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Previous studies have observed that tubal ligation and hysterectomy are associated with a decreased risk of ovarian cancer; however, little is known about whether these associations vary by surgical characteristics, individual characteristics or tumor histology. We used logistic regression to examine tubal ligation, simple hysterectomy and hysterectomy with unilateral oophorectomy in relation to risk of epithelial ovarian cancer in the New England Case-Control Study. Our primary analysis included 2,265 cases and 2,333 controls. Overall, tubal ligation was associated with a lower risk of epithelial ovarian cancer [odds ratio (OR) = 0.82, 95% confidence interval (CI): 0.68-0.97], especially for endometrioid tumors (OR = 0.45, 95% CI: 0.29-0.69). The inverse association between tubal ligation and ovarian cancer risk was stronger for women who had undergone the procedure at the time of last delivery (OR = 0.60, 95% CI: 0.42-0.84) rather than at a later time (OR = 0.93, 95% CI: 0.75-1.15). Overall, simple hysterectomy was not associated with ovarian cancer risk (OR: 1.09, 95% CI: 0.83-1.42), although it was associated with a nonsignificant decreased risk of ovarian cancer among women who underwent the procedure at age 45 or older (RR: 0.64, 95% CI: 0.40-1.02) or within the last 10 years (OR = 0.65, 95% CI: 0.38-1.13). Overall, women who had a hysterectomy with a unilateral oophorectomy had significantly lower risk of ovarian cancer (OR = 0.65, 95% CI: 0.45-0.94). In summary, tubal ligation and hysterectomy with unilateral oophorectomy were inversely associated with ovarian cancer risk in a large population-based case-control study. Additional research is necessary to understand the potential biologic mechanisms by which these procedures may reduce ovarian cancer risk.

Lignans are plant-based phytoestrogens with both estrogenic and anti-estrogenic properties that may be important for breast carcinogenesis. Retrospective studies have observed decreased breast cancer risk associated with high circulating enterolactone concentrations, a biomarker of lignan intake, but results from prospective studies are conflicting. To prospectively examine this association, we measured plasma enterolactone levels in 802 breast cancer cases and 802 matched controls nested among predominantly premenopausal women in the Nurses’ Health Study II cohort. We used conditional logistic regression and polytomous logistic regression models, adjusting for known breast cancer risk factors, to calculate relative risks (RR) and 95 % confidence intervals (CI). Compared to women with enterolactone concentrations ≤4 nmol/L, the multivariate-adjusted RRs for breast cancer were 1.18 (95 % CI 0.86–1.62), 0.91 (95 % CI 0.66–1.25), and 0.96 (95 % CI 0.70–1.33) for women with enterolactone levels in the second to the fourth quartiles, respectively; P trend = 0.60. Results were similar across tumors defined by estrogen and progesterone receptor status. Among premenopausal women with follicular estradiol levels below the median (

Differentiating ovarian tumors based on developmental pathway may further enhance our understanding of the disease. Traditionally, ovarian cancers were thought to arise from the ovarian surface epithelium; however, recent evidence suggests that some tumors originate in the fallopian tube. We classified cases in a population-based case-control study (New England Case-Control [NECC] Study) and two cohort studies (Nurses' Health Study [NHS]/Nurses' Health Study II [NHSII]) by tumor dominance, a proxy for tissue of origin. Dominant tumors (likely ovarian origin) are restricted to one ovary or are at least twice as large on one ovary compared to the other. Ovarian cancer risk factors were evaluated in relation to dominant and nondominant tumors (likely tubal origin) using polytomous logistic regression (NECC) or competing risks Cox models (NHS/NHSII). Results were combined using random-effects meta-analyses. Among 1,771 invasive epithelial ovarian cancer cases, we observed 1,089 tumors with a dominant mass and 682 with no dominant mass. Dominant tumors were more likely to be mucinous, endometrioid or clear cell, whereas nondominant tumors were more likely to be serous. Tubal ligation, two or more births, endometriosis and age were more strongly associated with dominant tumors (rate ratio [RR] = 0.60, 0.83, 1.58 and 1.37, respectively) than nondominant tumors (RR = 1.03, 0.93, 0.84 and 1.14, respectively; p-difference = 0.0001, 0.01, 0.0003 and 0.01, respectively). These data suggest that risk factors for tumors putatively arising from ovarian versus fallopian tube sites may differ; in particular, reproductive factors may be more important for ovarian-derived tumors. As this is the first study to evaluate ovarian cancer risk factors by tumor dominance, these results need to be validated by other studies.

