Risk Of Epithelial Ovarian Cancer Research Articles

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.

RIPK1 polymorphisms and expression levels: impact on genetic susceptibility and clinical outcome of epithelial ovarian cancer

BackgroundThe aim of this study was to explore the associations of RIPK1 polymorphisms, plasma levels and mRNA expression with susceptibility to epithelial ovarian cancer (EOC) and clinical outcome.MethodsThree hundred and nineteen EOC patients included in a 60-month follow-up program and 376 controls were enrolled. Two tag SNPs (rs6907943 and rs9392453) of RIPK1 were genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. Plasma levels of RIPK1 and RIPK1 mRNA expression in white blood cells were determined by ELISA and qPCR, respectively.ResultsFor rs9392453, significantly increased EOC risk was found to be associated with C allele (P = 0.002, OR = 1.49, 95%CI 1.15–1.92), and with CT/CC genotypes in the dominant genetic model (P = 0.006, OR = 1.54, 95%CI 1.12–2.08). CC haplotype (rs6907943-rs9392453) was associated with increased EOC susceptibility. CC genotype of rs6907943 and CT/CC genotypes of rs9392453 were associated with early onset (age ≤ 50 years) of EOC (OR = 2.5, 95%CI 1.03–5.88, and OR = 1.64, 95%CI 1.04–2.63, respectively). AC genotype of rs6907943 was associated with better overall survival of EOC patients in the over-dominant genetic model (P = 0.035, HR = 0.41, 95%CI 0.18–0.94). Multivariate survival analysis identified the AC genotype of rs6907943 as an independent protective factor for survival of early onset patients (P = 0.044, HR = 0.12, 95%CI 0.02–0.95). Compared to controls, significantly increased plasma levels of RIPK1 and reduced RIPK1 mRNA expression were observed in patients.ConclusionsOur results suggest that tag SNPs of RIPK1, increased plasma levels of RIPK1 protein and reduced RIPK1 mRNA expression in white blood cells, may influence the susceptibility to EOC. SNP rs6907943 may be a useful marker to distinguish EOC patients with high risk of death.

Pelvic inflammatory disease and risk of epithelial ovarian cancer: a national population-based case-control study in Sweden

Epithelial ovarian cancer is an insidious disease, and women are often diagnosed when the disease is beyond curative treatment. Accordingly, identifying modifiable risk factors is of paramount importance. Inflammation predisposes an individual to cancer in various organs, but whether pelvic inflammatory disease is associated with an increased risk of epithelial ovarian cancer has not been fully determined. The aim of the present study was to investigate a possible association between clinically verified pelvic inflammatory disease and risk of epithelial ovarian cancer. In this national population-based case-control study, we identified all women in Sweden diagnosed with epithelial ovarian cancer between 1999 and 2020 and ten controls for each, matched for age and residential district. Using several Swedish nationwide registers, we retrieved data on previous pelvic inflammatory disease and potential confounding factors (age, parity, educational level, and previous gynecological surgery). Adjusted odds ratios and 95% confidence intervals were estimated using conditional logistic regression. We performed histotype-specific analyzes for the subgroup of women diagnosed with epithelial ovarian cancer between 2015 and 2020. Hormonal contraceptives and menopausal hormone therapy were also adjusted for in addition to the aforementioned confounders. We included 15,072 women with epithelial ovarian cancer and 141,322 controls. A majority had serous carcinoma (n=9102, 60.4%). In a subgroup of cases diagnosed between 2015 and 2020 we identified high-grade serous carcinoma (n=2319, 60.0%). A total of 1.1% (n=168) of cases and 0.9% (n=1270) of controls were diagnosed with pelvic inflammatory disease. Previous pelvic inflammatory disease was associated with increased risk of epithelial ovarian cancer (adjusted odds ratio, 1.39; 95% confidence interval, 1.17-1.66) and serous carcinoma (adjusted odds ratio, 1.46; 95% confidence interval, 1.18-1.80) for the entire study population. For the subgroup of women diagnosed in 2015-2020, pelvic inflammatory disease was associated with high-grade serous carcinoma (adjusted odds ratio, 1.43; 95% confidence interval, 1.01-2.04). Odds ratios of the other histotypes were as follows: endometrioid (adjusted odds ratio, 0.13; 95% confidence interval, 0.02-1.06); mucinous (adjusted odds ratio, 1.55; 95% confidence interval, 0.56-4.29); and clear cell carcinoma (adjusted odds ratio, 2.30; 95% confidence interval, 0.90-5.86). A dose-response relationship was observed between the number of pelvic inflammatory disease episodes and risk of epithelial ovarian cancer (Ptrend<0.001). A history of pelvic inflammatory disease is associated with an increased risk of epithelial ovarian cancer and a dose-response relationship is evident. Histotype-specific analyzes show an association with increased risk of serous epithelial ovarian cancer and high-grade serous carcinoma, and potentially also with clear cell carcinoma, but no significant association with other histotypes. In conclusion, infection and inflammation of the upper reproductive tract might have serious long-term consequences, including epithelial ovarian cancer.

