Risk Of Serous Ovarian Cancer Research Articles

Ovarian cancer risk factors in relation to family history.

Women with a family history of breast and/or ovarian cancer have an increased ovarian cancer risk. Yet it remains uncertain if common ovarian cancer risk factors-especially those which are modifiable-affect this high-risk population similarly to the general population. Using the Danish and Swedish nationwide registers, we established two nested case-control study populations in women with a family history of breast and/or ovarian cancer (2,138 ovarian cancers, 85,240 controls) and women without (10,730 ovarian cancers, 429,200 controls). The overall and histology-specific associations were assessed with conditional logistic regression. The country-specific estimates were combined based on a fixed-effect assumption. Multiparity, hysterectomy, tubal ligation, salpingectomy, and oral contraceptive (OC) use were associated with a reduced risk of ovarian cancer in both women with and without a family history, while endometriosis and menopausal hormone treatment (MHT) were associated with increased risk. Multiparity and OC use presented protective effects across all histologic subtypes except mucinous ovarian cancer which was not associated with OC use. MHT increased the risk of serous ovarian cancer but decreased the risk of the mucinous and clear cell cancers. Endometriosis was especially related to an increased risk of endometrioid and clear cell ovarian cancer. Factors associated with a decreased ovarian cancer risk were similar between women with and without a family history of breast and/or ovarian cancer. Given the higher baseline risk for women with a family history, special attention should be paid to risk factors like endometriosis and nulliparity in this high-risk population.

ChromMAGMA: regulatory element-centric interrogation of risk variants.

Candidate causal risk variants from genome-wide association studies reside almost exclusively in noncoding regions of the genome and innovative approaches are necessary to understand their biological function. Multi-marker analysis of genomic annotation (MAGMA) is a widely used program that nominates candidate risk genes by mapping single-nucleotide polymorphism summary statistics from genome-wide association studies to gene bodies. We augmented MAGMA to create chromatin-MAGMA (chromMAGMA), a method to nominate candidate risk genes based on the presence of risk variants within noncoding regulatory elements (REs). We applied chromMAGMA to a genetic susceptibility dataset for epithelial ovarian cancer (EOC), a rare gynecologic malignancy characterized by high mortality. This identified 155 unique candidate EOC risk genes across five EOC histotypes; 83% (105/127) of high-grade serous ovarian cancer risk genes had not previously been implicated in this EOC histotype. Risk genes nominated by chromMAGMA converged on mRNA splicing and transcriptional dysregulation pathways. chromMAGMA is a pipeline that nominates candidate risk genes through a gene regulation-focused approach and helps interpret the biological mechanism of noncoding risk variants for complex diseases.

Circulating estrogens and postmenopausal ovarian and endometrial cancer risk among current hormone users in the Women's Health Initiative Observational Study.

Menopausal hormone therapy (MHT) use induces alterations in circulating estrogens/estrogen metabolites, which may contribute to the altered risk of reproductive tract cancers among current users. Thus, the current study assessed associations between circulating estrogens/estrogen metabolites and ovarian and endometrial cancer risk among MHT users. We conducted a nested case-control study among postmenopausal women using MHT at baseline in the Women's Health Initiative Observational Study (179 ovarian cancers, 396 controls; 230 endometrial cancers, 253 controls). Multivariable logistic regression was utilized to estimate odds ratios and 95% confidence intervals overall and by subtype. Estrogen/estrogen metabolite levels were not associated with overall or serous ovarian cancer risk, examined separately. However, unconjugated estradiol was positively associated with non-serous ovarian cancer risk [quintile 5 vs. quintile 1: 3.01 (1.17-7.73); p-trend = 0.03; p-het < 0.01]. Endometrial cancer risk was unrelated to estrogen/estrogen metabolite levels among women who took combined estrogen/progestin therapy (EPT). These findings provide novel evidence that may support a heterogeneous hormonal etiology across ovarian cancer subtypes. Circulating estrogens did not influence endometrial cancer risk among women with EPT-induced high-estrogen levels. Larger studies are needed to delineate the relationship between ovarian/endometrial cancer subtypes and estrogen levels in the context of MHT use.