Contains fulltext : 118139.pdf (Publisher’s version ) (Closed access) PURPOSE: The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology. METHODS: We used data from 21 case-control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model. RESULTS: Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03-1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39-2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12-1.50). For these histological types, consistent dose-response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer. CONCLUSIONS: Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease.

Do reproductive risk factor associations differ across subgroups of invasive epithelial ovarian cancer (EOC) defined by the dualistic model (type I/II) or a histologic pathway-based classification?Associations with parity, history of endometriosis, tubal ligation and hysterectomy were found to differ in the context of the type I/II and the histologic pathways classification of ovarian cancer.Shared molecular alterations and candidate precursor lesions suggest that tumor histology and grade may be used to classify ovarian tumors into likely etiologic pathways.This case-control study included 1571 women diagnosed with invasive EOC and 2100 population-based controls that were enrolled from 1992 to 2008. Reproductive risk factors as well as other putative risk factors for ovarian cancer were assessed through in-person interviews.Eligible cases were diagnosed with incident ovarian cancer, were aged 18 and above and resided in eastern Massachusetts or New Hampshire, USA. Controls were identified through random digit dialing, drivers' license and town resident lists and were frequency matched with the cases based on age and study center.We used polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for type I/II EOC or using a pathway-based grouping of histologic subtypes. In multivariate analyses, we observed that having a history of endometriosis (OR = 1.92, 95% CI: 1.36-2.71) increased the risk for a type I tumor. Factors that were strongly inversely associated with risk for a type I tumor included parity (≥ 3 versus 0 children, OR = 0.15, 95% CI: 0.11-0.21), having a previous tubal ligation (OR = 0.40, 95% CI: 0.26-0.60) and more weakly hysterectomy (OR = 0.71, 95% CI: 0.45-1.13). In analyses of histologic pathways, parity (≥ 3 versus 0 children, OR = 0.13, 95% CI: 0.10-0.18) and having a previous tubal ligation (OR = 0.41, 95% CI: 0.28-0.60) or hysterectomy (OR = 0.54, 95% CI: 0.34-0.86) were inversely associated with risk of endometrioid/clear cell tumors. Having a history of endometriosis strongly increased the risk for endometrioid/clear cell tumors (OR = 2.41, 95% CI: 1.78-3.26). We did not observe significant differences in the risk associations across these tumor classifications for age at menarche, menstrual cycle length or infertility.A potential limitation of this study is that dividing the cases into subgroups may limit the power of these analyses, particularly for the less common tumor types. Since cases were enrolled after their diagnosis, it is possible that the most aggressive cases were not included in the study.This study provides insights about the role of reproductive factors in relation to risk of pathway-based subgroups of ovarian cancer that with further confirmation may assist with the development of improved strategies for the prevention of these different tumor types.This research is funded by grants from the National Cancer Institute, the Department of Defense Ovarian Cancer Research Program and the Ovarian Cancer Research Fund. The authors have no competing interests to declare.Not applicable.

Background: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987–. ©2013 AACR.

Contains fulltext : 167177.pdf (Publisher’s version ) (Open Access) BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Oral contraceptives (OCs) have been consistently associated with a reduced ovarian cancer risk; however, most previous studies included women in older birth cohorts using high-dose OC formulations. We assessed OC use, including type and dose, and ovarian cancer risk among women born between 1947 and 1964 using more recent formulations. We included 110,929 Nurses’ Health Study II participants. Women reported duration of OC use and brands used from age 13 to baseline (1989) and every 2 years thereafter through 2009. We categorized brands by estrogen and progestin type, dose, and potency, and used Cox proportional hazards models, adjusted for age, calendar time, reproductive factors, and body mass index, to assess associations with ovarian cancer. Over 2,178,679 person-years of follow-up, we confirmed 281 cases. At baseline, 83% of participants reported ever using OCs. Compared to never use, we observed an increased risk of ovarian cancer with ≤6 months of OC use (HR 1.82; 95% CI 1.13–2.93) but a non-significant 57% (95% CI 0.18–1.03) decreased risk with ≥15 years of OC use. The increased risk among short-term users (≤1 year) was restricted to OCs containing mestranol (HR 1.83; 95% CI 1.16–2.88) and first-generation progestin (HR 1.72; 95% CI 1.11–2.65). The associations between OCs and ovarian cancer observed for this younger birth cohort differ substantially from the results of previous cohort studies, possibly reflecting changes in OC formulations and use patterns over time, although these results could be due to chance. Additional studies should evaluate newer OC formulations and ovarian cancer risk.

