Elevated Risk Of Ovarian Cancer Research Articles

Association of the Single Nucleotide Polymorphisms rs11556218, rs4778889, rs4072111, and rs1131445 of the Interleukin-16 Gene with Ovarian Cancer.

Single nucleotide polymorphisms (SNPs) of the IL-16 gene have been reported to influence the risk of several cancers, but their role in ovarian cancer (OC) has not been studied. Using the restriction fragment length polymorphism (PCR-RFLP) method, we examined four IL-16 SNPs: rs11556218 (T > G), rs4778889 (T > C), rs4072111 (C > T), and rs1131445 (T > C) in blood samples from 413 women of Central European descent, including 200 OC patients and 213 healthy controls. Among the patients, 62% were postmenopausal, 84.5% were diagnosed in late stages (FIGO IIb-IV), and 73.5% had high-grade serous OC (HGSOC). Minor allele frequencies in controls were 9.2% for rs11556218 (G allele), 13.7% for rs4778889 (C allele), 10.4% for rs4072111 (T allele), and 32.3% for rs1131445 (C allele). We found significant associations of rs11556218 (G vs. T allele: OR 2.76, 95% CI 1.84-4.14, p < 0.0001) with elevated OC risk in the whole cohort (p < 0.001) and in both premenopausal (p < 0.001) and postmenopausal (p = 0.001) subgroups. These associations remained significant across heterozygote (p < 0.001), dominant (p < 0.001), and overdominant (p < 0.001) models. IL-16 rs4778889 was associated with OC risk predominantly in premenopausal women (p < 0.0001 in almost all models). In the whole cohort, the C allele was associated with OC risk (OR 1.54, CI 95% 1.06-2.23, p = 0.024), and the association of rs4778889 was significant in dominant (p = 0.019), overdominant (p = 0.033), and heterozygote (p = 0.027) models. Furthermore, rs4778889 was linked with HGSOC (p = 0.036) and endometriosis-related OC subtypes (p = 0.002). No significant associations were found for rs4072111 or rs1131445 (p = 0.81 or 0.47, respectively). In conclusion, rs11556218 and rs4778889 SNPs are associated with OC risk, especially in premenopausal women.

Genetically identification of endometriosis and cancers risk in women through a two-sample Mendelian randomization study

Endometriosis is a prevalent and chronic inflammatory gynecologic disorder affecting approximately 6–10% of women globally, and has been associated with an increased risk of cancer. Nevertheless, previous studies have been hindered by methodological limitations that compromise the validity and robustness of their findings. In this study we conducted a comprehensive two-sample Mendelian randomization analysis to explore the genetically driven causal relationship between endometriosis and the risk of cancer. We conducted the analysis via the inverse variance weighted method, MR Egger method, and weighted median method utilizing publicly available genome-wide association study summary statistics. Furthermore, we implemented additional sensitivity analyses to assess the robustness and validity of the causal associations identified. We found strong evidence of a significant causal effect of endometriosis on a higher risk of ovarian cancer via inverse-variance weighted method (OR = 1.19, 95% CI 1.11–1.29, p < 0.0001), MR-Egger regression, and weighted median methodologies. Remarkably, our findings revealed a significant association between endometriosis and an increased risk of clear cell ovarian cancer (OR = 2.04, 95% CI 1.66–2.51, p < 0.0001) and endometrioid ovarian cancer (OR = 1.45, 95% CI 1.27–1.65, p < 0.0001). No association between endometriosis and other types of cancer was observed. We uncovered a causal relationship between endometriosis and an elevated risk of ovarian cancer, particularly clear cell ovarian cancer and endometrioid ovarian cancer. No significant associations between endometriosis and other types of cancer could be identified.

Racial Differences in the Association of Endometriosis and Uterine Leiomyomas With the Risk of Ovarian Cancer.