Associations of a Healthy Lifestyle Index With the Risks of Endometrial and Ovarian Cancer Among Women in the Women's Health Initiative Study.

Lifestyle-related factors influence risk of endometrial and ovarian cancers, but few studies have examined their joint associations with risk of these cancers. Using multivariable Cox regression models, we assessed the association of a healthy lifestyle index (HLI-a composite score (range, 0-20) involving diet, alcohol consumption, physical activity, body mass index, and smoking; higher scores represent healthier behavior) with risk of endometrial and ovarian cancers among 108,136 postmenopausal women who were recruited in the US Women's Health Initiative study between 1993 and 1998. After a median follow-up of 17.9 years, 1,435 endometrial cancer cases and 904 ovarian cancer cases had been ascertained. Women in the highest quintile of the HLI score had a lower risk of overall, type I, well-differentiated, moderately differentiated, poorly differentiated, and localized endometrial cancer than those in the lowest quintile (for quintile 5 vs. quintile 1, hazard ratio (HR) = 0.61 (95% CI: 0.51, 0.72), HR = 0.60 (95% CI: 0.49, 0.72), HR = 0.66 (95% CI: 0.46, 0.96), HR = 0.69 (95% CI: 0.52, 0.90), HR = 0.49 (95% CI: 0.34, 0.72), and HR = 0.61 (95% CI: 0.50, 0.74), respectively). The HLI score had a weak positive association with risk of serous ovarian cancer. Our findings underscore the potential importance of a healthy lifestyle in lowering endometrial cancer risk among postmenopausal women.

Social support and ovarian cancer incidence – A Swedish prospective population-based study

ObjectiveLow social support is associated with worse prognosis for epithelial ovarian cancer (EOC) patients. However, few studies have explored the relation between low social support and incidence of EOC. The aim of this prospective nested case-control study was to examine whether self-perceived low social support was associated with the incidence of EOC. MethodsThe Swedish Cancer Registry was used to identify participants in the Västerbotten Intervention Programme (VIP) comprising 58,000 women, who later developed EOC. Each case was matched to four cancer free controls. The VIP uses the Social Support questionnaire, a modified version of the validated questionnaire “The Interview Schedule for Social Interaction” (ISSI) measuring quantitative (AVSI) and qualitative (AVAT) aspects of social support. ResultsThe risk of EOC in relation to AVSI and AVAT was similar between the 239 cases and the 941 controls after adjustment for educational level, smoking, BMI, Cambridge Physical Activity Index and age (aOR 0.85, 95% CI 0.72–1.01 and aOR 0.54, 95% CI 0.16–1.81). Lagtime was found to have no impact. A decreased risk of serous ovarian cancer was seen in women with fewer persons available for informal socializing (aOR 0.75, 95% CI 0.59–0.95). Adjusted analyses showed non-significant odds ratios below 1.0 in the vast majority of histotypes. ConclusionsA general trend towards a decreased risk of ovarian cancer associated with low AVSI and AVAT was identified. Solely the serous subtype was significantly associated with low scores of AVSI. Prospective pathophysiological and epidemiological studies regarding social support are needed.

Is Pelvic Inflammatory Disease a Risk Factor for Ovarian Cancer?

Pelvic inflammatory disease (PID) has been proposed as a risk factor for ovarian cancer. However, the existing literature on the association between PID and ovarian cancer risk is inconclusive, and only few cohort studies have been conducted. Using nationwide Danish registries, we conducted a population-based cohort study including all women from the birth cohorts 1940 to 1970 in Denmark during 1978-2012 (n = 1,318,929) to investigate the association between PID and subsequent risk of epithelial ovarian cancer. Among women in the cohort, 81,281 women were diagnosed with PID and 5,356 women developed ovarian cancer during follow-up through 2012. Cox regression models were used to estimate HRs and 95% confidence intervals (CI) for the association between PID and ovarian cancer, both overall and according to histotype. For ovarian cancer overall, we observed no association with PID (HR, 1.05; 95% CI, 0.92-1.20). However, in histotype-specific analyses, we found a statistically significantly increased risk of serous ovarian cancer among women with PID (HR, 1.19; 1.00-1.41; P = 0.047). Conversely, PID was not convincingly associated with risk of any of the other histotypes of ovarian cancer. PID was associated with a modestly increased risk of serous ovarian cancer, but not other histotypes. Our results indicate that PID is not a strong risk factor for ovarian cancer. Whether PID is slightly associated with risk of serous ovarian cancer has to be confirmed in other studies. Cancer Epidemiol Biomarkers Prev; 26(1); 104-9. ©2016 AACR.

