Project description:Long and irregular menstrual cycles, a hallmark of polycystic ovary syndrome (PCOS), have been associated with higher androgen and lower sex hormone binding globulin levels and this altered hormonal environment may increase the risk of specific histologic subtypes of ovarian cancer. We investigated whether menstrual cycle characteristics and self-reported PCOS were associated with ovarian cancer risk among 2,041 women with epithelial ovarian cancer and 2,100 controls in the New England Case-Control Study (1992-2008). Menstrual cycle irregularity, menstrual cycle length, and PCOS were collected through in-person interview. Unconditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) for ovarian cancer risk overall, and polytomous logistic regression to evaluate whether risk differed between histologic subtypes. Overall, we observed no elevation in ovarian cancer risk for women who reported periods that were never regular or for those reporting a menstrual cycle length of >35 days with ORs of 0.87 (95% CI?=?0.69-1.10) and 0.83 (95% CI?=?0.44-1.54), respectively. We observed no overall association between self-reported PCOS and ovarian cancer (OR?=?0.97; 95% CI?=?0.61-1.56). However, we observed significant differences in the association with menstrual cycle irregularity and risk of ovarian cancer subtypes (pheterogeneity ?=?0.03) as well as by BMI and OC use (pinteraction ?<?0.01). Most notable, menstrual cycle irregularity was associated with a decreased risk of high grade serous tumors but an increased risk of serous borderline tumors among women who had never used OCs and those who were overweight. Future research in a large collaborative consortium may help clarify these associations.
Project description:BACKGROUND:Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer. METHODS:Utilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls). RESULTS:An inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P?=?0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR?=?0.77; 95% CI?=?0.65-0.92; P?=?0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations. CONCLUSION:Our study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.
Project description:Menstrual pain, a common gynecological condition, has been associated with increased risk of ovarian cancer in some, but not all studies. Furthermore, potential variations in the association between menstrual pain and ovarian cancer by histologic subtype have not been adequately evaluated due to lack of power. We assessed menstrual pain using either direct questions about having experienced menstrual pain, or indirect questions about menstrual pain as indication for use of hormones or medications. We used multivariate logistic regression to calculate the odds ratio (OR) for the association between severe menstrual pain and ovarian cancer, adjusting for potential confounders and multinomial logistic regression to calculate ORs for specific histologic subtypes. We observed no association between ovarian cancer and menstrual pain assessed by indirect questions. Among studies using direct question, severe pain was associated with a small but significant increase in overall risk of ovarian cancer (OR?=?1.07, 95% CI: 1.01-1.13), after adjusting for endometriosis and other potential confounders. The association appeared to be more relevant for clear cell (OR?=?1.48, 95% CI: 1.10-1.99) and serous borderline (OR?=?1.31, 95% CI: 1.05-1.63) subtypes. In this large international pooled analysis of case-control studies, we observed a small increase in risk of ovarian cancer for women reporting severe menstrual pain. While we observed an increased ovarian cancer risk with severe menstrual pain, the possibility of recall bias and undiagnosed endometriosis cannot be excluded. Future validation in prospective studies with detailed information on endometriosis is needed.
Project description:We prospectively investigated the association between different measures of smoking exposure and the risk of serous, mucinous, and endometrioid ovarian cancers (OC) in a cohort of more than 300?000 Norwegian women.We followed 300?398 women aged 19-67 years at enrolment until 31 December 2013 for OC incidence through linkage to national registries. We used Cox proportional hazards models with attained age as the underlying time scale to estimate multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for relevant confounders.During more than 5.9 million person-years and a median follow-up time of 19 years, 2336 primary invasive (1647, 71%) and borderline (689, 29%) OC were identified (53% serous, 19% mucinous). Compared with never smokers, current smokers who had smoked for ?10 years had a higher risk of mucinous OC (HR10-19 years vs never=1.73, 95% CI 1.24-2.42; HR?20 vs never=2.26, 95% CI 1.77-2.89, Ptrend <0.001). When stratified by invasiveness, current smokers had a higher risk of invasive mucinous OC (HR=1.78, 95% CI 1.20-2.64) and borderline mucinous OC (HR=2.26 95% CI, 1.71-2.97) (Pheterogeneity=0.34) than never smokers. Smoking was not associated with serous or endometrioid OC.Using a very large cohort of women, the current analysis provides an important replication for a similar risk of invasive and borderline mucinous OC related to smoking.
