Risk Of Epithelial Ovarian Cancer Research Articles

Exploring estrogen-related mechanisms in ovarian carcinogenesis: association between bone mineral density and ovarian cancer risk in a multivariable Mendelian randomization study.

Estrogen may play a role in epithelial ovarian cancer (EOC) carcinogenesis, with effects varying by EOC histotype. Measuring women's long-term exposure to estrogen is difficult, but bone mineral density (BMD) may be a reasonable proxy of longer-term exposure. We examined this relationship by assessing the association between genetic predisposition for higher BMD and risk of EOC by histotype. We used Mendelian randomization (MR) to assess associations between genetic markers for femoral neck and lumbar spine BMD and each EOC histotype. We used multivariable MR (MVMR) to adjust for probable pleiotropic traits, including body mass index, height, menarcheal age, menopausal age, smoking, alcohol intake, and vitamin D. Univariable analyses suggested greater BMD was associated with increased risk of endometrioid EOC (per standard deviation increase; lumbar spine OR = 1.21; 95% CI 0.93,1.57, femoral neck: OR = 1.25; 0.99,1.57), but sensitivity analyses indicated that pleiotropy was likely. Adjustment using MVMR reduced the magnitude of estimates slightly (lumbar spine: OR = 1.13; 95% CI 1.00,1.28, femoral neck: OR = 1.18; 1.03,1.36). Results for lumbar spine BMD and high-grade serous EOC were also suggestive of an association (univariable MR: OR = 1.16; 95% CI 1.03,1.30; MVMR: OR = 1.06; 0.99,1.14). Our study found associations between genetic predisposition to higher BMD, a proxy for long-term estrogen exposure, and risk of developing endometroid and high-grade serous EOC cancers. These findings add to existing evidence of the relationship between estrogen and increased risk of EOC for certain histotypes.

Appraisal of the causal effect of Chlamydia trachomatis infection on epithelial ovarian cancer risk: a two-sample Mendelian randomisation study.

History of Chlamydia trachomatis infection has previously been associated with epithelial ovarian cancer (EOC) in observational studies. We conducted a two-sample univariable Mendelian randomisation (MR) study to examine whether genetically predicted seropositivity to the C. trachomatis major outer membrane protein (momp) D is causally associated with EOC. MR analyses employed genetic associations derived from UK Biobank as proxies for momp D seropositivity in 25 509 EOC cases and 40 941 controls that participated in the Ovarian Cancer Association Consortium. Findings were replicated using a GWAS meta-analyses of global biobanks including the UK Biobank, FinnGen and BioBank Japan. Genetically predicted momp D seropositivity was associated with overall and high-grade serous EOC risk in inverse-variance weighted (IVW) and MR-Egger univariable MR analysis (odds ratio (OR) 1.06; 95% confidence interval (CI) 1.02-1.10, and OR 1.08; 95%CI 1.01-1.16, respectively). Replication yielded similar results for overall EOC (OR 1.11; 95%CI 1.01-1.22). This MR study supports a causative link between C. trachomatis infection and overall and high-grade serous EOC.

Improving on polygenic scores across complex traits using select and shrink with summary statistics (S4) and LDpred2

BackgroundAs precision medicine advances, polygenic scores (PGS) have become increasingly important for clinical risk assessment. Many methods have been developed to create polygenic models with increased accuracy for risk prediction. Our select and shrink with summary statistics (S4) PGS method has previously been shown to accurately predict the polygenic risk of epithelial ovarian cancer. Here, we applied S4 PGS to 12 phenotypes for UK Biobank participants, and compared it with the LDpred2 and a combined S4 + LDpred2 method.ResultsThe S4 + LDpred2 method provided overall improved PGS accuracy across a variety of phenotypes for UK Biobank participants. Additionally, the S4 + LDpred2 method had the best estimated PGS accuracy in Finnish and Japanese populations. We also addressed the challenge of limited genotype level data by developing the PGS models using only GWAS summary statistics.ConclusionsTaken together, the S4 + LDpred2 method represents an improvement in overall PGS accuracy across multiple phenotypes and populations.

Rare germline genetic variation in PAX8 transcription factor binding sites and susceptibility to epithelial ovarian cancer.