A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer.

Menopausal estrogen-alone therapy (ET) is a well-established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome-wide association studies. The interplay among these loci, ET use and ovarian cancer risk has yet to be evaluated. We analyzed data from 1,414 serous cases, 337 endometrioid cases and 4,051 controls across 10 case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Conditional logistic regression was used to determine the association between the confirmed susceptibility variants and risk of serous and endometrioid ovarian cancer among ET users and non-users separately and to test for statistical interaction. A splicing variant in TERT, rs10069690, showed a statistically significant interaction with ET use for risk of serous ovarian cancer (pint = 0.013). ET users carrying the T allele had a 51% increased risk of disease (OR = 1.51, 95% CI 1.19-1.91), which was stronger for long-term ET users of 10+ years (OR = 1.85, 95% CI 1.28-2.66, pint = 0.034). Non-users showed essentially no association (OR = 1.08, 95% CI 0.96-1.21). Two additional genomic regions harboring rs7207826 (C allele) and rs56318008 (T allele) also had significant interactions with ET use for the endometrioid histotype (pint = 0.021 and pint = 0.037, respectively). Hence, three confirmed susceptibility variants were identified whose associations with ovarian cancer risk are modified by ET exposure; follow-up is warranted given that these interactions are not adjusted for multiple comparisons. These findings, if validated, may elucidate the mechanism of action of these loci.

Abstract 1761: Serous ovarian cancer risk factors by grade: Evidence for etiologic heterogeneity

Abstract Background: Growing evidence suggests that high grade serous ovarian carcinomas may arise from the fallopian tube, while low-grade serous ovarian cancer may develop on the ovaries. Previous studies have suggested differences in ovarian cancer risk factors by histologic subtypes, but few have evaluated differences in risk factors for high- vs. low-grade serous cancers. In the Ovarian Cancer Cohort Consortium (OC3), a pooling project of individual-level data from 23 prospective cohort studies, we evaluated associations of hormonal, reproductive, demographic and lifestyle factors, and family history of cancer with for serous ovarian cancer subtypes. Methods: Among 16 studies that abstracted grade information from pathology reports, 3,095 serous ovarian cancers were identified during follow-up (125 well differentiated, 506 moderately differentiated, 1671 poorly differentiated, 793 undetermined). We used competing risks Cox proportional hazards regression to compute relative risks (RRs) and 95% confidence intervals (CIs) for differences in association by grade. Models were stratified on study and year of birth and adjusted for age, parity and OC use; subtype heterogeneity was evaluated by likelihood ratio tests. Results: Although sample sizes were small for low-grade tumors, there was evidence for heterogeneity in the associations for oral contraceptive (OC) use, age at menopause, endometriosis, and family history of ovarian cancer. For example, each 5-year increase in OC use was associated with a 21% decrease in risk of low-grade serous ovarian cancer (RR: 0.79; 95% CI: 0.62-1.00), but only a 10% decrease in risk of high-grade serous cancers (RR: 0.90; 95% CI: 0.84-0.96; p-heterogeneity = 0.09). Consistent with a prior report in the Ovarian Cancer Association Consortium, endometriosis was associated with increased risk of low-grade serous tumors (RR: 3.77; 95% CI: 1.24-11.48), but not with high-grade serous tumors (RR: 1.11; 95% CI: 0.70-1.74; p-heterogeneity = 0.12). Conclusion: Our results demonstrate heterogeneous associations of risk factors with subtypes of serous ovarian cancer, supporting the idea that the high- and low-grade serous tumors develop through different pathways. Despite the small sample size for low-grade serous tumors, most risk factors were more strongly associated with low-grade tumors compared to high-grade serous carcinomas, suggesting that risk prediction may be more challenging for the most fatal subtype. Identifying subtype-specific risk factor and biomarkers is important both for better understanding ovarian cancer etiology and for targeted development of novel prevention approaches. These results underscore the importance of consortial projects to evaluate rare subtypes (low-grade serous cancers) for the better understanding of etiologic heterogeneity of this deadly disease. Citation Format: Elizabeth M. Poole, Nicolas A. Wentzensen, Britton Trabert, Shelley S. Tworoger, The Ovarian Cancer Cohort Consortium. Serous ovarian cancer risk factors by grade: Evidence for etiologic heterogeneity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1761.

