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 (p value <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.

CD163+ macrophages in the triple-negative breast tumor microenvironment are associated with improved survival in the Women's Circle of Health Study and the Women's Circle of Health Follow-Up Study.

BACKGROUND: Tumor-associated macrophages (TAMs) are a prominent immune subpopulation in the tumor microenvironment that could potentially serve as therapeutic targets for breast cancer. Thus, it is important to characterize this cell population across different tumor subtypes including patterns of association with demographic and prognostic factors, and breast cancer outcomes. METHODS: We investigated CD163+ macrophages in relation to clinicopathologic variables and breast cancer outcomes in the Women's Circle of Health Study and Women's Circle of Health Follow-up Study populations of predominantly Black women with breast cancer. We evaluated 611 invasive breast tumor samples (507 from Black women, 104 from White women) with immunohistochemical staining of tissue microarray slides followed by digital image analysis. Multivariable Cox proportional hazards models were used to estimate hazard ratios for overall survival (OS) and breast cancer-specific survival (BCSS) for 546 cases with available survival data (median follow-up time 9.68 years (IQR: 7.43-12.33). RESULTS: Women with triple-negative breast cancer showed significantly improved OS in relation to increased levels of tumor-infiltrating CD163+ macrophages in age-adjusted (Q3 vs. Q1: HR = 0.36; 95% CI 0.16-0.83) and fully adjusted models (Q3 vs. Q1: HR = 0.30; 95% CI 0.12-0.73). A similar, but non-statistically significant, association was observed for BCSS. Macrophage infiltration in luminal and HER2+ tumors was not associated with OS or BCSS. In a multivariate regression model that adjusted for age, subtype, grade, and tumor size, there was no significant difference in CD163+ macrophage density between Black and White women (RR = 0.88; 95% CI 0.71-1.10). CONCLUSIONS: In contrast to previous studies, we observed that higher densities of CD163+ macrophages are independently associated with improved OS and BCSS in women with invasive triple-negative breast cancer. Trial registration Not applicable.

Paternal lineage early onset hereditary ovarian cancers: A Familial Ovarian Cancer Registry study.

Given prior evidence that an affected woman conveys a higher risk of ovarian cancer to her sister than to her mother, we hypothesized that there exists an X-linked variant evidenced by transmission to a woman from her paternal grandmother via her father. We ascertained 3,499 grandmother/granddaughter pairs from the Familial Ovarian Cancer Registry at the Roswell Park Cancer Institute observing 892 informative pairs with 157 affected granddaughters. We performed germline X-chromosome exome sequencing on 186 women with ovarian cancer from the registry. The rate of cancers was 28.4% in paternal grandmother/granddaughter pairs and 13.9% in maternal pairs consistent with an X-linked dominant model (Chi-square test X2 = 0.02, p = 0.89) and inconsistent with an autosomal dominant model (X2 = 20.4, p<0.001). Paternal grandmother cases had an earlier age-of-onset versus maternal cases (hazard ratio HR = 1.59, 95%CI: 1.12-2.25) independent of BRCA1/2 status. Reinforcing the X-linked hypothesis, we observed an association between prostate cancer in men and ovarian cancer in his mother and daughters (odds ratio, OR = 2.34, p = 0.034). Unaffected mothers with affected daughters produced significantly more daughters than sons (ratio = 1.96, p<0.005). We performed exome sequencing in reported BRCA negative cases from the registry. Considering age-of-onset, one missense variant (rs176026 in MAGEC3) reached chromosome-wide significance (Hazard ratio HR = 2.85, 95%CI: 1.75-4.65) advancing the age of onset by 6.7 years. In addition to the well-known contribution of BRCA, we demonstrate that a genetic locus on the X-chromosome contributes to ovarian cancer risk. An X-linked pattern of inheritance has implications for genetic risk stratification. Women with an affected paternal grandmother and sisters of affected women are at increased risk for ovarian cancer. Further work is required to validate this variant and to characterize carrier families.

Habitual recreational physical activity is associated with significantly improved survival in cancer patients: evidence from the Roswell Park Data Bank and BioRepository.

