonated soft drinks. Among teas, neither herbal/decaffeinated nor black teas were associated with risk; however, women who reported drinking >or=1 cup/d of green tea had a 54% reduction in risk (P trend = 0.01). Associations of green tea with risk were similar when invasive and borderline cases were considered separately and when Asian women were excluded from analysis. Green tea, which is commonly consumed in countries with low ovarian cancer incidence, should be further investigated for its cancer prevention properties.

Substantial increase in the use of menopausal hormone therapy (HT) throughout the 1990s, followed by widespread discontinuation after the 2002 publication of the Women's Health Initiative findings, has resulted in large numbers of former HT users among U.S. women. However, few studies have examined whether ovarian cancer risk varies according to recency and duration of specific HT regimens. We assessed risk of epithelial ovarian cancer among users of unopposed estrogen (ET) and combined estrogen/progestogen (EPT). In a population-based study in Washington state, 812 women with ovarian cancer diagnosed in 2002 to 2005 and 1,313 controls were interviewed in person about the use of HT and other characteristics. Women who used a single form of therapy (ET or EPT) were compared with women who never used HT using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CIs). Risk was increased among current or recent (within the last 3 years) users of ET with > or = 5 years of use (ORs, 95% CIs: 1.6, 1.1-2.5 and 1.8, 0.8-3.7, respectively). Little increase in risk was noted among long-term ET users who discontinued use in the more distant past (OR, 1.2; 95% CI, 0.6-2.6). No increase in risk was noted among women who used only EPT, regardless of duration. Compared with women who never used HT, current users of EPT had an OR of 1.1 (95% CI, 0.8-1.5), and risk declined with increasing time since stopping; the OR was 0.7 (95% CI, 0.4-1.0) among women who had discontinued EPT within the last 3 years and 0.5 (95% CI, 0.3-0.7) among women who stopped at an earlier point. Long-term ET may be associated with an increased ovarian cancer risk that wanes after use ceases. We did not observe an increased risk with EPT, and with increasing time after stopping, a reduction in risk became increasingly evident. The progestogen component of HT may confer a risk reduction that is masked by an opposing effect of estrogen until, among former users, estrogenic influences have diminished. These findings, if replicated, may have implications both for public health and development of chemoprevention strategies.

Objective: We conducted a population-based case-control study of epithelial ovarian cancer in relation to measures of body size and adult weight change. In particular, we sought to characterize the independent relation of body weight at particular ages with risk., Methods: In-person interviews were sought with 35-54 year-old female residents of metropolitan Atlanta, Seattle or Detroit diagnosed with ovarian cancer during 1994-1998, and with controls sampled from these populations. Information provided by 355 cases and 1,637 controls was analyzed using unconditional logistic regression., Results: The risk among women in the top tenth, relative to women in the lowest fourth, of the distribution of body weight at age 18 years was 1.5 (95% confidence interval, 1.0-2.2); at age 30, 1.9 (1.2-2.9); and 5 years before the reference date, it was 2.1 (1.4-3.3). While our results did not substantiate risk elevations reported in previous studies among subsets of women (e.g., with particular histologic tumor subtypes or according to past oral contraceptive use), we noted a particularly increased risk among women who reported 10 or more pounds gained during their first year of oral contraceptive use., Conclusions: Our findings suggest that risk of epithelial ovarian cancer may be most closely linked with body weight in the relatively recent past (but before the time in which the disease may manifest as weight loss) among women who develop this disease during the years before or shortly after menopause.

Objective: To estimate the effect of body mass index (BMI) and weight on risk of pregnancy while using oral contraceptives (OCs)., Methods: We conducted a case-control study of 248 health maintenance organization enrollees who became pregnant while using OCs between 1998 and 2001 and 533 age-matched enrollees who were nonpregnant OC users during the same period. Using logistic regression we calculated adjusted odds ratios (ORs) to estimate the risk of pregnancy according to BMI and weight quartile., Results: Among all OC users, when compared with women having a BMI of 27.3 or less, the risk of pregnancy was nearly 60% higher in women with BMI greater than 27.3 (OR 1.58, 95% confidence interval [CI] 1.11-2.24) and over 70% higher in women with BMI greater than 32.2 (OR 1.72, 95% CI 1.04-2.82). Among consistent users (women who missed no pills in reference month), the risk of pregnancy was more than doubled in women with BMI greater than 27.3 (OR 2.17, 95% CI 1.38-3.41) or BMI greater than 32.2 (OR 2.22, 95% CI 1.18-4.20). When compared with women weighing 74.8 kg or less, among consistent OC users the risk of pregnancy was over 70% higher in women weighing more than 74.8 kg (OR 1.71, 95% CI 1.08-2.71) and nearly doubled in women weighing more than 86.2 kg (OR 1.95, 95% CI 1.06-3.67)., Conclusion: Our results suggest that being overweight may increase the risk of becoming pregnant while using OCs. If causal, this association translates to an additional 2-4 pregnancies per 100 woman-years of use among overweight women, for whom consideration of additional or effective alternative contraceptive methods may be warranted.

The authors conducted a population-based, case-control study among women aged 35-54 years to assess the influence of infertility and use of ovulation-inducing drugs on ovarian cancer risk. The study was conducted from 1994 to 1998 in three regions (metropolitan Atlanta, Georgia, Detroit, Michigan, and Seattle, Washington) and included 378 cases and 1,637 controls. Data were obtained through in-person interviews, and analysis was conducted using unconditional logistic regression. Among parous women, the authors observed no association of cancer risk with a history of infertility, medical evaluation for infertility, specific types of infertility, or use of ovulation-inducing drugs. Among nulliparous women, risk was increased among women with a history of infertility (odds ratio = 1.6, 95% confidence interval: 1.0, 2.6), particularly when infertility first became manifest relatively late in reproductive life (for first infertility at > or =30 years of age: odds ratio = 2.2, 95% confidence interval: 1.1, 4.5); risk was not associated with medical evaluation for infertility, specific types of infertility, or use of ovulation-inducing drugs. Findings were similar when borderline and invasive epithelial tumors were considered separately. While the results of this study support the hypothesis that a subset of nulliparous women who experience infertility may be at increased risk of ovarian cancer, the reasons for this increase in risk remain unclear.