Hormone therapy and risk of ovarian cancer in postmenopausal women: a systematic review and meta-analysis.

Our objective was to perform a meta-analysis examining the risk of ovarian cancer with different types and regimens (continuous or sequential) of hormone therapy (HT). PubMed, Cochrane, and Embase databases were searched until December 2014 using the terms: HT, estrogen therapy (ET), ovarian cancer, postmenopausal, and menopausal. HT was considered unopposed ET, estrogen-progestin therapy (EPT), or ET+EPT (ET followed by EPT). Of 180 studies identified, 12 were included in the meta-analysis. Of the 12 studies, 9 were cohort studies including 2,350,546 women and 7,549 cases of ovarian cancer, and 3 were case-control studies including a total of 1,347 cases and 2,052 controls. ET, EPT, and ET+EPT were associated with an increased risk of ovarian cancer: pooled hazard ratio (HR)/relative risk (RR) =1.37, 95% CI: 1.19 to 1.58, P<0.001; pooled HR/RR=1.27, 95% CI: 1.18 to 1.36, P<0.001; pooled HR/RR=1.55, 95% CI: 1.05 to 2.30, P=0.027, respectively. Continuous and sequential regimens were associated with an increased risk: pooled HR/RR=1.27, 95% CI: 1.04 to 1.54, P=0.018; pooled HR/RR=1.31, 95% CI: 1.08 to 1.58, P=0.006, respectively. HT was associated with an increased risk of serous ovarian cancer (pooled HR/RR=1.46, 95% CI=1.28-1.67, P<0.001), but not clear cell, endometrioid, or mucinous ovarian cancer. Hormone therapy, regardless of type or regimen, is associated with an increased ovarian cancer risk.

Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk.

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. 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). 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. We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

Gene polymorphism of CYP19А1 and CYP1А2 in belarusian patients with serous ovarian cancer

The aim of the research was to study the frequency distribution of polymorphic variants of the genes СYP19A1 and CYP1A2 in belarusian patients with serous ovarian cancer. The highest risk of serous ovarian cancer of Belarusian patients is associated with carrier of genotype 734 СС of rs762551 polymorphism of the gene CYP1А2 (OR=7,41; 95%CI: 2,13–25,73). In this population established the influence of genetic polymorphism rs10046 of the genes СYP19A1 in the risk of serous ovarian cancer in women older than 50 years: CT genotype in a group of patients with serous ovarian cancer had met significantly less than the control group (OR=0,54; 95%CI: 0,32–0,91).

Abstract POSTER-CTRL-1201: Periodontal bone loss and risk of epithelial ovarian cancer in nurses’ health study