PURPOSE: The association of recreational physical activity (RPA) with mortality is well established only for breast and colon cancers and few studies have evaluated relationships for exercising before and after diagnosis, across multiple disease sites. We examined the joint associations of pre- and post- diagnosis RPA with mortality in a cohort of 5,807 patients enrolled in the Data Bank and BioRepository at Roswell Park. METHODS: Patients were classified into one of four activity categories (habitually active, increased activity after diagnosis, decreased activity after diagnosis, habitually inactive). Cox proportional hazards models were used to estimate the associations of activity status with mortality. RESULTS: In comparison to patients who were habitually inactive, habitually active patients experienced a 39% decreased hazard of all-cause mortality (HR = 0.61, 95% CI 0.54-0.69) and a 36% decreased hazard of cancer-specific mortality (HR = 0.64, 95% CI 0.56-0.73). Previously inactive patients who began exercising after diagnosis experienced a 28% decreased hazard of all-cause (HR = 0.72, 95% CI 0.59-0.89) and cancer-specific mortality (HR = 0.72, 95% CI 0.57-0.91) in comparison to patients who remained inactive. Patients engaging in 3-4 sessions/week experienced the greatest survival advantages, but 1-2 sessions/week also yielded significant survival advantages in comparison to inactivity. CONCLUSION: Low-to-moderate frequency pre- and post-diagnosis RPA was associated with significantly decreased mortality in patients diagnosed with a variety of malignancies. These observations solidify the clinical and public health importance of the message that some regular activity is better than inactivity, which is particularly encouraging, given that cancer survivors can be overwhelmed by current daily physical activity recommendations.

Joint exposure to smoking, excessive weight, and physical inactivity and survival of ovarian cancer patients, evidence from the Ovarian Cancer Association Consortium.

PURPOSE: Previous epidemiologic studies have shown that smoking, obesity, and physical inactivity are associated with poor survival following a diagnosis of ovarian cancer. Yet, the combined relationship of these unfavorable lifestyle factors on ovarian cancer survival has not been sufficiently investigated. METHODS: Using data pooled from 13 studies, we examined the associations between combined exposures to smoking, overweight/obesity weight, and physical inactivity and overall survival (OS) as well as progression-free survival (PFS) among women diagnosed with invasive epithelial ovarian carcinoma (n = 7,022). Using age- and stage-adjusted Cox proportional hazards regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with joint exposure to these factors. RESULTS: Combined exposure to current smoking, overweight/obesity, and physical inactivity prior to diagnosis was associated with a significantly increased risk of mortality compared to women who never smoked, had normal body mass index (BMI), and were physically active (HR = 1.37; 95% CI 1.10-1.70). The association for a joint exposure to these factors exceeded that of each exposure individually. In fact, exposure to both current smoking and overweight/obesity, and current smoking and physical inactivity was also associated with increased risk of death (HR = 1.28; 95% CI 1.08-1.52, and HR = 1.26; 95% CI 1.04-1.54, respectively). The associations were of a similar magnitude when former smoking was assessed in combination with the other exposures and when excessive weight was limited to obesity only. No significant associations were observed between joint exposure to any of these factors and PFS. CONCLUSIONS: Joint exposure to smoking, excessive weight, and physical inactivity may negatively impact survival of ovarian cancer patients. These results suggest the importance of examining the combined effect of lifestyle factors on ovarian cancer patients' survival.

Associations between self-reported diet during treatment and chemotherapy-induced peripheral neuropathy in a cooperative group trial (S0221).