Common genetic variation throughout the genome together with rare coding variants identified to date explain about a half of the inherited genetic component of epithelial ovarian cancer risk. It is likely that rare variation in the non-coding genome will explain some of the unexplained heritability, but identifying such variants is challenging. The primary problem is lack of statistical power to identifying individual risk variants by association as power is a function of sample size, effect size and allele frequency. Power can be increased by using burden tests which test for association of carriers of any variant in a specified genomic region. This has the effect of increasing the putative effect allele frequency. PAX8 is a transcription factor that plays a critical role in tumour progression, migration and invasion. Furthermore, regulatory elements proximal to target genes of PAX8 are enriched for common ovarian cancer risk variants. We hypothesised that rare variation in PAX8 binding sites are also associated with ovarian cancer risk, but unlikely to be associated with risk of breast, colorectal or endometrial cancer. We have used publicly available, whole-genome sequencing data from the UK 100,000 Genomes Project to evaluate the burden of rare variation in PAX8 binding sites across the genome. Data were available for 522 ovarian cancers, 2,984 breast cancers, 2,696 colorectal cancers, 836 endometrial cancers and 2253 non-cancer controls. Active binding sites were defined using data from multiple PAX8 and H3K27 ChIPseq experiments. We found no association between the burden of rare variation in PAX8 binding sites (defined in several ways) and risk of ovarian, breast or endometrial cancer. An apparent association with colorectal cancer was likely to be a technical artefact as a similar association was also detected for rare variation in random regions of the genome. Despite the null result this study provides a proof-of -principle for using burden testing to identify rare, non-coding germline genetic variation associated with disease. Larger sample sizes available from large-scale sequencing projects together with improved understanding of the function of the non-coding genome will increase the potential of similar studies in the future.

Caregiver burden and risk of epithelial ovarian cancer in the Nurses' Health Studies.

Psychosocial stress may increase ovarian cancer risk and accelerate disease progression. We examined the association between caregiver burden, a common stressor, and risk of epithelial ovarian cancer. We prospectively followed 67,724 women in the Nurses' Health Study (NHS; 1992-2012) and 70,720 women in the NHSII (2001-2009) who answered questions on informal caregiving (i.e., caregiving outside of work). Women who reported no informal caregiving were considered non-caregivers while, among women who provided care outside of work, caregiver burden was categorized by time spent caregiving and perceived stress from caregiving. For the 34% of women who provided informal care for ≥15 hours per week, 42% described caregiving as moderately to extremely stressful. Pooled multivariate analyses indicated no difference in ovarian cancer risk for women providing ≥15 hours of care per week compared to non-caregivers (hazard ratio (HR)=0.96; 95% confidence interval (CI): 0.79-1.18), and no association was evident for women who reported moderate or extreme stress from caregiving compared to non-caregivers (HR=0.96; 95% CI: 0.75-1.22). Together with prior work evaluating job strain and ovarian cancer risk, our findings suggest that, when evaluating a stressor's role in cancer risk, it is critical to consider how the stressor contributes to the overall experience of distress.

Use of an emulated trial to investigate the association between use of nitrogen-based bisphosphonates and risk of epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the eighth most common cancer in women, with poor survival outcomes. Observational evidence suggests that nitrogen-based bisphosphonate (NBB) use may be associated with reduced risk of EOC, particularly the endometrioid and serous histotypes; however, confounding by indication is a concern. An alternative approach to investigate the chemo-preventive potential of NBBs is to emulate a target trial by identifying all women who initiate use of NBBs and investigate the risk of EOC for continued users compared with discontinued users. Using population-based linked data, we identified all Australian women aged over 50 years who first used NBBs over 2004-12. We used the year after first use to define treatment for each woman as either continued or discontinued use. We emulated randomization using stabilized inverse probability weights to balance the treatment groups using covariates including age, comorbidities and socioeconomic status. We followed women from treatment assignment until EOC diagnosis, death or 31 December 2013. We assessed the risk of EOC (overall and by histotype) using flexible parametric time-to-event models allowing for time-varying effects, and produced time-varying coefficients. Of the 313 383 women in the study, 472 were diagnosed with EOC during follow-up (261 serous EOC), with an average age at diagnosis of 72 years. Continued use of NBBs was associated with reduced risk of EOC overall (HR = 0.87, 95% CI: 0.69, 1.10), and serous EOC (HR = 0.71, 95% CI: 0.53, 0.96), compared with discontinued treatment, with estimates remaining constant over the 9-year follow-up. Results from our emulated trial suggest that in women who initiated NBB treatment, those who continued use had 13% and 29% lower hazards of being diagnosed with EOC overall and serous EOC, respectively, compared with women who discontinued use.