Risk of ovarian cancer after salpingectomy and tubal ligation: Prospects on histology and time since the procedure

ObjectiveRecent theories propose that most epithelial ovarian cancer (EOC), depending on histological type, originate from other gynecological tissues and involve the ovary secondarily. According to these theories, any protective effect of salpingectomy and tubal ligation may vary by histological type. The study aim was to examine the association between salpingectomy and tubal ligation, respectively, and risk of EOC, with a focus on associations specific for histological types. MethodsWe identified EOC cases and matching controls in national registries and gathered information on surgical procedures and potential confounders. Conditional logistic regression was used to estimate odds ratio (OR) with 95% confidence interval (CI) of EOC related to salpingectomy and tubal ligation, respectively, overall and stratified by histological type. Furthermore, we investigated the association according to timing of the procedures. ResultsOur study comprised 16,822 EOC cases. Each case was matched with 40 controls. There was an overall EOC risk reduction after unilateral (OR = 0.73; 95% CI: 0.60–0.87) and bilateral salpingectomy (OR = 0.46; 95% CI: 0.31–0.67). A slight risk reduction was seen among women with previous tubal ligation (OR = 0.91; 95% CI: 0.83–0.99). For salpingectomy, the risk reduction increased with increasing time since the surgical procedure and was only present among women younger than 50 years at salpingectomy. Unilateral and bilateral salpingectomy was associated with a risk reduction for most histological types. ConclusionThe association between previous salpingectomy and reduced risk of several histological subtypes of EOC supports the suggested theories about the site of origin of EOC and may be of clinical importance.

Salpingectomy and the Risk of Ovarian Cancer in Ontario

A body of pathological and clinical evidence supports the position that the fallopian tube is the site of origin for a large proportion of high-grade serous ovarian cancers. Consequently, salpingectomy is now considered for permanent contraception (in lieu of tubal ligation) or ovarian cancer prevention (performed opportunistically at the time of surgical procedures for benign gynecologic conditions). To evaluate the association between salpingectomy and the risk of invasive epithelial ovarian, fallopian tube, and peritoneal cancer. This population-based retrospective cohort study included all women aged 18 to 80 years who were eligible for health care services in Ontario, Canada. Participants were identified using administrative health databases from Ontario between January 1, 1992, and December 31, 2019. A total of 131 516 women were included in the primary (matched) analysis. Women were followed up until December 31, 2021. Salpingectomy (with and without hysterectomy) vs no pelvic procedure (control condition) among women in the general population. Women with a unilateral or bilateral salpingectomy in Ontario between April 1, 1992, and December 31, 2019, were matched 1:3 to women with no pelvic procedure from the general population. Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and 95% CIs for ovarian, fallopian tube, and peritoneal cancer combined. Among 131 516 women (mean [SD] age, 42.2 [7.6] years), 32 879 underwent a unilateral or bilateral salpingectomy, and 98 637 did not undergo a pelvic procedure. After a mean (range) follow-up of 7.4 (0-29.2) years in the salpingectomy group and 7.5 (0-29.2) years in the nonsurgical control group, there were 31 incident cancers (0.09%) and 117 incident cancers (0.12%), respectively (HR, 0.82; 95% CI, 0.55-1.21). The HR for cancer incidence was 0.87 (95% CI, 0.53-1.44) when comparing those with salpingectomy vs those with hysterectomy alone. In this cohort study, no association was found between salpingectomy and the risk of ovarian cancer; however, this observation was based on few incident cases and a relatively short follow-up time. Studies with additional years of follow-up are necessary to define the true level of potential risk reduction with salpingectomy, although longer follow-up will also be a challenge unless collaborative efforts that pool data are undertaken.