To evaluate associations between endometriosis and uterine leiomyomas with ovarian cancer risk by race and the effect of hysterectomy on these associations. We used data from four case-control studies and two case-control studies nested within prospective cohorts in the OCWAA (Ovarian Cancer in Women of African Ancestry) consortium. The study population included 3,124 Black participants and 5,458 White participants, of whom 1,008 Black participants and 2,237 White participants had ovarian cancer. Logistic regression was used to calculate odds ratios (ORs) and 95% CIs for the associations of endometriosis and leiomyomas with ovarian cancer risk, by race, stratified by histotype and hysterectomy. The prevalences of endometriosis and leiomyomas were 6.4% and 43.2% among Black participants and 7.0% and 21.5% among White participants, respectively. Endometriosis was associated with an increased risk of endometrioid and clear-cell ovarian cancer in both racial groups (eg, OR for endometrioid tumors for Black and White participants 7.06 [95% CI 3.86-12.91] and 2.17 [95% CI 1.36-3.45], respectively, Phetereogeneity =.003). The association between endometriosis and ovarian cancer risk in White participants was stronger in those without hysterectomy, but no difference was observed in Black participants (all Pinteraction ≥.05). Leiomyomas were associated with an elevated risk of ovarian cancer only in those without hysterectomy in both Black (OR 1.34, 95% CI 1.11-1.62) and White (OR 1.22, 95% CI 1.05-1.41) participants (all Pinteraction ≥.05). Black and White participants with endometriosis had a higher risk of ovarian cancer, and hysterectomy modified this association among White participants. Leiomyomas were associated with an increased risk of ovarian cancer in both racial groups, with hysterectomy modifying the risk in both groups. Understanding how racial differences in access to care and treatment options (eg, hysterectomy) may help guide future risk reduction strategies.

Single-cell transcriptomic analysis of endometriosis.

Endometriosis is a common condition in women that causes chronic pain and infertility and is associated with an elevated risk of ovarian cancer. We profiled transcriptomes of >370,000 individual cells from endometriomas (n = 8), endometriosis (n = 28), eutopic endometrium (n = 10), unaffected ovary (n = 4) and endometriosis-free peritoneum (n = 4), generating a cellular atlas of endometrial-type epithelial cells, stromal cells and microenvironmental cell populations across tissue sites. Cellular and molecular signatures of endometrial-type epithelium and stroma differed across tissue types, suggesting a role for cellular restructuring and transcriptional reprogramming in the disease. Epithelium, stroma and proximal mesothelial cells of endometriomas showed dysregulation of pro-inflammatory pathways and upregulation of complement proteins. Somatic ARID1A mutation in epithelial cells was associated with upregulation of pro-angiogenic and pro-lymphangiogenic factors and remodeling of the endothelial cell compartment, with enrichment of lymphatic endothelial cells. Finally, signatures of ciliated epithelial cells were enriched in ovarian cancers, reinforcing epidemiologic associations between these two diseases.

Abstract C105: Racial differences in the association of endometriosis and fibroids with risk of ovarian cancer

Abstract PURPOSE: Women with endometriosis have a 2 to 3-fold greater risk of endometrioid and clear cell ovarian cancer than other women, based on estimates from studies predominantly of White women. Fibroids have not been consistently associated with ovarian cancer risk but are the most common indication for hysterectomies in the U.S. Hysterectomy has been associated with lower ovarian cancer risk in subgroups of women including those with fibroids; thus fibroids may indirectly impact ovarian cancer risk. We evaluated the association of endometriosis and fibroids with ovarian cancer risk among Black and White women, taking into consideration the impact of hysterectomy. METHODS: We used data from six studies in the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium. Participants included 2,995 Black women and 5,281 White women. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between endometriosis and fibroids with ovarian cancer risk, overall, by race, and stratified by histotype. We also assessed effect modification by hysterectomy. RESULTS: Overall the prevalences of endometriosis and fibroids were 6.4% and 43.2% among Black women and 7.0% and 21.5% among White women, respectively. Endometriosis was associated with an increased risk of endometrioid and clear cell ovarian cancer in Black and White women. Among Black women the association was strongest for endometrioid tumors (OR=7.06; 95% CI=3.86-12.91) compared to White women (OR=2.17; 95% CI=1.36-3.45) with a significant difference by race (phetereogeneity=0.003). When stratified by hysterectomy the association between endometriosis and ovarian cancer risk in White women was stronger in those who did not report a hysterectomy. However, in Black women, the elevated risk of ovarian cancer among women with endometriosis was present among those with and without hysterectomy. Fibroids were associated with a slightly elevated risk of ovarian cancer in Black (OR=1.34; 95% CI=1.11-1.62) and White women (OR=1.22; 95% CI=1.05-1.41). For both groups, the association was present only in those who did not report a hysterectomy. Black women who had a history of fibroids and no hysterectomy had a 53% greater odds of ovarian cancer (95% CI=1.23-1.89) compared to those without fibroids, while there was no association with fibroids in the hysterectomy group (OR=0.92, 95% CI=0.62-1.36) (pinteraction=0.05). A similar pattern was observed among White women, but the interaction was not significant (pinteraction=0.21). CONCLUSION: Both Black and White women with endometriosis had a higher risk of ovarian cancer, and hysterectomy modified this association only among White women. Fibroids were associated with modestly increased risk of ovarian cancer among Black and White women, with hysterectomy modifying the risk in both groups. Further research is needed to understanding how racial differences in diagnoses of these conditions, and differential access to care and treatment options, impact or modify ovarian cancer risk. Citation Format: Holly Harris, Lauren Peres, Courtney Johnson, Kristin Guertin, Alicia Beeghly-Fadiel, Elisa Bandera, Traci Bethea, Charlotte Joslin, Anna Wu, Patricia Moorman, Heather Ochs-Balcom, Jessica Petrick, Veronica Setiawan, Lynn Rosenberg, Joellen Schildkraut, Evan Myers. Racial differences in the association of endometriosis and fibroids with risk of ovarian cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C105.