Impact of insomnia on ovarian cancer risk and survival: a Mendelian randomization study

Insomnia is the most common sleep disorder in patients with epithelial ovarian cancer (EOC). We investigated the causal association between genetically predicted insomnia and EOC risk and survival through a two-sample Mendelian randomization (MR) study. Insomnia was proxied using genetic variants identified in a genome-wide association study (GWAS) meta-analysis of UK Biobank and 23andMe. Using genetic associations with EOC risk and overall survival from the Ovarian Cancer Association Consortium (OCAC) GWAS in 66,450 women (over 11,000 cases with clinical follow-up), we performed Iterative Mendelian Randomization and Pleiotropy (IMRP) analysis followed by a set of sensitivity analyses. Genetic associations with survival and response to treatment in ovarian cancer study of The Cancer Genome Atlas (TCGA) were estimated controlling for chemotherapy and clinical factors. Insomnia was associated with higher risk of endometrioid EOC (OR=1.60, 95% CI 1.05-2.45) and lower risk of high-grade serous EOC (HGSOC) and clear cell EOC (OR=0.79 and 0.48, 95% CI 0.63-1.00 and 0.27-0.86, respectively). In survival analysis, insomnia was associated with shorter survival of invasive EOC (OR=1.45, 95% CI 1.13-1.87) and HGSOC (OR=1.4, 95% CI 1.04-1.89), which was attenuated after adjustment for body mass index and reproductive age. Insomnia was associated with reduced survival in TCGA HGSOC cases who received standard chemotherapy (OR=2.48, 95% CI 1.13-5.42), but was attenuated after adjustment for clinical factors. This study supports the impact of insomnia on EOC risk and survival, suggesting treatments targeting insomnia could be pivotal for prevention and improving patient survival. National Institutes of Health, National Cancer Institute. Full funding details are provided in acknowledgments.

Development and validation of radiomics nomogram for metastatic status of epithelial ovarian cancer

To develop and validate an enhanced CT-based radiomics nomogram for evaluating preoperative metastasis risk of epithelial ovarian cancer (EOC). One hundred and nine patients with histologically confirmed EOC were retrospectively enrolled. The volume of interest (VOI) was delineated in preoperative enhanced CT images, and 851 radiomics features were extracted. The radiomics features were selected by the least absolute shrinkage and selection operator (LASSO), and the rad-score was calculated using the formula of the radiomics label. A clinical model, radiomics model, and combined model were constructed using the logistic regression classification algorithm. Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) were used to evaluate the diagnostic performance of the models. Seventy-five patients (68.8%) were histologically confirmed to have metastasis. Eleven optimal radiomics features were retained by the LASSO algorithm to develop the radiomic model. The combined model for evaluating metastasis of EOC achieved area under the curve (AUC) values of 0.929 (95% CI 0.8593–0.9996) in the training cohort and 0.909 (95% CI 0.7921–1.0000) in the test cohort. To facilitate clinical use, a radiomic nomogram was built by combining the clinical characteristics with rad-score. The DCA indicated that the nomogram had the most significant net benefit when the threshold probability exceeded 15%, surpassing the benefits of both the treat-all and treat-none strategies. Compared with clinical model and radiomics model, the radiomics nomogram has the best diagnostic performance in evaluating EOC metastasis. The nomogram is a useful and convenient tool for clinical doctors to develop personalized treatment plans for EOC patients.

Racial and ethnic differences in epithelial ovarian cancer risk: an analysis from the Ovarian Cancer Association Consortium.

Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n=785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n=99 case and 167 control participants), 1149 Hispanic (n=505 case and 644 control participants), and 24 189 White (n=9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations by race and ethnicity (P≤.02) was observed for oral contraceptive (OC) use, parity, tubal ligation, and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in Native Hawaiian/Pacific Islander and Asian women. The inverse association for tubal ligation with risk was most pronounced for Native Hawaiian/Pacific Islander participants (odds ratio (OR)=0.25; 95% CI, 0.13-0.48) compared with Asian and White participants (OR=0.68 [95% CI, 0.51-0.90] and OR=0.78 [95% CI, 0.73-0.85], respectively). Differences in EOC risk factor associations were observed across racial and ethnic groups, which could be due, in part, to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies. This article is part of a Special Collection on Gynecological Cancers.

Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5×10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (pvalue <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

Abstract LB147: Fine-scale mapping of chromosome 9q22.33 identifies candidate causal variant in ovarian cancer

Abstract Ovarian cancer is a complex polygenic disease in which genetic factors play a significant role in disease etiology. Genome-wide association study(GWAS) identified a novel variant on chromosome 9q22.33as a susceptibility locus of epithelial ovarian cancer (EOC) in Han Chinese population. However, the underline mechanism of this region was still unknown. In this study, we conducted a fine-mapping analysis of 130kb region including 1,039 variants in 200 health women. Ten variants were selected to evaluate the association with EOC risk in 1,099 EOC cases and 1,591 controls. We identified two variants were significantly associated with ovarian cancer risk (rs7027650, P=1.91 × 10−7; rs1889268, P=3.71 × 10−2). Expression quantitative trait locus (eQTL) analysis found thatrs7027650was significantly correlated with COL15A1 gene expression (P=0.009). Luciferase reporter gene assay confirmed that rs7027650 could interact with the promoter region of COL15A1 to reduce its activity. Electrophoretic Mobility ShiftAssay (EMSA) showed theallele-specific binding capacity of rs7027650. These findings revealed that rs7027650 may be a potential causal variant at 9q22.33 region and may regulate the expression level of COL15A1. This study provided a clue for the molecular mechanism of potential causal variantaffecting the risk of ovarian cancer. Citation Format: an Li, Tongyu Xing, Yanrui Zhao, Kexin Chen, Hong Zheng. Fine-scale mapping of chromosome 9q22.33 identifies candidate causal variant in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB147.

Abstract 2195: Intrauterine device use and risk of invasive epithelial ovarian cancer: A population-based case-control study

Abstract Introduction: Ovarian, fallopian tube, and primary peritoneal cancers (hereafter referred to as ovarian cancer) are the most fatal gynecologic cancers. Thus, it is imperative to identify strategies that can reduce the risk of the disease. Several contraceptive methods have been shown to be associated with a reduced risk of ovarian cancer, including combined oral contraceptives, injectable progestins, and tubal ligation. However, the use of these contraceptive methods has been decreasing in the U.S., with a growing preference for intrauterine devices (IUDs) for pregnancy prevention. Previous case-control studies on the association between IUD use and ovarian cancer risk have found inconsistent results. Notably, previous studies had small sample sizes and did not restrict to invasive epithelial tumors. The current analysis assessed the association between IUD use and risk of invasive epithelial ovarian cancer in a large population-based case-control study. Methods: This analysis used data from 1,713 people diagnosed with primary invasive epithelial ovarian cancer (cases) and 2,348 cancer-free people (controls) participating in a case-control study conducted in Los Angeles, CA from 1992-2010. The study consisted of four waves of recruitment with similar enrollment and data collection methods. Logistic regression models were fit to assess the association between IUD use and risk of invasive epithelial ovarian cancer. All models were adjusted for age, race/ethnicity, education, first-degree family history of ovarian cancer, endometriosis, body mass index, duration of combined oral contraceptive use, parity, duration of breastfeeding, tubal ligation, and study wave. Heterogeneity across the study waves and the ovarian cancer histotypes was evaluated using standard meta-analysis techniques. Results: There was no statistically significant association between IUD use and risk of invasive epithelial ovarian cancer (odds ratio=1.09, 95% confidence interval 0.93-1.28). This result was consistent across the study waves and the ovarian cancer histotypes (p-values for heterogeneity&amp;gt;0.05). Conclusion: IUD use was not associated with the risk of invasive epithelial ovarian cancer. Analysis by IUD type (i.e., hormone-releasing vs copper IUDs) was not possible in this study as these data were not collected. Future research should examine whether the type of IUD (i.e. copper versus hormone-releasing) may have different effects on risk of ovarian cancer. Citation Format: Minh Tung Phung, Yuting Wang, Alice W. Lee, Malcolm C. Pike, Anna H. Wu, Celeste Leigh Pearce. Intrauterine device use and risk of invasive epithelial ovarian cancer: A population-based case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2195.

Abstract 2217: Associations between intrauterine device use and ovarian cancer risk among 11 population-based case-control studies