BACKGROUND: The pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) is not well understood. Currently, dose reduction is the only recommendation for alleviating symptoms, often leading to premature treatment cessation. The primary aim of this analysis was to determine the association between components of diet during taxane treatment for breast cancer and change in CIPN symptoms over treatment. METHODS: Women with stage II or III invasive breast cancer were enrolled into an ancillary study to the North American Breast Cancer Intergroup phase III trial (S0221) led by the Southwest Oncology Group (SWOG). Questionnaires including a food frequency questionnaire and the Functional Assessment of Cancer Treatment Gynecologic Oncology Group-Neurotoxicity were administered to assess diet and neuropathic conditions at baseline and during chemotherapy. Ordinal regression was used to estimate odds ratios (ORs) for associations between various food groups and change in neuropathy score (< 10%, 10-30%, > 30%) (n = 900). RESULTS: The odds of worse neuropathy decreased by 21% for each increase in tertile of grain consumption (OR = 0.79, 95% CI 0.66-0.94, p = 0.009). We also observed a nominal 19% increase with higher consumption of citrus fruits (OR = 1.19, 95% CI 1.01-1.40, p = 0.05). CONCLUSIONS: Distinguishing between those who experienced a moderate and a severe change in neuropathy, we found that citrus fruit and grain consumption may play a role in the severity of symptoms. Since there are no existing dietary recommendations for the management of CIPN, further research is needed to investigate whether there may be certain foods that could worsen or alleviate neuropathy symptoms associated with treatment for breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03413761 . Registered retrospectively on 29 January 2018.

Anthropometric characteristics and ovarian cancer risk and survival.

PURPOSE: Multiple studies have examined the role of anthropometric characteristics in ovarian cancer risk and survival; however, their results have been conflicting. We investigated the associations between weight change, height and height change and risk and outcome of ovarian cancer using data from a large population-based case-control study. METHODS: Data from 699 ovarian cancer cases and 1,802 controls who participated in the HOPE study were included. We used unconditional logistic regression adjusted for age, race, number of pregnancies, use of oral contraceptives, and family history of breast or ovarian cancer to examine the associations between self-reported height and weight and height change with ovarian cancer risk. Cox proportional hazards regression models adjusted for age and stage were used to examine the association between the exposure variables and overall and progression-free survival among ovarian cancer cases. RESULTS: We observed an increased risk of ovarian cancer mortality and progression for gaining more than 20 pounds between ages 18-30, HR 1.36; 95% CI 1.05-1.76, and HR 1.31; 95% CI 1.04-1.66, respectively. Losing weight and gaining it back multiple times was inversely associated with both ovarian cancer risk, OR 0.78; 95% CI 0.63-0.97 for 1-4 times and OR 0.73; 95% CI 0.54-0.99 for 5-9 times, and mortality, HR 0.63; 95% CI 0.40-0.99 for 10-14 times. Finally, being taller during adolescence and adulthood was associated with increased risk of mortality. Taller stature and weight gain over lifetime were not related to ovarian cancer risk. CONCLUSIONS: Our results suggest that height and weight and their change over time may influence ovarian cancer risk and survival. These findings suggest that biological mechanisms underlying these associations may be hormone driven and may play an important role in relation to ovarian carcinogenesis and tumor progression.

rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

Shared genetics underlying epidemiological association between endometriosis and ovarian cancer.

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.

History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report.

BACKGROUND: Findings from in vitro studies suggest that increased exposure to thyroid hormones can influence progression of ovarian tumours. However, epidemiologic evidence on this topic is limited. METHODS: We pooled data from 11 studies from the Ovarian Cancer Association Consortium. Using multivariate Cox proportional hazards models, we estimated associations between hyper- and hypothyroidism and medications prescribed for these conditions with 5-year all-cause survival among women diagnosed with invasive ovarian cancer. RESULTS: Overall, there was a nonsignificant association with history of hyperthyroidism (n=160 cases) and mortality (HR=1.22; 95% CI=0.97-1.53). Furthermore, diagnosis of hyperthyroidism within the 5 years before ovarian cancer diagnosis was associated with an increased risk of death (HR=1.94; 95% CI=1.19-3.18). A more modest association was observed with history of hypothyroidism (n=624 cases) and mortality (HR=1.16; 95% CI=1.03-1.31). Neither duration of hypothyroidism nor use of thyroid medications was associated with survival. CONCLUSIONS: In this large study of women with ovarian cancer, we found that recent history of hyperthyroidism and overall history of hypothyroidism were associated with worse 5-year survival.

Ovarian cancer epidemiology in the era of collaborative team science.