Prospective Analyses of Sedentary Behavior in Relation to Risk of Ovarian Cancer.

We examined the association of sedentary behavior with risk of ovarian cancer overall, by tumor subtype, and by participant characteristics in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II). A total of 69,558 NHS participants (1992-2016) and 104,130 NHS II participants (1991-2015) who reported on time spent sitting at home, at work, and while watching television were included in the analysis, which included 884 histologically confirmed ovarian cancer cases. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for ovarian cancer by sitting time (no mutual adjustment for individual sitting types in primary analyses). We examined potential heterogeneity by tumor histological type (type I or II), body mass index (weight (kg)/height (m)2; < 25 or ≥25), and total physical activity (<15 or ≥15 metabolic equivalent of task-hours/week). We observed an increased risk of ovarian cancer for women who sat at work for 10-19 hours/week (HR=1.25, 95% CI: 1.04, 1.51) and≥20 hours/week (HR=1.40, 95% CI: 1.14, 1.71) versus <5 hours/week. This association did not vary by body mass index, physical activity, or histotype (P for heterogeneity ≥ 0.43). No associations were observed for overall sitting, sitting while watching television, or other sitting at home. Longer sitting time at work was associated with elevated risk of ovarian cancer. Further investigations are required to confirm these findings and elucidate underlying mechanisms.

Body Fat Distribution and Risk of Breast, Endometrial, and Ovarian Cancer: A Two-Sample Mendelian Randomization Study.

Simple SummaryThe causal impact of body fat distribution on female-specific cancers is largely unknown. For the first time we used a two-sample multivariable Mendelian randomization (MR) approach to elucidate the role and causal relations of body composition assessed by segmental bioelectrical impedance analysis on the risks of breast, endometrial and ovarian cancers and their subtypes. We found that abdominal fat content increases the risk for ovarian cancer and its endometrioid and clear cell subtypes independent of overall fat content. General adiposity has a protective effect on risk of breast cancer and its ER- and ER+ subtypes but increases the risk for endometrial cancer, ovarian cancer, and the endometrioid ovarian cancer subtype. This study extends the literature by addressing specifically the causal role of visceral fat on female-specific cancers.Background: Mounting evidence shows that adiposity increases female-specific cancer risk, but the role of body fat distribution is less clear. We used a two-sample Mendelian randomization (MR) approach to elucidate causal relations of body fat distribution to the risks of breast, endometrial and ovarian cancers and their subtypes. Methods: Body composition was assessed using segmental bioelectrical impedance analysis, yielding trunk, arm, and leg fat ratios (TFR, AFR, LFR) and BMI including 195,043 and 434,794 European women, respectively. The sample sizes for the outcomes ranged between 58,396 and 228,951. Causal effects were estimated per one standard deviation increment in the respective exposure within the radial regression framework. Robust sensitivity analyses were performed to verify MR assumptions. In a multivariable MR setting, the proportion of risk attributable to overall and abdominal fat content was assessed. Results: TFR, which represents abdominal fat content, was associated with ovarian cancer and its clear cell and endometrioid histotypes independent of overall fat content. BMI was inversely associated with breast cancer and its ER− and ER+ subtypes, but positively with endometrial cancer and ovarian cancer, including its endometrioid histotype. These estimates were confirmed using AFR as proxy for overall body fat. Conclusions: Visceral adiposity seems to be a driver of elevated ovarian cancer risk, particularly of the endometrioid and clear cell ovarian cancer histotypes. General adiposity decreases the risk of breast cancer but increases the risk of endometrial and ovarian cancer.

