SummaryBackgroundEndometriosis 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.MethodsData 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.Findings13 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).InterpretationClinicians 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.FundingOvarian 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.

Objective To describe reproductive and lifestyle correlates of surgically confirmed fibroids. Design Prospective Cohort Study Setting The California Teachers Study (CTS), an ongoing prospective study of over 133,000 female teachers and school administrators identified through the California State Teachers Retirement System. Patients CTS cohort members reporting no prior history of fibroids were ascertained prospectively for surgical diagnosis of fibroids using hospital patient discharge records. Main Outcome Measure(s) Multivariable Cox proportional hazards regression methods were used to assess the association of self-reported menstrual, reproductive, and lifestyle characteristics with fibroids, using ages at the start and end of follow-up (in months) to define time on study. Hazard rate ratios, presented as relative risks (RR) with 95% confidence intervals (CI), were estimated. Results The strongest risk factor we identified was African-American race/ethnicity, as compared to non-Latina white women. We observed a reduced risk of fibroids for postmenopausal women in comparison to premenopausal women, but use of hormone replacement therapies (regardless of formulation) were associated with an increased risk. Other risk factors included race, a family history of fibroids, being overweight and drinking alcohol, Smoking and diabetes were associated with a decreased risk of fibroids. Conclusions These observations provide a more detailed epidemiologic profile of women with surgically managed fibroids

HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR) = 1.13, P = 3.1 × 10−10) and clear cell (rs11651755 OR = 0.77, P = 1.6 × 10−8) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.

Factors that increase inflammation have been suggested to influence the development of ovarian cancer, but these factors have not been well studied. To further investigate this question we studied the role of talc use, history of endometrioisis, and use of non-steroidal anti-inflammatory drugs (NSAIDs) and risk of ovarian cancer in a population-based case-control study in Los Angeles County involving 609 women with newly diagnosed epithelial ovarian cancer and 688 population-based control women. Risk of ovarian cancer increased significantly with increasing frequency and duration of talc use; compared to never users risk was highest among longduration (20+ years), frequent (at least daily) talc users (adjusted relative risk (RR) =2.08, 95% confidence interval (CI)=1.34-3.23). A history of physician-diagnosed endometriosis was statistically significantly associated with risk (RR=1.66, 95% CI=1.01-2.75). Women who were talc users and had a history of endometriosis showed a 3-fold increased risk (RR=3.12, 95% CI=1.36-7.22). Contrary to the hypothesis that risk of ovarian cancer may be reduced by use of NSAIDs; risk increased with increasing frequency (per 7 times/week, RR=1.27, 95% CI=1.14-1.43) and years of NSAID use (per 5 years of use, RR=1.25, 95% CI=1.10-1.42); this was consistent across types of NSAIDs. We conclude that risk of ovarian cancer is significantly associated with talc use and with a history of endometriosis, as has been found in previous studies. The NSAID finding was unexpected and suggests that factors associated with inflammation are associated with ovarian cancer risk. This result needs confirmation with careful attention to the reasons for NSAID use.

These observations provide the first epidemiologic profile of women with a surgical diagnosis of adenomyosis and indicate that this profile differs from that of women with a surgical diagnosis of endometriosis. Our results also suggest that adenomyosis but not endometriosis is associated with increased endogenous exposure to estrogen.