Project description:The aldehyde dehydrogenase 2 (ALDH2) polymorphism rs671 (Glu504Lys) causes ALDH2 inactivation and adverse acetaldehyde exposure among Asians, but little is known of the association between alcohol consumption and rs671 and ovarian cancer (OvCa) in Asians. We conducted a pooled analysis of Asian ancestry participants in the Ovarian Cancer Association Consortium. We included seven case-control studies and one cohort study comprising 460 invasive OvCa cases, 37 borderline mucinous OvCa and 1274 controls of Asian descent with information on recent alcohol consumption. Pooled odds ratios (OR) with 95% confidence intervals (CI) for OvCa risk associated with alcohol consumption, rs671 and their interaction were estimated using logistic regression models adjusted for potential confounders. No significant association was observed for daily alcohol intake with invasive OvCa (OR comparing any consumption to none = 0.83; 95% CI = 0.58-1.18) or with individual histotypes. A significant decreased risk was seen for carriers of one or both Lys alleles of rs671 for invasive mucinous OvCa (OR = 0.44; 95% CI = 0.20-0.97) and for invasive and borderline mucinous tumors combined (OR = 0.48; 95% CI = 0.26-0.89). No significant interaction was observed between alcohol consumption and rs671 genotypes. In conclusion, self-reported alcohol consumption at the quantities estimated was not associated with OvCa risk among Asians. Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse genetic association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype. This association will require replication in a larger sample.
Project description:Endometriosis is a risk factor for epithelial ovarian cancer; however, whether this risk extends to all invasive histological subtypes or borderline tumours is not clear. We undertook an international collaborative study to assess the association between endometriosis and histological subtypes of ovarian cancer.Data from 13 ovarian cancer case-control studies, which were part of the Ovarian Cancer Association Consortium, were pooled and logistic regression analyses were undertaken to assess the association between self-reported endometriosis and risk of ovarian cancer. Analyses of invasive cases were done with respect to histological subtypes, grade, and stage, and analyses of borderline tumours by histological subtype. Age, ethnic origin, study site, parity, and duration of oral contraceptive use were included in all analytical models.13?226 controls and 7911 women with invasive ovarian cancer were included in this analysis. 818 and 738, respectively, reported a history of endometriosis. 1907 women with borderline ovarian cancer were also included in the analysis, and 168 of these reported a history of endometriosis. Self-reported endometriosis was associated with a significantly increased risk of clear-cell (136 [20·2%] of 674 cases vs 818 [6·2%] of 13?226 controls, odds ratio 3·05, 95% CI 2·43-3·84, p<0·0001), low-grade serous (31 [9·2%] of 336 cases, 2·11, 1·39-3·20, p<0·0001), and endometrioid invasive ovarian cancers (169 [13·9%] of 1220 cases, 2·04, 1·67-2·48, p<0·0001). No association was noted between endometriosis and risk of mucinous (31 [6·0%] of 516 cases, 1·02, 0·69-1·50, p=0·93) or high-grade serous invasive ovarian cancer (261 [7·1%] of 3659 cases, 1·13, 0·97-1·32, p=0·13), or borderline tumours of either subtype (serous 103 [9·0%] of 1140 cases, 1·20, 0·95-1·52, p=0·12, and mucinous 65 [8·5%] of 767 cases, 1·12, 0·84-1·48, p=0·45).Clinicians should be aware of the increased risk of specific subtypes of ovarian cancer in women with endometriosis. Future efforts should focus on understanding the mechanisms that might lead to malignant transformation of endometriosis so as to help identify subsets of women at increased risk of ovarian cancer.Ovarian Cancer Research Fund, National Institutes of Health, California Cancer Research Program, California Department of Health Services, Lon V Smith Foundation, European Community's Seventh Framework Programme, German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research, German Cancer Research Centre, Eve Appeal, Oak Foundation, UK National Institute of Health Research, National Health and Medical Research Council of Australia, US Army Medical Research and Materiel Command, Cancer Council Tasmania, Cancer Foundation of Western Australia, Mermaid 1, Danish Cancer Society, and Roswell Park Alliance Foundation.