PURPOSE: Over the past decade, a number of consortia have formed to further investigate genetic associations, pathogenesis, and epidemiologic risk and prognostic factors for ovarian cancer. Here, we review the benefits that ovarian cancer consortia provide as well as challenges that have arisen. Methods for managing key challenges are also discussed. METHODS: We review the structural organization and some of the milestone epidemiologic publications of five consortia dedicated to the study of ovarian cancer, including the Ovarian Cancer Association Consortium (OCAC), the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Ovarian Cancer Cohort Consortium (OC3), the Collaborative Group on Epidemiological Studies of Ovarian Cancer (The Oxford Collaborative Group), and the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium. RESULTS: As ovarian cancer is a rare and heterogeneous disease, consortia have made important contributions in the study of risk factors by improving statistical power beyond what any single study, or even a few studies, would provide. Thus, a major accomplishment of consortial research is enhanced characterization of histotype-specific risk factor associations. In addition, consortia have facilitated impressive synergy between researchers across many institutions, spawning new collaborative research. Importantly, through these efforts, many challenges have been met, including difficulties with data harmonization and analysis, laying a road map for future collaborations. CONCLUSIONS: While ovarian cancer consortia have made valuable contributions to the ovarian cancer epidemiological literature over the past decade, additional efforts comprising of new, well-designed case-control studies are needed to further elucidate novel, histotype-specific risk, and prognostic factors which are not consistently available in existing studies.

History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium.

PURPOSE: Survival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype. METHODS: Using pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes. RESULTS: History of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94. CONCLUSIONS: Histories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.

The Association of Peripheral Blood Regulatory T-Cell Concentrations With Epithelial Ovarian Cancer: A Brief Report.

OBJECTIVE: There is a mounting body of evidence demonstrating higher percentages of regulatory T (Treg) cells in the peripheral blood of patients with cancer in comparison to healthy controls, but there is a paucity of epidemiological literature characterizing circulating Treg cells among patients with epithelial ovarian cancer (EOC). To investigate the role of peripheral Treg cells in ovarian neoplasms, we conducted a case-control study to characterize circulating concentrations of Treg cells among patients with EOC, women with benign ovarian conditions, and healthy controls without a history of cancer. MATERIALS AND METHODS: Participants were identified for inclusion due to their participation in the Data Bank and BioRepository program at Roswell Park Cancer Institute in Buffalo, NY. Patients included 71 women with a primary diagnosis of EOC and 195 women with a diagnosis of benign ovarian conditions. Controls included 101 age- and race-matched women without a history of cancer. Nonfasting, pretreatment peripheral blood levels of CD3+CD4+CD25+FOXP3+ Treg cells were measured using flow cytometric analyses and expressed as a percentage of total CD3+ cells and as a percentage of total CD3+CD4+ cells. RESULTS: Compared to healthy controls and women with benign ovarian conditions, patients with EOC had significantly higher frequency of Treg cells (P < 0.04). In multivariable logistic regression analyses using Treg frequency expressed as a percentage of CD+3 cells, we observed a significant positive association between Treg cell percentage and EOC risk, with each 1% increase associated with a 37% increased risk of EOC (odds ratio, 1.37; 95% confidence interval, 1.04-1.80). We observed a similar trend when Treg frequency was expressed as a percentage of CD3+CD+4 cells (odds ratio, 1.22; 95% confidence interval, 0.99-1.49). CONCLUSIONS: The current study provides support that peripheral Treg cell frequency is elevated in patients with EOC in comparison to women with benign ovarian conditions and healthy controls.

The association of lifetime physical inactivity with head and neck cancer: a hospital-based case-control analysis.