Association of pelvic inflammatory disease (PID) with ovarian cancer: a nationwide population-based retrospective cohort study from Taiwan

BackgroundPelvic inflammatory disease (PID) is an important health issue for women. Infection and inflammation play an important role in carcinogenesis and PID has been reported to be associated with ovarian cancer in some small scale studies.AimWe sought to determine whether PID is associated with an elevated risk of ovarian cancer in Asian women.MethodsUsing data from Taiwan’s National Health Insurance Research Database (NHIRD), our retrospective cohort study included women diagnosed with PID (cases) between the years of 2000 till 2012. Each case was matched with two women without PID (controls) by age and the year of first entry into the database. Both study cohorts were followed-up until the first event of ovarian cancer, withdrawal from the NHI program, death, or the end of the study period (December 31, 2012). Cox proportional hazards regression models were used to estimate crude and adjusted hazard ratios (HRs and aHRs) with their corresponding 95% confidence intervals (95% CIs) for the association of PID and ovarian cancer risk, with and without adjusting for potential confounders.ResultsDuring an approximate 10 years of follow-up, cases were significantly more likely than controls to develop ovarian cancer (incidence rates of 0.27 and 0.16 per 1,000 person-years, respectively; P < 0.001). Women with a history of PID had a 1.49-fold elevated risk for ovarian cancer (aHR, 1.49; 95% CI, 1.21–1.84; P < 0.001).ConclusionOur study evidence supports the contention that PID increases the risk of developing ovarian cancer among Taiwanese women. Gynecologists should undertake careful assessments and closely follow patients with PID, who are at long-term risk of developing ovarian cancer. Our findings need further verification in other international cohorts.

Early Life Exposure to Tobacco Smoke and Ovarian Cancer Risk in Adulthood

Abstract Background: Ovarian cancer risk in adulthood may be affected by early life exposure to tobacco smoke. We investigated this relationship in two large prospective cohorts, the Nurses' Health Study (NHS) and NHSII. Methods: In total, analyses included 110,305 NHS participants (1976–2016) and 112,859 NHSII participants (1989–2017). Self-reported early life smoking exposures were queried at baseline or follow-up questionnaires. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of ovarian cancer overall and by tumor histotype. Results: Compared with women who never smoked, ovarian cancer risk was similar for women who started to smoke at age &amp;lt;18 (HR = 0.98, 95%CI: 0.86–1.11) or ≥18 (HR = 1.02, 95%CI: 0.93–1.12). Overall, ovarian cancer risk was not different among participants whose mother did versus did not smoke during pregnancy (HR = 1.05, 95%CI: 0.87–1.27); however, an increased risk was observed among women who themselves were never smokers (HR = 1.38, 95%CI: 1.05–1.81) but not ever smokers (HR = 0.86, 95%CI: 0.66–1.14; Pheterogeneity = 0.02). These associations did not differ by histotype (Pheterogeneity≥0.35). Parental smoking in the home during childhood/adolescence was related to a 15% increased risk of ovarian cancer in adulthood (HR = 1.15, 95%CI: 1.04–1.27) and this association was notably stronger among women with non-serous/ low- grade serous tumors (HR = 1.28, 95%CI: 1.02–1.61) versus high-grade serous/ poorly differentiated tumors (HR = 1.09, 95%CI: 0.93–1.28, Pheterogeneity = 0.25). Conclusions: Exposure to parental tobacco smoke, but not early initiation of smoking, was associated with a modest elevated risk of ovarian cancer. Further investigations are required to confirm these findings and elucidate underlying mechanisms.

A prospective controlled study of sexual function and sexually related personal distress up to 12 months after premenopausal risk-reducing bilateral salpingo-oophorectomy.