Paracetamol use and risk of epithelial ovarian cancer: A nationwide nested case-control study.

To investigate whether paracetamol use is associated with a reduced risk of epithelial ovarian cancer (EOC). A nationwide nested case-control study. Danish female population. A total of 9589 EOC cases diagnosed from 2000 to 2019 were age-matched with 383 549 randomly selected female controls using risk set sampling. Paracetamol use, reproductive history, history of medication and history of surgery were retrieved from Danish national registers. Paracetamol use was defined as at least two prescriptions for up to 1 year before the index date, and was further classified according to recency, duration, cumulative dose and intensity of dose. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals for the association between paracetamol and EOC risk, overall and by histological subtypes. 'Ever' use of paracetamol was associated with a reduced EOC risk after adjusting for potential confounding factors (OR 0.92, 95% CI 0.87-0.97). The association was only significant among recent users (OR 0.89, 95% CI 0.84-0.95). The risk declined further with the increasing level of cumulative dose and intensity; women from the group with a high cumulative dose and a high intensity had a 13% (OR 0.87, 95% CI 0.80-0.94) and 14% (OR 0.86, 95% CI 0.79-0.93) reduced risk, respectively. In the histological subtype analysis, reduced risk with 'ever' use was most pronounced for serous and clear cell tumours. Paracetamol use was associated with a decreased risk of EOC in a dose-response manner. Future studies are needed to validate the findings and investigate the mechanisms behind the association.

The Association of Kidney Function and Inflammatory Biomarkers with Epithelial Ovarian Cancer Risk.

One of the mechanisms of ovarian tumorigenesis is through inflammation. Kidney dysfunction is associated with increased inflammation; thus, we assessed its relationship with ovarian cancer risk. In prospectively collected samples, we evaluated the association of kidney function markers and C-reactive protein (CRP) with ovarian cancer risk in the UK Biobank. We used multivariable-adjusted Cox proportional hazards models to evaluate quartiles of serum and urine markers with ovarian cancer risk overall and by histology. We assessed effect modification by CRP (≤3.0, >3.0 mg/L). Among 232,908 women (1,110 ovarian cancer cases diagnosed from 2006-2020), we observed no association between estimated glomerular filtration rate and ovarian cancer risk (Q4 vs. Q1: HR, 1.00; 95% confidence intervals, 0.83-1.22). Potassium was associated with endometrioid (Q4 vs. Q1: 0.33, 0.11-0.98) and clear cell (4.74, 1.39-16.16) tumors. Poor kidney function was associated with a nonsignificant increase in ovarian cancer risk among women with CRP>3.0 mg/L (e.g., uric acid Q4 vs. Q1; 1.23, 0.81-1.86), but not CRP≤3.0 mg/L (0.83, 0.66-1.05). Other associations did not vary across CRP categories. Kidney function was not clearly associated with ovarian cancer risk. Larger studies are needed to evaluate possible histology specific associations. Given the suggestive trend for increased ovarian cancer risk in women with poor kidney function and high CRP, future work is needed, particularly in populations with a high prevalence of inflammatory conditions. This study provided the first evaluation of markers of kidney function in relation to ovarian cancer risk.