Abstract Background: Intrauterine device (IUD) use has increased while oral contraceptive (OC) use has decreased among premenopausal women. It is unknown whether IUDs offer protection against epithelial ovarian cancer (EOC), similar to OCs, or may increase risk. Therefore, we examined the association between IUD use and EOC risk. Methods: Information on contraception use was obtained through questionnaires from 11 studies participating in the Ovarian Cancer Association Consortium and African-American Cancer Epidemiology Study. Study-specific odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional multivariable logistic regression, and heterogeneity between studies was assessed using Cochran Q and I2 statistics. There was no evidence of heterogeneity, thus data were pooled. We assessed potential effect modification by decade of birth, race, parity, and personal history of endometriosis by reporting stratum-specific estimates and tested for multiplicative interaction by comparing models with and without interaction terms via likelihood ratio test. Polytomous logistic regression was used to estimate histotype-specific associations. Results: Results were pooled for 11,033 EOC cases and 13,358 controls. There were 2,656 (19.9%) IUD users (mostly non-hormonal) and 8,923 (66.8%) OC users among controls compared to 1,933 (17.5%) IUD users and 6,318 (57.3%) OC users among cases. IUD use was associated with lower risk of endometrioid (OR: 0.73, 95% CI: 0.62-0.86) and clear cell (OR: 0.63, 95% CI: 0.48-0.80), but not high-grade serous subtypes (OR: 1.05, 95% CI: 0.98-1.14), with significant heterogeneity by histotype (p=0.0006). Among studies that collected data on IUD type, we observed a non-significant inverse association between hormonal IUD use and EOC (OR: 0.72, 95% CI: 0.51-1.03); however, only 51 cases reported hormonal IUD use. Among those who used both IUD and OCs, there was no association with the order of contraception use and EOC. There were no major differences in the associations of age at first use, duration of use, or time since last use and EOC risk. Among parous women, IUD use before first pregnancy was associated with a non-significant reduced odds of EOC (OR: 0.82, 95% CI: 0.65-1.04). We also observed a statistically significant interaction between IUD use and endometriosis with reduced odds of EOC associated with IUD use among women with endometriosis (OR: 0.77, 95% CI: 0.60-0.98) but not those without endometriosis (OR: 0.96, 95% CI: 0.90-1.03, p-interaction=0.05). Discussion: IUD use was associated with lower clear cell and endometrioid EOC risk and may be most protective among women with endometriosis. Future research should include cohorts of women with a higher prevalence of hormonal IUD use to determine the impact of changing contraceptive trends on ovarian cancer burden and identifying preventive strategies for women at high risk. Citation Format: Jennifer M. Mongiovi, Ana Babic, Naoko Sasamoto, Lauren Peres, Holly Harris, Mollie E. Barnard, Shelley S. Tworoger, Anita Koushik, Joellen M. Schildkraut, Jennifer A. Doherty, Kathryn L. Terry, the Ovarian Cancer Association Consortium &amp; the African-American Cancer Epidemiology Study. Associations between intrauterine device use and ovarian cancer risk among 11 population-based case-control studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2217.

Matrix Metalloproteinase-7 Promoter Site Single Nucleotide Polymorphism (-181A>G) in Epithelial Ovarian Cancer in the Eastern Indian Population.

Matrix metalloproteinase-7 (MMP7) plays multiple roles in different stages of tumor development. Elevated MMP7 activity has been reported in ovarian cancer. Single nucleotide polymorphism (SNP) of promoter sites of the MMP7 gene has been shown to cause alteration in gene expression, hence resulting in changes in susceptibility to various diseases and tumor development. The current study evaluated the association of epithelial ovarian cancer risk with MMP7 promoter site -181A>G polymorphism in the population of eastern India. The present case-control study included 64 histopathologically confirmed cases of epithelial ovarian cancer and 100 control subjects. The MMP7 -181A/G polymorphism was identified using polymerase chain reaction-restriction fragment length polymorphism. The association between genotypes and epithelial ovarian cancer risk was analyzed by odds ratio (OR) with a 95% confidence interval. The frequencies of AA, AG, and GG genotypes in ovarian cancer cases were 37.5%, 46.9%, and 15.6%, respectively, while that of control subjects were 56%, 36%, and 8%, respectively, in the study population. By taking the wild-type AA genotype as a reference, it was found that genotypeGG was associated with a significant risk for epithelial ovarian cancer (OR: 2.92). Frequency distribution of genotypes did not show any significant association with tumor characteristics like the International Federation of Gynecology and Obstetrics (FIGO) stage, histology, lymph node status, and distant metastasis. The present study demonstrated the association of MMP7 promoter site -181 GG genotype and the G allele with increased risk for epithelial ovarian cancer in the eastern Indian population.

