Alice W. Lee

Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case–control studies

Summary 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 Communitys 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.

Population Distribution of Lifetime Risk of Ovarian Cancer in the United States

Background: In U.S. women, lifetime risk of ovarian cancer is 1.37%, but some women are at a substantially lower or higher risk than this average. Methods: We have characterized the distribution of lifetime risk in the general population. Published data on the relative risks and their variances for five well-accepted risk and protective factors for ovarian cancer, oral contraceptive use, parity, tubal ligation, endometriosis, and first-degree family history of ovarian cancer in conjunction with a genetic risk score using genome-wide significant common, low penetrance variants were used. The joint distribution of these factors (i.e., risk/protective factor profiles) was derived using control data from four U.S. population–based studies, providing a broad representation of women in the United States. Results: A total of 214 combinations of risk/protective factors were observed, and the lifetime risk estimates ranged from 0.35% [95% confidence interval (CI), 0.29–0.42] to 8.78% (95% CI, 7.10–10.9). Among women with lifetime risk ranging from 4% to 9%, 73% had no family history of ovarian cancer; most of these women had a self-reported history of endometriosis. Conclusions: Profiles including the known modifiable protective factors of oral contraceptive use and tubal ligation were associated with a lower lifetime risk of ovarian cancer. Oral contraceptive use and tubal ligation were essentially absent among the women at 4% to 9% lifetime risk. Impact: This work demonstrates that there are women in the general population who have a much higher than average lifetime risk of ovarian cancer. Preventive strategies are available. Should effective screening become available, higher than average risk women can be identified. Cancer Epidemiol Biomarkers Prev; 24(4); 671–6. ©2015 AACR.

Combined and Interactive Effects of Environmental and GWAS-Identified Risk Factors in Ovarian Cancer

Background: There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied. Methods: Data from 14 ovarian cancer case–control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histologic subtypes. A genetic “risk score” was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk. Results: Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared with women in the lowest [95% confidence interval (CI), 1.48–1.84]. Analyses by histologic subtype yielded risk differences across subtype for endometriosis (Phet < 0.001), parity (Phet < 0.01), and tubal ligation (Phet = 0.041). Conclusions: The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of the effect of each risk factor that sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histologic subtype is warranted. Cancer Epidemiol Biomarkers Prev; 22(5); 880–90. ©2013 AACR.

Association Between Menopausal Estrogen-Only Therapy and Ovarian Carcinoma Risk

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 therapys 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 (P trend<.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.

Expression of Wnt signaling pathway genes in human endometriosis tissue: a pilot study

Despite the high prevalence of endometriosis, little is known about the underlying disease mechanisms [1]. The development and maintenance of endometriosis lesions are linked to the process of epithelial–mesenchymal transition (EMT), which describes the transformation of stationary epithelial cells into proliferative and invasive mesenchymal cells [2]. Since the canonical Wnt-signaling system is an important driver for EMT [3], we hypothesized that Wnt-signaling might be altered in different types of endometriosis lesions [4] leading to changes in related EMT processes. Hence, this study’s objective was to quantify the expression changes of (1) Wnt-signaling pathway genes such as Wnt-agonists, antagonists and receptors and (2) Wnt-target genes (e.g. E-cadherin and S100A4), which play a role in EMT, in endometrium from women with endometriosis (cases) and without (controls) as well as endometriosis lesions at different stages of the cycle.

The association between socioeconomic status and tumour stage at diagnosis of ovarian cancer: A pooled analysis of 18 case-control studies

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.

Timing of births and oral contraceptive use influences ovarian cancer risk

Increasing parity and duration of combined oral contraceptive (COC) use provide substantial protection against ovarian carcinoma (cancer). There are limited data on the impact of the age of the births or age of COC use on reducing ovarian cancer risk. Here, we examined the effects of age at first and last births and age at use of COCs using data from studies conducted in Los Angeles County, California, USA (1,632 cases, 2,340 controls). After adjusting for the number of births, every 5 years that a first birth was delayed reduced the risk of ovarian cancer by 13% (95% CI 5–21%; p = 0.003); a first birth after age 35 was associated with a 47% lower risk than a first birth before age 25. COC use before age 35 was associated with greater protection per year of use than COC use at older ages. Considering previously published results as well as the results presented here, increasing parity and a later age at births are both important protective factors against ovarian cancer and the protection extends over 30 or more years from last birth. Current models of the etiology of ovarian cancer do not encompass an effect of late age at births. Our result of an attenuation of the protective effect with COC use after around age 35 needs further investigation as it has not been seen in all studies.