Premenopausal risk-reducing bilateral salpingo-oophorectomy (RRBSO) may impair sexual function, but the nature and degree of impairment and impact of estrogen therapy on sexual function and sexually related personal distress after RRBSO are uncertain. Prospective observational study of 73 premenopausal women at elevated risk of ovarian cancer planning RRBSO and 68 premenopausal controls at population risk of ovarian cancer. Participants completed the Female Sexual Function Index and the Female Sexual Distress Scale-Revised. Change from baseline in sexual function following RRBSO was compared with controls at 12 months according to estrogen therapy use. Baseline sexual function domains did not differ between controls and those who underwent RRBSO and subsequently initiated (56.2%) or did not initiate (43.8%) estrogen therapy. At 12 months, sexual desire and satisfaction were unchanged in the RRBSO group compared with controls. After RRBSO, nonestrogen therapy users demonstrated significant impairment in sexual arousal (β-coefficient (95% confidence interval) -2.53 (-4.86 to -0.19), P < 0.03), lubrication (-3.40 (-5.84 to -0.96), P < 0.006), orgasm (-1.64 (-3.23 to -0.06), P < 0.04), and pain (-2.70 (-4.59 to 0.82), P < 0.005) compared with controls. Although sexually related personal distress may have been more likely after RRBSO, irrespective of estrogen therapy use, there was insufficient data to formally test this effect. The findings suggest premenopausal RRBSO adversely affects several aspects of sexual function which may be mitigated by the use of estrogen therapy. Further research is needed to understand the effects of RRBSO on sexual function and sexually related personal distress, and the potential for estrogen therapy to mitigate against any adverse effects.

Posttraumatic Stress Disorder and Likelihood of Hormone Therapy Use among Women in the Nurses' Health Study II: A 26-Year Prospective Analysis.

Posttraumatic stress disorder (PTSD) is associated with higher risk of certain chronic diseases, including ovarian cancer, but underlying mechanisms remain unclear. Although prior work has linked menopausal hormone therapy (MHT) use with elevated ovarian cancer risk, little research considers PTSD to likelihood of MHT use. We examined whether PTSD was prospectively associated with greater likelihood of initiating MHT use over 26 years. Using data from the Nurses' Health Study II, with trauma and PTSD (symptoms and onset date) assessed by screener in 2008 and MHT assessed via biennial survey (from 1989), we performed Cox proportional regression models with women contributing person-years from age 36 years. Relevant covariates were assessed at biennial surveys. We considered potential effect modification by race/ethnicity, age at baseline, and period (1989-2002 vs. 2003-2015). Over follow-up, 22,352 of 43,025 women reported initiating MHT use. For example, compared with women with no trauma, the HR for initiating MHT was 1.18 for those with trauma/1-3 PTSD symptoms [95% confidence interval (CI), 1.13-1.22] and 1.31 for those with trauma/4-7 PTSD symptoms (95% CI, 1.25-1.36; P trend < 0.001), adjusting for sociodemographic factors. Associations were maintained when adjusting for reproductive factors and health conditions. We found evidence of effect modification by age at baseline. Trauma and number of PTSD symptoms were associated with greater likelihood of initiating MHT use in a dose-response manner. MHT may be a pathway linking PTSD to altered chronic disease risk. It is important to understand why women with PTSD initiate MHT use.

Early life exposure to tobacco smoke and ovarian cancer risk in adulthood.

Ovarian cancer risk in adulthood may be affected by early life exposure to tobacco smoke. We investigated this relationship in two large prospective cohorts, the Nurses' Health Study (NHS) and NHSII. In total, analyses included 110305 NHS participants (1976-2016) and 112859 NHSII participants (1989-2017). Self-reported early life smoking exposures were queried at baseline or follow-up questionnaires. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of ovarian cancer overall and by tumour histotype. Overall, ovarian cancer risk was not different among participants whose mothers did versus did not smoke during pregnancy (HR = 1.05, 95% CI: 0.87-1.27); however, an increased risk was observed among women who themselves were never smokers (HR = 1.38, 95% CI: 1.05-1.81) but not among ever smokers (HR = 0.86, 95% CI: 0.66-1.14; Pheterogeneity = 0.02). Compared with women who never smoked, ovarian cancer risk was similar for women who started to smoke at age <18 (HR = 0.98, 95% CI: 0.86-1.11) or ≥18 (HR = 1.02, 95% CI: 0.93-1.12). These associations did not differ by histotype (Pheterogeneity ≥0.35). Parental smoking in the home during childhood/adolescence was related to a 15% increased risk of ovarian cancer in adulthood (HR = 1.15, 95% CI: 1.04-1.27) and this association was suggestively stronger among women with non-serous/low-grade serous tumours (HR = 1.28, 95% CI: 1.02-1.61) versus high-grade serous/poorly differentiated tumours (HR = 1.09, 95% CI: 0.93-1.28; Pheterogeneity = 0.25). Exposure to parental tobacco smoke in the home, but not early initiation of smoking, was associated with a modest elevated risk of ovarian cancer. Further investigations are required to confirm these findings and elucidate underlying mechanisms.