Abstract Introduction: Epidemiologic and biomarker studies suggest that inflammation is associated with ovarian cancer. Periodontal disease is an inflammatory response to microbial biofilms in dental plaque, affecting 30-35% of adult US population and potentially leading to loss of periodontal bone tissue and teeth loss. It is associated with several inflammation-related diseases, including cardiovascular disease, lung cancer, and pancreatic cancer. In this study we investigated the association between periodontal bone loss, a marker for advanced periodontal disease, and risk of epithelial ovarian cancer, in the Nurses’ Health Study, a prospective cohort of US-based nurses. Methods: Periodontal bone loss was self-reported by participants in 1998 and updated in 2000. This analysis included women with baseline information on periodontal bone loss, with no previous history of bilateral oophorectomy, pelvic radiation, or cancer (except non-melanoma skin cancer). Detailed information on relevant lifestyle and reproductive factors was updated every two years and participants were followed for incident ovarian epithelial cancer cases until June 2010. Relative risks (RR) and 95% confidence intervals (CI) for the association of periodontal bone loss with risk of ovarian cancer were assessed using Cox proportional hazards models adjusted for age and other potential confounders, listed below. Results: During follow-up (1998-2010), 352 incident epithelial ovarian cancer cases were identified among the 55,554 women who provided information on periodontal bone loss in 1998. In the main analysis, adjusted for age, duration of oral contraceptive use, tubal ligation, parity and family history of ovarian or breast cancer, periodontal disease was associated with a suggestively decreased risk of ovarian cancer (RR: 0.83; 95% CI: 0.61-1.13). While there was no association (RR=1.51, 95% CI: 0.82-2.81) between periodontal bone loss and non-serous ovarian cancer, participants with periodontal bone loss were at significantly lower risk of serous ovarian cancer than those with no bone loss (RR=0.64, 95% CI: 0.43-0.98). We observed no evidence of confounding by duration and type of menopausal hormone therapy, regularity of menstrual periods, diet quality (as measured by the alternative healthy eating index), physical activity, body mass index (BMI), diabetes, vitamin D status, NSAID use, smoking, or intakes of caffeine, alcohol, or lactose. The association was similar when stratifying by smoking, history of diabetes, use of hormone therapy, or BMI. History of periodontal bone loss was inversely associated with risk of ovarian cancer in women younger than 68 (median age; RR: 0.61, 95% CI: 0.36-1.00), but not in older women (RR: 1.09, 95% CI: 0.74-1.62)(P-heterogeneity = 0.08). Conclusions: This is the first study to investigate the association between ovarian cancer and periodontal health. We observed that women with history of advanced periodontal disease, as reflected by periodontal bone loss, may be at decreased risk of serous ovarian cancer, particularly for younger women. Future studies should confirm these findings and investigate the underlying mechanism. Citation Format: Ana Babic, Elizabeth M. Poole, Kathryn L. Terry, Shelley S. Tworoger. Periodontal bone loss and risk of epithelial ovarian cancer in nurses’ health study [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1201.

Abstract 3288: Integration of GWAS, gene expression and protein interaction data identifies a HOX-centric gene network associated with serous ovarian cancer risk

Abstract GWAS have so far identified 12 loci associated with serous epithelial ovarian cancer (sEOC) risk at genome-wide significance. Network-based integration of other molecular data with GWAS is one way to elucidate the functional basis of these loci. We hypothesized that some of these loci may impact sEOC development via transcription factor (TF) genes encoded at the locus and target genes of these TFs may also harbor weaker association signals. Therefore, we began our multi-step network analysis by selecting all known TF genes within 1 Mb of the top SNP at each of the 12 loci. Since 19/29 TF genes selected belonged to either the HOXB or HOXD cluster, whose targets remain poorly characterized by other approaches, we used co-expression to identify potential TF target genes. Specifically, a mutual information algorithm with a strict threshold was used to infer networks of genes highly co-expressed with each risk locus TF gene in the 489-tumor TCGA high-grade sEOC unified expression microarray data set. All genes in the genome that were also profiled in TCGA data (11,864 genes) were then ranked according to their association with sEOC. The rank was derived from the minimum p value among all SNPs in each gene (adjusted for gene size, SNP density and intra- and intergenic linkage) after mapping ∼2.5 million SNPs to genes from a GWAS meta-analysis of sEOC risk (2,196 cases/4,396 controls). Gene set enrichment analysis (GSEA) showed that genes in co-expression networks centered on six TF genes, four at the 17q21.32 risk locus (HOXB2, HOXB5, HOXB6, HOXB7) and two at the 2q31.1 locus (HOXD1, HOXD3) were significantly over-represented (P&amp;lt;0.05 and FDR&amp;lt;0.05, 10,000 permutations) at the sEOC-associated end of the ranked list. To explore translational conservation of these transcriptional relationships, we pooled the genes driving the GSEA signal in each of the six significant co-expression networks to yield a single module of 49 genes and overlaid them on a database of 169,810 high confidence protein-protein interactions (PPIs). The single largest connected component after overlay had 29/49 genes and significantly more indirect connectivity than 10,000 random networks permuted with similar topology (P=0.01). Finally, we further demonstrated the context-specificity of the significant networks to sEOC in two separate analyses using microarray data from an additional 245 sEOC tumors (GSE9899) and non-cancer GWAS results. We will discuss the power of our approach by highlighting the identification of both novel and established sEOC genes in the final set of 49 obtained from the six seed HOX genes. Thus by combining the largest available sEOC GWAS and gene expression data sets and PPI data in a network paradigm, we adopted a method more context-specific than conventional GWAS pathway analysis. This identified a HOX-centric network contributing to sEOC susceptibility and prioritized risk locus genes for ongoing follow-up. Citation Format: Siddhartha Kar, Jonathan Tyrer, Thomas Sellers, Simon Gayther, Paul Pharoah, Ovarian Cancer Association Consortium. Integration of GWAS, gene expression and protein interaction data identifies a HOX-centric gene network associated with serous ovarian cancer risk. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3288. doi:10.1158/1538-7445.AM2014-3288