Robust Tests for Additive Gene-Environment Interaction in Case-Control Studies Using Gene-Environment Independence

There have been recent proposals advocating the use of additive gene-environment interaction instead of the widely used multiplicative scale, as a more relevant public health measure. Using gene-environment independence enhances statistical power for testing multiplicative interaction in case-control studies. However, under departure from this assumption, substantial bias in the estimates and inflated type I error in the corresponding tests can occur. In this paper, we extend the empirical Bayes (EB) approach previously developed for multiplicative interaction, which trades off between bias and efficiency in a data-adaptive way, to the additive scale. An EB estimator of the relative excess risk due to interaction is derived, and the corresponding Wald test is proposed with a general regression setting under a retrospective likelihood framework. We study the impact of gene-environment association on the resultant test with case-control data. Our simulation studies suggest that the EB approach uses the gene-environment independence assumption in a data-adaptive way and provides a gain in power compared with the standard logistic regression analysis and better control of type I error when compared with the analysis assuming gene-environment independence. We illustrate the methods with data from the Ovarian Cancer Association Consortium.

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 797: 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 carcinoma. Genetics also plays an important role in ovarian carcinoma etiology, which is partly attributable to 18 confirmed susceptibility loci identified by genome-wide association studies (GWASs). Each of these common variants is associated with a modest relative risk estimate, but it is possible that interactions between non-genetic and genetic risk factors exist, thereby putting some women at higher risk. This interplay among the 18 loci, ET use, and ovarian carcinoma risk has yet to be evaluated. In our analysis, we used individual questionnaire 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). The genotype data was based on information from three GWASs, their replication efforts, and two large-scale arrays. Conditional logistic regression was used to determine the association between the 18 confirmed variants and risk of serous and endometrioid ovarian carcinoma among ET users and non-users separately. A likelihood ratio test was used to test for statistical interaction (i.e., departure from a multiplicative model). After controlling for well-established ovarian carcinoma risk factors as well as genetic ancestry, a splicing variant in TERT, rs10069690, showed a significant interaction with ET use for risk of serous ovarian carcinoma (pint = 0.014). ET users carrying the T allele had a 50% increased risk of disease (OR = 1.50, 95% CI 1.16-1.93); the impact of this allele was even stronger for long-term ET users of 10+ years (OR = 2.13, 95% CI 1.39-2.37, pint = 0.036). Non-ET users showed essentially no association with the disease (OR = 1.09, 95% CI 0.97-1.22). In addition, two SNPS, rs7207826 (C allele) and rs56318008 (T allele), in other genomic regions had significant interactions with ET use for the endometrioid histotype (pint = 0.030 and pint = 0.042, respectively). Overall, we have shown evidence of statistical interactions between postmenopausal ET use and three confirmed ovarian cancer susceptibility alleles with risk of serous and endometrioid ovarian cancer. We observed four statistically significant interactions, which is twice as many as would be expected by chance at the p≤0.05 level, although none survived correction for multiple comparisons. This is the first study, to our knowledge, to suggest potential gene-environment interactions in ovarian carcinoma in the context of hormone therapy use with confirmed susceptibility alleles. It is also intriguing that the identified interactions include confirmed variants that are located in or adjacent to genes in which estrogen is biologically involved. These findings, if replicated, may be critical for future risk prediction modeling. Citation Format: Alice W. Lee, Ashley Bomkamp, Elisa V. Bandera, Allan Jensen, Susan J. Ramus, Marc T. Goodman, Mary Anne Rossing, Francesmary Modugno, Kirsten B. Moysich, Jenny Chang-Claude, Anja Rudolph, Aleksandra Gentry-Maharaj, Kathryn L. Terry, Simon A. Gayther, Daniel W. Cramer, Jennfier A. Doherty, Joellen M. Schildkraut, Susanne K. Kjaer, Roberta B. Ness, Usha Menon, Andrew Berchuck, Bhramar Mukherjee, Lynda Roman, Paul D. Pharoah, Georgia Chenevix-Trench, Anna H. Wu, Malcolm C. Pike, Celeste L. Pearce. A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer. [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 797.