Abstract A042: History of infertility and risk of ovarian cancer in the women’s health initiative

Abstract Background: Given the consistent relationship between reproductive factors (e.g. parity) and risk of epithelial ovarian cancer, several studies have investigated the relation between infertility and ovarian cancer with conflicting results. Prior research has suggested differences in risk by specific infertility subgroups, which may have contributed to the conflicting findings. Further, few studies examined associations by ovarian cancer histotypes or were able to disentangle the influence of infertility vs. fertility treatment. Differences across studies could also have been influenced by different study populations (e.g., population-based vs. clinical population/registry of in-vitro fertilization [IVF]) and lack of consistent statistical control for important confounding factors including nulliparity, number of pregnancies, and age at first pregnancy. Finally, prior prospective studies have had limited follow-up, thus not capturing cancers that occur after menopause and which may have different risk factor profiles. Our objective was to determine the association between history of infertility and risk of postmenopausal ovarian cancer in a population that had not received treatment with IVF. Methods: We utilized the Women’s Health Initiative (n=114,761) with over 25 years of follow-up. At study baseline participants were asked whether they had ever tried to become pregnant for more than one year without becoming pregnant and whether a reason was found. Cox proportional hazards models were used to calculate the hazard ratios (HRs) of incident ovarian cancer comparing participants with a history of infertility to parous participants without infertility. Logistic regression models were used to calculate odds ratios (OR) for prevalent ovarian cancer at study baseline. Results: Approximately 16% of participants reported a history of infertility. 1,376 participants reported prevalent ovarian cancer at study baseline and 852 cases of ovarian cancer were diagnosed during study follow-up. In the prospective analyses, no statistically significant association was observed between infertility and risk of ovarian cancer overall (HR=1.16; 95% CI=0.98-1.37), by histotype, or with any specific infertility diagnoses. When prevalent ovarian cancer was examined, those reporting a history of infertility had a greater odds of ovarian cancer diagnosis (1.34; 95% CI=1.13-1.58) at WHI cohort baseline. This association was present for most infertility diagnoses with the strongest associations for hormonal/ovulatory (OR=1.97;95% CI=1.24-3.12), tubal/uterine factor (OR=1.63; 95% CI=1.15-2.31), and male factor (OR=1.71; 95% CI=1.19-2.47) infertility. Conclusions: We observed no significant association between infertility history and incident ovarian cancer in our population of postmenopausal participants. An association between infertility and ovarian cancer was present when prevalent ovarian cancer cases were examined, consistent with prior analyses that show stronger associations between ovarian cancer risk factors and ovarian cancer among younger women. Citation Format: Holly Harris, Kimberly Lind, Cynthia Thomson, Nazmus Saquib, Aladdin Shadyab, Peter Schnatz, Rogelio Robles-Morales, Lihong Qi, Howard Strickler, Denise Roe, Leslie Farland. History of infertility and risk of ovarian cancer in the women’s health initiative [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A042.

Abstract A089: Influence of pre-diagnosis aspirin use on epithelial ovarian cancer tumor immune microenvironment markers: results from the Nurses’ Health Study (NHS) and NHSII

Abstract Background: Daily aspirin use versus never use is associated with a 10-20% lower risk of developing epithelial ovarian cancer (EOC). Among women with EOC, aspirin use after diagnosis compared with never use is associated with a 30% improvement in ovarian cancer-specific survival. Inhibition of enzymes in prostaglandin synthesis is a key mechanism responsible for the anti-inflammatory and anti-neoplastic effects of aspirin. Prostaglandins influence immune inflammatory cells in the tumor microenvironment therefore our objective was to evaluate how aspirin use may influence the EOC tumor immune microenvironment. Methods: Tissue microarrays (TMAs) representing EOC tumor tissues from participants in the Nurses’ Health Study (NHS) and NHSII were assessed for total T cells, T cell activation and T cell exhaustion markers within the tumor (epithelium) area using multiplex immunofluorescence. Data on aspirin use and information on EOC risk factors and lifestyle variables were collected by questionnaire every two years. Beta-binomial models were used to estimate odds ratios (ORs) and 95% CIs; these models estimate the odds that a cell was positive for the marker(s) of interest comparing recent regular aspirin use (2+ times per week in the questionnaire cycle prior to diagnosis) versus never use, accounting for the total tumor cells in each core. Former users of aspirin were excluded. Multivariable models were adjusted for cohort, histotype (type 1 versus type 2), age and year of cancer diagnosis, number of CD3+ T cells (in tertiles), hysterectomy, tubal ligation, duration of oral contraceptive use, family history of breast or ovarian cancer, parity and body mass index (as fixed effects) and the participant (random effect) to account for multiple tissue cores per case. Results: We compared tumor tissues from 209 participants with recent pre-diagnosis use of aspirin with 88 participants who never used aspirin. Compared with cases who never used aspirin, recent aspirin users had higher odds of having tumors with recently activated cytotoxic T cells (CD3+CD8+CD69+, OR=1.69, 95% CI: 1.10, 2.59) and T cells expressing exhaustion markers (CD3+Lag-3+, OR=1.63, 95% CI: 1.09, 2.43; CD3+Tim-3+, OR= 1.62, 95% CI: 0.96, 2.72). In contrast, there was no association between recent aspirin use versus never use and odds of a tumor being positive for total T cells (CD3+, OR=1.20, 95% CI: 0.80, 1.79). Conclusions: Our data suggest that recent aspirin use before diagnosis was associated with higher odds of having EOC tumors expressing both recently activated cytotoxic T cells and T cell exhaustion markers. By improving our biological understanding of how aspirin use influences the ovarian tumor immune microenvironment, these results will assist to inform the optimal use of aspirin to improve EOC patient outcomes. Future work will focus on additional immune markers, assess non-aspirin nonsteroidal anti-inflammatory drug (NSAID) use and evaluate associations between aspirin/NSAID use with EOC survival considering the context of tumor immune microenvironment biomarkers. Citation Format: Nicola S. Meagher, Cassandra Hathaway, Mary K. Townsend, Mollie E. Barnard, Jose R. Conejo-Garcia, Brooke L. Fridley, Daryoush Saeed-Vafa, Britton Trabert, Shelley S. Tworoger, Melissa A. Merritt. Influence of pre-diagnosis aspirin use on epithelial ovarian cancer tumor immune microenvironment markers: results from the Nurses’ Health Study (NHS) and NHSII [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A089.