Prophylactic Bilateral Salpingectomy as a Prevention Strategy in Women at High-Risk of Ovarian Cancer: A Mini-Review

Risk-reducing bilateral salpingo-oophorectomy is a proven strategy to reduce the risk of serous ovarian cancer associated with germline BRCA mutations. It is most effective when performed before natural menopause, but it will render a woman prematurely menopausal. The tubal hypothesis of serous ovarian cancer brings with it the possibility of the alternative surgical approach in younger women comprising of risk-reducing bilateral salpingectomy while conserving their ovaries until nearer the age of natural menopause, when a delayed bilateral oophorectomy can be performed. This article will review the evidence behind the tubal hypothesis of serous ovarian cancer and explore the opportunities for translating this into clinical cancer prevention practice.

Common single nucleotide polymorphisms that increase ovarian cancer risk: Update from the Ovarian Cancer Association Consortium

Objective: About 10% of epithelial ovarian cancers arise in women with mutations in high penetrance genes (BRCA1/2), but these account for only about 40% of excess familial risk. The Ovarian Cancer Association Consortium (OCAC) has previously found 6 common single nucleotide polymorphisms (SNPs) using genome wide association studies (GWAS) that increase overall and serous ovarian cancer risk, but these only account for an additional 4% of familial risk. The Collaborative Oncological Gene-Environment Study (COGS), an ovarian, breast and prostate cancer consortium, sought to validate additional risk SNPs at a genome wide level of significance.

Use of analgesic drugs and risk of ovarian cancer: results from a Danish case–control study

The role of analgesic drug use in development of ovarian cancer is not fully understood. We examined the association between analgesic use and risk of ovarian cancer. In addition, we examined whether the association differed according to histological types. Population-based case-control study. Denmark in the period 1995-1999. We included 756 women with epithelial ovarian cancer and 1564 randomly selected control women aged 35-79 years. Information on analgesic drug use was collected from personal interviews. Analgesic drugs were divided into the following categories: any analgesics; aspirin; non-aspirin non-steroidal anti-inflammatory drugs; paracetamol; and other analgesic drugs. The association between analgesic drug use and ovarian cancer risk was analysed using multiple logistic regression models. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. Epithelial ovarian cancer. Women with a regular use of any analgesics (OR = 0.79; 95% CI 0.62 - 1.01) or aspirin (OR = 0.68; 95% CI 0.46 - 1.02) had a decreased risk of ovarian cancer, although not statistically significant. Regular use of non-aspirin non-steroidal anti-inflammatory drugs, paracetamol or other analgesics did not decrease ovarian cancer risk. Use of any analgesics (OR = 0.72; 95% CI 0.53-0.98) or aspirin (OR = 0.60; 95% CI 0.36-1.00) resulted in a statistically significant decreased risk of serous ovarian cancer but not mucinous or other ovarian tumors. In accordance with most previous studies, our results indicate a possible inverse association between analgesic use, particularly aspirin, and ovarian cancer risk.