Salpingectomy for the Risk Reduction of Ovarian Cancer: Is It Time for a Salpingectomy-alone Approach?

To summarize published evidence supporting current strategies for the prevention of epithelial ovarian cancer in women with a genetic, elevated risk for the development of this disease, as well as the emerging data on the novel salpingectomy with delayed oophorectomy (SDO) strategy. Furthermore, we will explore whether salpingectomy alone is a viable risk-reducing strategy for these women. We will also discuss current national guidelines for risk-reducing surgery based on patients' individual genetic predisposition. MEDLINE, PubMed, EMBASE, and the Cochrane Database, with a focus on randomized controlled trials and large prospective, observational studies. The key search terms for our review included Medical Subject Headings: "salpingectomy," "ovarian cancer," and "risk-reducing surgery." The fallopian tube is now well established as the site of origin for most ovarian cancers, particularly high-grade serous carcinomas. This finding has led to the development of new preventive surgical techniques, such as SDO, which may be associated with fewer side effects. However, until the results of ongoing trials are reported and the impact of SDO on ovarian cancer risk reduction is established, it should not be recommended outside of clinical trials, and bilateral salpingo-oophorectomy remains the treatment of choice for risk-reducing surgery, especially in women with a genetic, high risk for ovarian cancer. The decision to undergo risk-reducing surgery among women with an elevated risk for ovarian cancer should be made after comprehensive consultation and individually based on genetic predisposition, childbearing status, and personal preference.

Abstract 3498: Ovarian cancer risk factors multiply to create high risk in pre-menopausal women

Abstract Background: Ovarian cancer is the eighth-most common cancer among women. Although a number of established risk factors exist for this disease, analyses of these exposures have largely not taken into account potential interactions. We present an interaction analysis of eight ovarian cancer risk factors, followed by the creation of modifiable and non-modifiable risk scores for the disease. Methods: Data used in this analysis come from nine studies in the Ovarian Cancer Association Consortium (OCAC): one from Australia, one from Europe and seven from the US. Analyses were restricted to pre-menopausal women without first-degree family histories of ovarian cancer, leading to a final study population of 1504 cases and 3515 controls. Five potentially modifiable predictors (oral contraceptive (OC) use duration, body mass index, tubal ligation, hysterectomy and breastfeeding) and three non-modifiable predictors (parity, incomplete pregnancies and history of endometriosis) were considered. A complete analysis of interactions between the eight variables as well as with age, race/ethnicity, education level and study site was conducted. No statistically significant pairwise interactions were found with likelihood ratio statistics, thus suggesting no departure from multiplicativity in the odds ratios. The modifiable and non-modifiable risk scores were calculated as the product of the odds ratios for each group of exposures. Logistic regression was used to model the association between ovarian cancer and the risk scores. Age, race/ethnicity, education level and study site were included in the model. Results: The associations between the second, third and fourth quartiles of the modifiable risk score compared to the lowest quartile were 1.67 (95% CI 1.35-2.09), 2.18 (95% CI 1.76-2.71) and 3.72 (95% CI 3.04-4.57), respectively. The odds ratios for the non-modifiable risk score were 1.17 (95% CI 0.95-1.44), 1.24 (95% CI 0.99-1.54) and 2.06 (95% CI 1.68-2.53), respectively for the second, third and fourth quartiles compared to the first. Women in the highest quartiles of both the modifiable and non-modifiable risk scores, representing 14.6% of the women, had a 7.67-fold increased risk of ovarian cancer (95% CI 4.68-11.39) compared to women in the lowest quartiles for both risk scores (3.6% of the women). Conclusions: Pre-menopausal women in the highest risk quartiles have a substantially elevated risk of ovarian cancer based on these eight exposures. Modifiable factors contribute more than non-modifiable factors to ovarian cancer risk among pre-menopausal women with no family history in our study. Women in the highest risk group (fourth quartile of both risk scores) could reduce their risk by intervening on the modifiable exposures; for example, 63% of women in this group had not used oral contraceptives and 93% had not had tubal ligation. However, careful consideration of the risks and benefits of such prevention measures is needed. Citation Format: Minh Tung Phung, Bhramar Mukherjee, Alice W. Lee, Penelope M. Webb, Harvey A. Risch, Jennifer Anne Doherty, Holly R. Harris, Marc T. Goodman, Roberta B. Ness, Francesmary Modugno, Allan Jensen, Susanne K. Kjaer, Kathryn L. Terry, Daniel W. Cramer, Argyrios Ziogas, Hoda Anton-Culver, Malcolm C. Pike, Anna H. Wu, Celeste Leigh Pearce. Ovarian cancer risk factors multiply to create high risk in pre-menopausal women [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3498.