Despite mounting epidemiological evidence suggesting an inverse association between recreational physical activity and cancer risk, evidence associated with head and neck cancer is scant. We conducted a case-control analysis to examine the associations of lifetime physical inactivity with the risk of head and neck squamous cell carcinoma (HNSCC). We utilized data from the Patient Epidemiology Data System at Roswell Park Cancer Institute (RPCI). Participants included 246 patients with HNSCC and 504 cancer-free controls who received medical services at RPCI between 1990 and 1998. Participants were considered physically inactive if they did not participate in any regular, weekly recreational physical activity throughout their lifetime, prior to diagnosis. Multivariate logistic regression models were utilized to estimate odds ratios (OR) and 95% confidence intervals (CI) representing the association between lifetime physical inactivity and HNSCC risk. We observed a significant positive association between recreational physical inactivity and HNSCC risk (OR = 2.73, 95% CI 1.87-3.99, p < 0.001). In subgroup analyses by body mass index (BMI) (underweight/normal-weight: OR = 3.40, 95% CI 1.89-6.12, p < 0.001; overweight/obese: OR = 2.40, 95% CI 1.43-4.02, p < 0.001) and smoking status (former smoker: OR = 3.12, 95% CI 1.89-5.14, p < 0.001; never smoker: OR = 2.71, 95% CI 1.21-6.05, p = 0.020; current smoker: OR = 1.61, 95% CI 0.66-3.95, p = 0.300), significant positive associations were also observed. Results of the current analyses suggest that lifetime physical inactivity associates with HNSCC independent of BMI. In addition, physical inactivity may be a modifiable risk factor among never smokers. These data add to the growing body of evidence suggesting that physical inactivity may be an independent risk factor for cancer.

Recreational physical inactivity and mortality in women with invasive epithelial ovarian cancer: evidence from the Ovarian Cancer Association Consortium.

BACKGROUND: Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality. METHODS: Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years. RESULTS: In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18-1.52) and without (HR=1.22, 95% CI: 1.12-1.33) further adjustment for residual disease, respectively. CONCLUSION: In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC.

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Impact of Physical Inactivity on Risk of Developing Cancer of the Uterine Cervix: A Case-Control Study.

OBJECTIVE: In this study, we investigated whether physical inactivity was associated with risk of cervical cancer in women treated at an American cancer hospital. METHODS: This case-control study included 128 patients with cervical cancer and 512 controls matched on age. Controls were women suspected of having but not ultimately diagnosed with a neoplasm. Physical inactivity was defined in accordance with the 2008 Physical Activity Guidelines for Americans. Thus, participants reporting, on average, no moderate or vigorous recreational physical activity were classified as inactive. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Compared with noncancer controls, those with cervical cancer had significantly increased odds of reporting abstinence from recreational physical activity (OR, 2.43; 95% CI, 1.56-3.80). No association was noted between occupational-related physical inactivity and cervical cancer (OR, 0.88; 95% CI, 0.58-1.36). CONCLUSIONS: Our findings suggest that abstinence from regular recreational physical activity is associated with increased odds of cervical cancer. To our knowledge, this is the first US-based study examining these associations. Given the 2008 Physical Activity Guidelines for Americans, this study has identified yet another potential public health benefit to regular physical activity. Further investigation is needed using a larger sample and prospectively collected data to characterize dose of activity to mitigate risk and the optimal window of susceptibility.

Epithelial ovarian cancer and recreational physical activity: A review of the epidemiological literature and implications for exercise prescription.

UNLABELLED: Despite the publication of two dozen observational epidemiological studies investigating the association between recreational physical activity (RPA) and epithelial ovarian cancer (EOC) risk and survival over the past two decades, taken collectively, data from retrospective and prospective studies are mixed and remain inconclusive. OBJECTIVE: Our primary purpose was to conduct a careful review and summary of the epidemiological literature depicting the association between EOC and RPA in the framework of identifying factors which may be impeding our ability to observe consistent associations in the literature. Secondly, in the backdrop of the more broad scientific evidence regarding the benefits of RPA, we provide a summary of guidelines for practitioners to utilize in the context of exercise prescription for cancer patients, including a discussion of special considerations and contraindications to exercise which are unique to EOC patients and survivors. METHODS: We performed a comprehensive literature search via PubMed to identify epidemiologic investigations focused on the association between RPA and EOC. To be included in the review, studies had to assess RPA independently of occupational or household activities. RESULTS: In total, 26 studies were identified for inclusion. Evidence of a protective effect of RPA relative to EOC risk is more consistent among-case control studies, with the majority of studies demonstrating significant risk reductions between 30 and 60% among the most active women. Among cohort studies, half yielded no significant associations, while the remaining studies provided mixed evidence of an association. CONCLUSIONS: Given the limitations identified in the current body of literature, practitioners should not rely on inconclusive evidence to dissuade women from participating in moderate or vigorous RPA. Rather, emphasis should be placed on the greater body of scientific evidence which has demonstrated that RPA results in a plethora of health benefits that can be achieved in all populations, including those with cancer.