Endometriosis is associated with ovarian cancer, but the relation with endometrial cancer is unclear. Prior studies generally were retrospective and had potential limitations, including use of self-reported endometriosis, failure to account for delays between symptom onset and endometriosis diagnosis, and changes in risk factors post-endometriosis diagnosis. We evaluated whether these limitations obscured a weak association with endometrial cancer and the extent to which these limitations impacted associations with ovarian cancer.Cox proportional hazards regression models were used to assess associations between endometriosis and cancer risk, evaluating the impacts of self-reported vs. laparoscopically confirmed endometriosis, delayed diagnosis, and post-endometriosis diagnosis changes in risk factor exposures on relative risk estimates.Over 18 years of follow-up, we identified 228 ovarian and 166 endometrial cancers among 102,025 and 97,109 eligible women, respectively. Self-reported endometriosis was associated with ovarian cancer [relative risk (RR): 1.81; 95% confidence interval (CI): 1.26-2.58]; this association was stronger for laparoscopically confirmed endometriosis (HR: 2.14; 95% CI 1.45-3.15). No association was observed with endometrial cancer (self-report RR: 0.78; 95% CI 0.42-1.44; laparoscopic-confirmation RR: 0.76; 95% CI 0.35-1.64). Accounting for diagnosis delays or post-endometriosis diagnosis changes in risk factors had a little impact.This study adds to the evidence that endometriosis is not strongly linked to endometrial cancer risk and that the association with ovarian cancer is robust to misclassification, diagnostic delay, and changes in exposures post-endometriosis diagnosis. Our analysis suggests that confounding and misclassification do not obscure a weak association for endometrial cancer risk, although our results should be replicated.

Contains fulltext : 174140.pdf (Publisher’s version ) (Closed access) 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.

Purpose: About 60% of ovarian cancers are diagnosed at late stage, when 5-year survival is less than 30% in contrast to 90% for local disease. This has prompted search for early detection biomarkers. For initial testing, specimens taken months or years before ovarian cancer diagnosis are the best source of information to evaluate early detection biomarkers. Here we evaluate the most promising ovarian cancer screening biomarkers in prospectively collected samples from the European Prospective Investigation into Cancer and Nutrition study. Experimental Design: We measured CA125, HE4, CA72.4, and CA15.3 in 810 invasive epithelial ovarian cancer cases and 1,939 controls. We calculated the sensitivity at 95% and 98% specificity as well as area under the receiver operator curve (C-statistic) for each marker individually and in combination. In addition, we evaluated marker performance by stage at diagnosis and time between blood draw and diagnosis. Results: We observed the best discrimination between cases and controls within 6 months of diagnosis for CA125 (C-statistic = 0.92), then HE4 (0.84), CA72.4 (0.77), and CA15.3 (0.73). Marker performance declined with longer time between blood draw and diagnosis and for earlier staged disease. However, assessment of discriminatory ability at early stage was limited by small numbers. Combinations of markers performed modestly, but significantly better than any single marker. Conclusions: CA125 remains the single best marker for the early detection of invasive epithelial ovarian cancer, but can be slightly improved by combining with other markers. Identifying novel markers for ovarian cancer will require studies including larger numbers of early-stage cases. Clin Cancer Res; 22(18); 4664–75. ©2016 AACR. See related commentary by Skates, p. 4542