Immune checkpoints as potential theragnostic biomarkers for epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the leading cause of death associated with gynecologic tumors. EOC is asymptomatic in early stages, so most patients are not diagnosed until late stages, highlighting the need to develop new diagnostic biomarkers. Mediators of the tumoral microenvironment may influence EOC progression and resistance to treatment. To analyze immune checkpoints to evaluate them as theranostic biomarkers for EOC. Serum levels of 16 immune checkpoints were determined in EOC patients and healthy controls using the MILLIPLEX MAP® Human Immuno-Oncology Checkpoint Protein Magnetic Bead Panel. Seven receptors: BTLA, CD40, CD80/B7-1, GITRL, LAG-3, TIM-3, TLR-2 are differentially expressed between EOC and healthy controls. Serum levels of immune checkpoints in EOC patients are positively significantly correlated with levels of their ligands, with a higher significant correlation between CD80 and CTLA4 than between CD28 and CD80. Four receptors, CD40, HVEM, PD-1, and PD-L1, are positively associated with the development of resistance to Taxol-platinum-based chemotherapy. All of them have an acceptable area under the curve (>0.7). This study has yielded a first panel of seven immune checkpoints (BTLA, CD40, CD80/B7-1, GITRL, LAG-3, TIM-3, TLR-2) associated with a higher risk of EOC and a second panel of four immune checkpoints (CD40, HVEM, PD-1, PD-L1) that may help physicians to identify EOC patients who are at high risk of developing resistance to EOC chemotherapy.

Optimization of polygenic risk scores in BRCA1/2 pathogenic variant heterozygotes in epithelial ovarian cancer

PurposeA third of familial epithelial ovarian cancer (EOC) is explained by BRCA1/2 pathogenic variants. Polygenic risk scores (PRSs) for BRCA1/2 heterozygotes associated with EOC have been created, but impact of combination with clinical and hormonal risk factors is unclear. MethodsWe genotyped 300 cases and 355 controls and constructed modified PRSs based on those validated by Barnes et al. Model discrimination and EOC risk was assessed by area under the curve (AUC) values and difference between lowest and highest quintile odds ratios (ORs). We investigated model optimization using logistic regression to combine models with clinical and hormonal data. ResultsUnadjusted AUC values ranged from 0.526 to 0.551 with 2.2- to 2.3-fold increase in OR between lowest and highest quintiles (BRCA1 heterozygotes) and 0.574 to 0.585 AUC values with a 6.3- to 7.7-fold increase (BRCA2 heterozygotes). The optimized model (parity, age at menarche, menopause, and first full-term pregnancy) estimated AUC values of 0.872 to 0.876 and 21- to 23-fold increase in OR (BRCA1 heterozygotes) and AUC values of 0.857 to 0.867 and 40- to 41-fold increase (BRCA2 heterozygotes). ConclusionThe combination of PRS with age, family history, and hormonal factors significantly improved the EOC risk discrimination ability. However, the contribution of the PRS was small. Larger prospective studies are needed to assess if combined-PRS models could provide information to inform risk-reducing decisions.

Sexually Transmitted Infections and Risk of Epithelial Ovarian Cancer: Results From the Finnish Maternity Cohort.

Sexually transmitted infections, specifically Chlamydia trachomatis (CT), may be associated with epithelial ovarian cancer (EOC) risk. The association between CT and EOC subtypes is unclear. Our aim was to investigate whether history of CT and other infections (Mycoplasma genitalium [MG], herpes simplex virus type 2 [HSV-2], and human papillomavirus [HPV]) are associated with EOC risk by histotype. We measured antibodies (Abs) to CT, MG, HSV-2, and HPV-16/18 in serum samples in a nested case-control study in the Finnish Maternity Cohort (N = 484 cases 1:1 matched to controls). Logistic regression was used to calculate relative risks (RRs) and 95% confidence intervals (CIs) in seropositive versus seronegative individuals in all cases, as well as serous (n = 249), clear cell and endometrioid (n = 91), and mucinous (n = 144) EOC. CT seropositivity was not associated with EOC risk (eg, CT pGP3-Ab: RR, 0.92 [95% CI, .72-1.19]), regardless of disease subtype. We observed a positive association between MG seropositivity and mucinous EOC (RR, 1.66 [95% CI, 1.09-2.54]; P for heterogeneity by histotype ≤ .001), but not other subtypes. No associations were observed with seropositivity to multiple STIs. CT infection was not associated with EOC risk, with associations observed only for MG and mucinous EOC. Mechanisms linking MG to mucinous EOC remain to be elucidated.