Fine-scale mapping of chromosome 9q22.33 identifies candidate causal variant in ovarian cancer.

Ovarian cancer is a complex polygenic disease in which genetic factors play a significant role in disease etiology. A genome-wide association study (GWAS) identified a novel variant on chromosome 9q22.33 as a susceptibility locus for epithelial ovarian cancer (EOC) in the Han Chinese population. However, the underlying mechanism of this genomic region remained unknown. In this study, we conducted a fine-mapping analysis of 130kb regions, including 1,039 variants in 200 healthy women. Ten variants were selected to evaluate the association with EOC risk in 1,099 EOC cases and 1,591 controls. We identified two variants that were significantly associated with ovarian cancer risk (rs7027650, P = 1.91 × 10-7; rs1889268, P = 3.71 × 10-2). Expression quantitative trait locus (eQTL) analysis found that rs7027650 was significantly correlated with COL15A1 gene expression (P = 0.009). The Luciferase reporter gene assay confirmed that rs7027650 could interact with the promoter region of COL15A1, reducing its activity. An electrophoretic mobility shift assay (EMSA) showed the allele-specific binding capacity of rs7027650. These findings revealed that rs7027650 could be a potential causal variant at 9q22.33 region and may regulate the expression level of COL15A1. This study offered insight into the molecular mechanism behind a potential causal variant that affects the risk of ovarian cancer.

Gene polymorphisms of METTL5 and METTL16 are related to epithelial ovarian cancer risk in South China: A three-center case-control study.

Background: The potential relation of methyltransferase-like gene polymorphisms and epithelial ovarian cancer (EOC) remains unclear. Methods: Five SNPs (METTL5 rs3769767 A>G, METTL16 rs1056321 T>C, METTL5 rs10190853 G>A, METTL5 rs3769768 G>A and METTL16 rs11869256 A>G) of methyltransferase-like genes was selected trough NCBI dbSNP database. Two hundred and eighty-eight cases and 361 controls were enrolled from three hospitals in South China to conduct the case-control study. Genomic DNA was abstracted from peripheral blood and genotyped through a TapMan assay. Stratified analysis was conducted to explore the association of rs10190853, rs3769768, rs11869256 genotype and EOC susceptibility. The combination analysis was adopted to evaluate the relation between inferred haplotypes of the METTL5, METTL16 genes and EOC risk. Multifactor dimensionality reduction (MDR) analysis was performed to verify the interaction of SNPs. Results: Among the five analyzed SNPs, METTL5 rs3769768 AA exhibited a significant association with increased EOC risk, while METTL5 rs10190853 GA, METTL16 rs11869256 GA was certified to decrease the susceptibility of EOC. The stratified analysis further revealed the harmful effect of METTL5 rs3769768 AA in EOC patients. On the contrary, METTL16 rs11869256 AG/GG and METTL5 rs10190853 AA showed the reduced risk of EOC in patients of specific subgroups. Combination analysis identified that haplotypes AAA highly connected with reduced risk of EOC. MDR analysis revealed that these SNPs existed no specific interactions. Conclusion: METTL5 rs3769768 was related to increased risk of EOC. METTL5 rs10190853 and METTL16 rs11869256 decreased the susceptibility in EOC. METTL5 and METTL16 could be potential target of molecular therapy and prognosis markers.