Oral Contraceptive Use and Reproductive Characteristics Affect Survival in Patients With Epithelial Ovarian Cancer: A Cohort Study.

OBJECTIVES: Prognostic risk factors influencing survival in patients with epithelial ovarian cancer (EOC) include tumor stage, grade, histologic subtype, debulking, and platinum status. Little is known about the impact of hormonal milieu and reproductive factors before cancer diagnosis on clinical outcome. We sought to evaluate whether oral contraceptive (OC) use carries any prognostic significance on overall survival (OS) in patients with EOC. METHODS: Newly diagnosed patients with EOC, fallopian tube, and primary peritoneal cancers between 1982 and 1998 were prospectively evaluated with a comprehensive epidemiologic questionnaire. A retrospective chart review was performed to abstract clinicopathologic data, including OS. A Kaplan-Meier analysis was performed to compare survival across various exposures. A Cox regression model was used to compute adjusted hazards ratios (aHRs) and 95% confidence intervals (CIs). RESULTS: We identified 387 newly diagnosed cancers with evaluable information in this cohort. Decreased risk of death was observed in women who reported prior use of OC (aHR, 0.79; 95% CI, 0.58-1.09), previous pregnancy (aHR, 0.77; 95% CI, 0.57-1.04), or a live birth (aHR, 0.81; 95% CI, 0.60-1.08) after adjusting for age at diagnosis, stage, and histologic subtype. Oral contraceptive use was associated with a crude reduced risk of death (HR, 0.55; 95% CI, 0.42-0.72), with reported median OS of 81 months in OC users versus 46 months in nonusers. Patients who reported a single live birth experienced the largest potential survival advantage (aHR, 0.61; 95% CI, 0.39-0.94). Oral contraceptive use and prior pregnancy were associated with improved survival across all strata. CONCLUSIONS: Oral contraceptive use may have lasting effects on epithelial ovarian tumor characteristics conferring favorable prognosis. Putative mechanisms that affect tumor biology include complex interactions between ovarian cells, host immune cells, and hormonal microenvironment during carcinogenesis. Future efforts should be directed to determine the role of reproductive factors in antitumor immunity.

Aspirin and Acetaminophen Use and the Risk of Cervical Cancer.

OBJECTIVE: In this study, we investigated whether regular use of aspirin or acetaminophen was associated with risk of cervical cancer in women treated at an American cancer hospital. METHODS: This case-control study included 328 patients with cervical cancer and 1,312 controls matched on age and decade enrolled. Controls were women suspected of having but not ultimately diagnosed with a neoplasm. Analgesic use was defined as regular (at least once per week for ≥6 months), frequent (≥7 tablets/week), very long term (≥11 years), or frequent, long term (≥7 tablets per week for ≥5 years). RESULTS: Compared to nonusers, frequent aspirin use was associated with decreased odds of cervical cancer (odds ratio, 0.53; 95% confidence interval, 0.29-0.97). A slightly larger association was observed with frequent, long-term use of aspirin (odds ratio, 0.46; 95% confidence interval, 0.22-0.95). Acetaminophen use was not associated with the risk of cervical cancer. CONCLUSIONS: Our findings suggest that frequent and frequent, long-term use of aspirin is associated with decreased odds of cervical cancer. To our knowledge, this is the first US-based study examining these associations. Given the widespread use of nonsteroidal anti-inflammatory drugs and acetaminophen worldwide, further investigations of the possible role of analgesics in cervical cancer, using a larger sample size with better-defined dosing regimens, are warranted.