Common Variation in Nemo-Like Kinase Is Associated with Risk of Ovarian Cancer

Overexpression of mitotic kinases has been associated with prognosis, histologic grade, and clinical stage in ovarian cancer, but the relationship between inherited variation in these genes and ovarian cancer risk has not been well defined. We measured associations between 397 single nucleotide polymorphisms (SNPs) from 67 mitotic kinases and invasive epithelial ovarian cancer risk in two case-control studies (n = 671 cases; n = 939 controls). Thirty-six candidate SNPs (P < 0.05) were assessed in a replication analysis consisting of three additional studies (n = 1,094 cases; n = 829 controls). In initial analysis, thirty-six SNPs were suggestive of association with risk of serous ovarian cancer, all subtypes of ovarian cancer, or both (P < 0.05). Replication analyses suggested an association between rs2125846 in the Nemo-like kinase (NLK) gene and ovarian cancer (serous OR = 1.36, 95% CI: 1.11-1.67, P = 1.77 × 10(-3); all subtypes OR = 1.30, 95% CI: 1.08-1.56, P = 2.97 × 10(-3)). Furthermore, rs2125846 was associated with risk in the combined discovery and replication sets (serous OR = 1.33, 95% CI: 1.15-1.54; all subtypes OR = 1.27, 95% CI: 1.12-1.45). Variation in NLK may be associated with risk of invasive epithelial ovarian cancer. Further studies are needed to confirm and understand the biologic relationship between this mitotic kinase and ovarian cancer risk. An association between SNPs in NLK and ovarian cancer may provide biologic insight into the development of this disease.

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. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15-1.74) and the HomOR = 1.63 (1.10-1.42), p-trend = 0.0002] and [HetOR = 0.97 (0.80-1.17), HomOR = 0.74 (0.58-0.93), p-trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele-specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele-specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer.

Xenobiotic‐Metabolizing gene polymorphisms and ovarian cancer risk

Because selected xenobiotic-metabolizing enzymes process pro-carcinogens that could initiate ovarian carcinogenesis, we hypothesized that single nucleotide polymorphisms (SNPs) in the genes encoding xenobiotic-metabolizing enzymes are associated with risk of ovarian cancer. Cases with invasive epithelial ovarian cancer (N = 1571 including 956 of serous sub-type) and controls (N = 2046) from three studies were genotyped at 11 SNPs in EPHX1, ADH4, ADH1A, NQO2, NAT2, GSTP1, CYP1A1, and NQO1, following an initial SNP screen in a subset of participants. Logistic regression analysis of genotypes obtained via Illumina GoldenGate and Sequenom iPlex technologies revealed the following age- and study-adjusted associations: EPHX1 rs1051740 with increased serous ovarian cancer risk [per-allele odds ratio (OR) 1.17, 95% confidence interval (95% CI) 1.04-1.32, P = 0.01), ADH4 r1042364 with decreased ovarian cancer risk (OR 0.90, 95% CI: 0.81-1.00, P = 0.05), and NQO1 rs291766 with increased ovarian cancer risk (OR 1.11, 95% CI: 1.00-1.23, P = 0.04). These findings are consistent with prior studies implicating these genes in carcinogenesis and suggest that this collection of variants is worthy of follow-up in additional studies.

MTHFR polymorphisms in relation to ovarian cancer risk

Objective Folate has been hypothesized to influence carcinogenesis due to its dual role in DNA methylation, which regulates gene expression, and synthesis of purine and thymidylate, which is vital for DNA repair. Thus, we examined ovarian cancer risk in relation to two functional polymorphisms (C677T and A1298C) in the MTHFR gene. Methods We genotyped the C677T (rs1801133) and A1298C (rs1801131) MTHFR polymorphisms in 1642 cases and 2068 controls from three studies, the New England Case Control Study (NEC), Nurses' Health Study (NHS), and Mayo Clinic Ovarian Cancer Case Control Study (MAY). Results Overall, we observed no association between either SNP and ovarian cancer risk (pooled C677T p trend = 0.59 and A1298C p trend = 0.58). Significant associations (C677T p trend = 0.001, A1298C p trend = 0.02) between these MTHFR SNPs and serous ovarian cancer risk were observed in the NEC study, but were not replicated in the NHS and MAY studies. Conclusions MTHFR SNPs C677T and A1298C are not associated with ovarian cancer risk. Our results highlight the need for validation of genetic findings.