Childhood body fatness and the risk of epithelial ovarian cancer: A population-based case-control study in Montreal, Canada

ObjectiveTo assess the association between childhood body fatness and epithelial ovarian cancer (EOC), and whether this association differs by type of EOC. MethodsUsing data from a population-based case-control study (497 cases and 902 controls) in Montreal, Canada conducted 2011–2016, we examined the association between childhood body fatness and EOC, overall and separately for invasive vs. borderline EOCs. A figure rating scale was used to measure body fatness at ages 5 and 10. Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). Quantitative bias analyses were conducted to assess the impact of exposure misclassification and non-participation. ResultsThe aOR (95% CI) of overall EOC for high vs. low body fatness was 1.07 (0.85–1.34) at age 5 and 1.28 (0.98–1.68) at age 10. The associations were stronger for invasive EOC, specifically the endometrioid histological type. For borderline cancers, the aORs were below the null value with wide confidence intervals. Bias analyses did not reveal a strong influence of non-participation. Non-differential exposure misclassification may have biased aORs towards the null for invasive cancers but did not appear to have an appreciable influence on the aORs for borderline cancers. ConclusionsChildhood body fatness may be a risk factor for invasive EOC in later adult life. Our study highlights the potential importance of examining early life factors for a comprehensive understanding of EOC development.

Relationship between PIWIL1 gene polymorphisms and epithelial ovarian cancer susceptibility among southern Chinese woman: a three-center case–control study

ObjectiveTo investigate the potential correlation between piwi-like RNA-mediated gene silencing 1 (PIWIL1) polymorphisms and susceptibility to epithelial ovarian cancer (EOC).MethodsA case–control study was conducted to evaluate the susceptibility of EOC using multinomial logistic regression analysis. The study analyzed the relationship between five functional single nucleotide polymorphisms (SNPs) in the PIWIL1 gene and EOC risk. Genotyping of 288 cases and 361 healthy samples from South China was identified using a TaqMan assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the relationship between the five selected SNPs and EOC susceptibility.ResultsAmong the five SNPs analyzed, the rs10848087 G > A and rs7957349 G > C variants significantly increased the susceptibility of EOC, rs10773771 C > T was associated with a decreased risk of EOC, while the rs35997018 and rs1106042 variants were not in Hardy–Weinberg equilibrium (p < 0.05). The rs10848087 G > A was significantly associated with increased risk of EOC in individuals with metastasis, FIGO stage I and III, low and high pathological grade, tumor numbers ≤ 3 and > 3, tumor size > 3 cm and ≤ 3 cm, pregnant more than 3 times, pre-menopausal status, and strong positive expression of ER (estrogen receptor), PR (progesterone receptor), PAX8 (paired-box 8), wild-type p53 (tumor protein 53), WT1 (Wilm’s tumor gene), P16 (cyclin-dependent kinase inhibitor 2A). In addition, rs10848087 G > A enhanced the EOC risk of cases with negative/mild positive expression of wild p53 and Ki67, and with or without mutant p53 expression. The rs7957349 G > C variant was linked to an increased risk of EOC in subgroups with certain characteristics, including age equal or less than 53 years, metastasis, clinical stage I, low pathological grade, tumor number, tumor size, pregnant times, post-menopause, pre-menopause, and strong positive expression of wild p53 and Ki67 (Antigen identified by monoclonal antibody Ki-67), as well as without mutant p53 expression. The rs10773771 CT/TT alleles were identified to have a protective effect on EOC in women aged 53 years or older, as well as in cases with metastasis, advanced clinical stage, high pathological grade, multiple tumors, tumor size equal to or less than 3 cm, history of pregnancy, post-menopausal status, and strong positive expression of ER, PR, wild-type p53, PAX8, WT1, P16, and Ki67. Furthermore, rs10773771 CT/TT also showed a protective effect in patients with negative or mildly positive expression of PR, PAX8, wild-type p53, WT1, and P16, as well as positive expression of mutant p53. Compared to the reference haplotype GCG, individuals harboring haplotypes GTG were found to have a significantly decreased susceptibility to EOC. PIWIL1 was significantly expressed in the thyroid, pituitary, and adrenal glands with rs7957349 CC alleles.ConclusionsPIWIL1 rs10848087 and rs7957349 were associated with increased risk of EOC, while rs10773771 may have a protective effect against EOC. These genetic variants may serve as potential biomarkers for EOC susceptibility in the South China population.