Methylenetetrahydrofolate reductase gene polymorphisms in the risk of polycystic ovary syndrome and ovarian cancer.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) in hormone metabolism pathways might cause metabolic disturbances and contribute to the development of polycystic ovary syndrome (PCOS) and ovarian cancer, but the published studies were inconsistent. The aim of the present study was to evaluate the MTHFR C677T (rs1801133) and A1298C (rs1801131) gene polymorphisms in the risk of PCOS and ovarian cancer by meta-analysis. A comprehensive electronic search was conducted in databases for studies published from 1995 to 2020. The pooled ORs were calculated by Revman 5.2 software. Twenty-nine articles including 45 case–control studies were included. We found that MTHFR C677T polymorphisms were correlated with elevated PCOS risk (TT vs. CT+CC: OR = 1.41, 95%CI = 1.20–1.67; TT+CT vs. CC: OR = 1.54, 95%CI = 1.07–2.22; CT vs. CC+TT: OR = 1.18, 95%CI 1.04–1.33; TT vs. CC: OR = 1.47, 95%CI = 1.03–2.11; T vs. C: OR = 1.25, 95%CI = 1.06–1.47), which were more obvious in Middle Eastern subgroup. MTHFR A1298C polymorphisms were also associated with overall PCOS susceptibility (CC vs. AC+AA: OR = 2.55, 95% CI = 1.61–4.03; CC+AC vs. AA: OR = 1.84, 95%CI = 1.04–3.28; CC vs. AA: OR = 2.66, 95%CI = 1.68–4.22; C vs. A: OR = 1.67, 95%CI = 1.03–2.71), which were mainly reflected in Asian subjects. For ovarian cancer, MTHFR C677T polymorphisms were only related with elevated ovarian cancer risk in Asian population, while no significant association was found for A1298C polymorphisms. This meta-analysis suggested that MTHFR C677T and MTHFR A1298C polymorphisms were correlated with elevated PCOS risk. MTHFR C667T only posed a higher risk for ovarian cancer in Asians instead of other populations, while MTHFR A1298C polymorphisms were not related to ovarian cancer risk. Further studies are needed to validate the conclusion.

Does preventive oophorectomy increase the risk of depression in BRCA mutation carriers?

BRCA mutation carriers are advised to undergo bilateral salpingo-oophorectomy to prevent ovarian cancer. The abrupt hormonal withdrawal associated with early surgical menopause has been shown to increase the risk of depression and anxiety among women in the general population. The impact in women with a BRCA1 or BRCA2 mutation is not known. We undertook a matched prospective study of BRCA mutation carriers to evaluate the impact of oophorectomy on self-reported initiation of antidepressant use. We identified women with no personal history of cancer or depression and prospectively evaluated the frequency of self-reported medication use after surgery. Each exposed participant (oophorectomy) was randomly matched to a control participant (no oophorectomy) according to year of birth (within 3 years), BRCA mutation type (BRCA1 or BRCA2), and country of residence (Canada, United States, Poland). A total of 506 matched sets were included. We estimated the odds ratio (OR) and 95% confidence intervals (CIs) of antidepressant use (ever/never) following preventive oophorectomy in the entire study population and stratified by age at oophorectomy and by use of hormone therapy. Oophorectomy was not associated with more frequent antidepressant use among BRCA mutation carriers (OR = 0.46; 95% CI 0.22-0.96). We observed reductions in the odds of antidepressant medication use among women who underwent oophorectomy before the age of 50 years (OR = 0.33; 95% CI 0.14-0.78) and among those who initiated hormone therapy use after oophorectomy (OR = 0.35; 95% CI 0.14-0.90). Findings were similar when the analysis was based on self-reported depression (rather than antidepressant use). Although based on a small number of women, these findings suggest that oophorectomy does not increase psychological distress among women at an elevated risk of ovarian cancer.