Project description:BACKGROUND:Sexually transmitted infections (STIs) are associated with pelvic inflammatory disease and tubal pathologies. Given the tubal origin of a proportion of ovarian cancers, STIs may be relevant in their aetiology. METHODS:Antibodies indicating past infection with Chlamydia trachomatis, Mycoplasma genitalium, herpes simplex virus type 2, and against human papillomavirus oncogenes (L1 and E6+E7 oncoproteins of types 16, 18, 45) were measured in prediagnosis plasma samples in a nested case-control study in the Nurses' Health Studies (n?=?337 cases 1:1 matched to controls). Logistic regression was used to estimate multivariable-adjusted relative risks (RRs) and 95% confidence intervals [CIs] comparing women seropositive vs. seronegative among all cases (invasive and borderline), invasive (n?=?257), and invasive serous ovarian cancers; n?=?170), and borderline ovarian tumours (n?=?80). RESULTS:C. trachomatis seropositivity was associated with higher risk of ovarian cancer overall (RR?=?2.07 [1.25-3.43]); results were similar for invasive, invasive serous, and borderline tumours. We observed no associations for the other STIs. Relative to women seronegative to all infections, strongest associations were observed for seropositivity to C. trachomatis plus another STI (2.74 [1.20-6.27]; C. trachomatis alone, 1.88 [1.03-3.42]; all cases); however, the RRs were not significantly different. CONCLUSIONS:C. trachomatis infection may increase ovarian cancer risk; additional studies are required.
Project description:Among European women, ovarian cancer is the fifth most common cancer. Smoking is an established risk factor for mucinous tumors. We estimated the impact of smoking in Norwegian women using population attributable fractions (PAFs) of epithelial ovarian cancer (EOC), by invasiveness and by histological subtypes in the Norwegian Women and Cancer Study with an average of 13.2 years of follow-up. During >2 million person-years, a total of 915 incident EOC cases, of which 667 (73%) invasive and 248 (27%) borderline, were identified among 154,234 women aged 34-70 years at enrolment. Compared with never smokers, current smokers had a nonstatistically significant increased risk of mucinous tumors (hazard ratio [HR] = 1.67 [95% confidence interval, (CI), 0.96-2.96]) and more than twice statistically significant risk of borderline mucinous tumors (HR = 2.17 [95% CI, 1.06-4.45]). The corresponding PAF estimates were 16.5% for mucinous and 25% for borderline mucinous. We found that among middle-aged women, one in six mucinous tumors and one in four borderline mucinous tumors could have been prevented if women did not smoke.
Project description:We conducted a population-based study to determine the contribution of germline mutations in known candidate genes to ovarian cancer diagnosed at age <30 years. Women with epithelial ovarian cancer were identified through cancer registries. DNA samples were analyzed for mutations in BRCA1, the "ovarian cancer-cluster region" (nucleotides 3139-7069) of BRCA2, and the mismatch-repair genes hMSH2 and hMLH1. Probable germline mutations in hMLH1 were identified in 2 (2%; 95% confidence interval 1%-8%) of 101 women with invasive ovarian cancer diagnosed at age <30 years. No germline mutations were identified in any of the other genes analyzed. There were no striking pedigrees suggestive of families with either breast/ovarian cancer or hereditary nonpolyposis colorectal cancer (HNPCC). There was a significantly increased incidence of all cancers in first-degree relatives of women with invasive disease (relative risk [RR] = 1.6, P=.01) but not in second-degree relatives or in relatives of women with borderline cases. First-degree relatives of women with invasive disease had increased risks of ovarian cancer (RR = 4.8, P=.03), myeloma (RR = 10, P=.01), and non-Hodgkin lymphoma (RR = 7, P=.004). Germline mutations in BRCA1, BRCA2, msh2, and mlh1 contribute to only a minority of cases of early-onset epithelial ovarian cancer. Our data suggest that early-onset ovarian cancer is not associated with a greatly increased risk of cancer in close relatives.
Project description:Ovarian cancer is characterized by multiple structural aberrations; most are passenger alterations which do not confer tumor growth. Like many cancers, it is a heterogeneous disease and till date, the histotype-specific copy number landscape has been difficult to elucidate. To dissect the heterogeneity of ovarian cancer and understand the pathogenesis of its various histotypes, we developed an in silico hypothesis-driven workflow to identify histotype-specific copy number aberrations across multiple datasets of epithelial ovarian cancer. In concordance with previous studies on global copy number changes, our study showed similar alterations. However, when the landscape was de-convoluted into histotypes, distinct alterations were observed. We report here a comprehensive histotype-specific copy number landscape of ovarian cancer and showed that there is genomic diversity between the histotypes; some involving well known cancer genes and some novel potential driver genes. Besides preferential occurrence of alterations in some histotypes, opposite trends of alteration were observed; such as ERBB2 amplification in mucinous but deletion in serous tumors. The landscape highlights the need for identifying histotype-specific aberrations in ovarian cancer and present potential to tailor management of ovarian cancer based on molecular signature of histotypes. 56 samples containing the 4 histotypes were used for this study. It contained 12 clear cell carcinoma, 6 endometrioid adenocarcinoma, 2 mucinous adenocarcinoma, 5 mucinous-borderline tumors, 26 serous adenocarcinoma, and 5 serous-borderline tumors.