Management of surgical menopause in women undergoing risk-reducing surgery for elevated risk of ovarian cancer: Can we do better?

Management of surgical menopause in women undergoing risk-reducing surgery for elevated risk of ovarian cancer: Can we do better?

Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients.

Constitutional loss-of-function pathogenic variants in the tumor suppressor genes BRCA1 and BRCA2 are widely associated with an elevated risk of ovarian cancer (OC). As only ~15% of OC individuals carry the BRCA1/2 pathogenic variants, the identification of other potential OC-susceptibility genes is of great clinical importance. Here, we established the prevalence and spectrum of the germline pathogenic variants in the BRCA1/2 and 23 other cancer-related genes in a large Polish population of 333 unselected OC cases. Approximately 21% of cases (71/333) carried the BRCA1/2 pathogenic or likely pathogenic variants, with c.5266dup (p.Gln1756Profs*74) and c.3700_3704del (p.Val1234Glnfs*8) being the most prevalent. Additionally, ~6% of women (20/333) were carriers of the pathogenic or likely pathogenic variants in other cancer-related genes, with NBN and CHEK2 reported as the most frequently mutated, accounting for 1.8% (6/333) and 1.2% (4/333) of cases, respectively. We also found ten pathogenic or likely pathogenic variants in other genes: 1/333 in APC, 1/333 in ATM, 2/333 in BLM, 1/333 in BRIP1, 1/333 in MRE11A, 2/333 in PALB2, 1/333 in RAD50, and 1/333 in RAD51C, accounting for 50% of all detected variants in moderate- and low-penetrant genes. Our findings confirmed the presence of the additional OC-associated genes in the Polish population that may improve the personalized risk assessment of these individuals.

Anticancer Activity of Metformin, an Antidiabetic Drug, Against Ovarian Cancer Cells Involves Inhibition of Cysteine-Rich 61 (Cyr61)/Akt/Mammalian Target of Rapamycin (mTOR) Signaling Pathway.

BackgroundOvarian cancer is considered one of the lethal cancers responsible for high mortality and morbidity across the world. The prognosis and the survival rate of ovarian cancer is far from decent. Cysteine-rich 61 (Cyr61) also known as CCN1, is a member of CCN-family of growth factors, reported to be significantly overexpressed in several malignancies which include, but are not limited to, ovarian cancer. Recent studies have revealed that women with type 2 diabetes mellitus have an elevated risk of ovarian cancer. Hence, administration of an antidiabetic drug with anticancer effects such as metformin may act as an effective therapeutic regime against ovarian cancer.Material/MethodsCell viability and apoptosis were examined by MTT and Annexin V/PI double staining respectively. Cell migration was determined by Boyden Chamber assay. Transient knockdown of Cyr61 in ovarian cancer cells was achieved by transecting the cells with siRNA for Cyr61using Lipofectamine 2000.ResultsOur results indicated that treatment of ovarian cancer cells with metformin caused significant downregulation of Cyr61 protein expression levels ultimately favoring apoptosis. Transient knockdown of Cyr61 resulted in the inhibition of cell proliferation and migration. This was also associated with the concomitant downregulation of pAkt and pmTOR confirming the role of Cyr61 as an upstream modulator of Akt signaling. Conversely the extracellular supplementation of recombinant Cyr61 attenuates the cytotoxic properties of metformin in ovarian cancer cells.ConclusionsTaken together, we concluded that metformin exhibits anticancer effects and Cyr61 acts as a direct target for metformin in ovarian cancer cells.

Abstract IA40: Obesity in breast and ovarian cancers: Racial/ethnic disparities

Abstract IA40: Obesity in breast and ovarian cancers: Racial/ethnic disparities