Although ovarian and endometrial cancers are both gynecologic tumors with some shared risk factors, they have many differences that distinguish them. Ovarian cancer is a rare, silent killer with no single mechanism defining its etiology, while endometrial cancer is the most common gynecologic cancer, has a high survival rate, and is generally attributable to excess estrogen. For each cancer, we describe the current population distributions and evaluate longitudinal trends and survival rates. The primary focus of this chapter is comparing and critically considering known and suspected risk factors for these two gynecologic tumors, with particular attention paid to implication for pathogenesis and future directions for discovery of improved diagnostics, precision treatments, and cancer prevention. For ovarian cancer, recent advances have focused on identification of subtypes that imply heterogeneous origins. A growing body of evidence suggests differential survival rates that are independent of stage at diagnosis and response to current treatment regimens. For endometrial cancer, robust risk factor establishment has led to deep understanding of the role of estrogens in benign, malignant, and metastatic tumor pathogenesis. Both gynecologic cancers reinforce the success of multidisciplinary approaches that require expertise from population- and clinical epidemiology, pathology, molecular biology, genetics, genomics, and bioinformatics.

Background Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4–21% in reproductive aged women. The altered metabolic and hormonal environment among women with PCOS may increase their risk of some types of cancer. Methods We performed a comprehensive review of the literature using numerous search terms for all studies examining the associations between polycystic ovary syndrome and related characteristics and cancer published in English through October 2016. This review summarizes the epidemiological findings on the associations between PCOS and endometrial, ovarian, and breast cancers and discusses the methodological issues, complexities, and underlying mechanisms of these associations. Results We identified 11 individual studies and 3 meta-analyses on the associations between PCOS and endometrial cancer, 8 studies and 1 meta-analysis for ovarian cancer, and 10 studies and 1 meta-analysis for breast cancer. Multiple studies reported that women with PCOS were at a higher risk for endometrial cancer; however, many did not take into account body mass index (BMI), a strong and well-established risk factor for endometrial cancer. The association with ovarian cancer was less clear, but a potentially increased risk of the borderline serous subtype was reported by two studies. No consistent association between PCOS risk and breast cancer was observed. Conclusion The associations between PCOS and endometrial, ovarian, and breast cancer are complex, with the need to consider many methodological issues in future analyses. Larger well-designed studies, or pooled analyses, may help clarify these complex associations.

Objectives. To review the Nurses’ Health Study’s (NHS’s) contribution to identifying risk factors and long-term health consequences of reproductive events. Methods. We performed a narrative review of the NHS I, NHS II, NHS3, and Growing Up Today Study (GUTS) publications between 1976 and 2016. Results. Collection of detailed reproductive history to identify breast cancer risk factors allowed the NHS to document an association between menstrual irregularities, a proxy for polycystic ovary syndrome (PCOS), and increased risk of diabetes and cardiovascular disease. The NHS II found that infertility associated with ovulation problems and gestational diabetes are largely preventable through diet and lifestyle modification. It also identified developmental and nutritional risk factors for pregnancy loss, endometriosis, and uterine leiomyomata. As women in NHS II age, it has become possible to address questions regarding long-term health consequences of pregnancy complications and benign gynecologic conditions on chronic disease risk. Furthermore, the NHS3 and GUTS are allowing new lines of research into human fertility, PCOS, and transgenerational effects of environmental exposures. Conclusions. The multigenerational resources of the NHSs and GUTS, including linkages of related individuals across cohorts, can improve women’s health from preconception through late adulthood and onto the next generation.

Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P ( )P≥5.0 ×10 (-) (7)) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 (-) (5); PSKAT-o = 9.23 × 10 (-) (4)) and KRT13 (PAML = 1.67 × 10 (-) (4); PSKAT-o = 1.07 × 10 (-) (5)), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease.

Contains fulltext : 171782.pdf (Publisher’s version ) (Closed access) 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.

Objective We assessed the association between reproductive and hormonal factors and ovarian cancer incidence characterized by estrogen receptor-α (ERα) and progesterone receptor (PR) status. Methods Tissue microarrays were used to assess ERα and PR expression among 197 Nurses' Health Study (NHS), 42 NHSII and 76 New England Case-Control Study (NECC) ovarian cancer cases. NHS/NHSII cases were matched to up to 4 controls (n=954) on diagnosis date and birth year. NECC controls (n=725) were frequency matched on age. Cases were considered receptor positive if ≥1% of tumor cells stained positive. Associations by ERα and PR status were assessed using polytomous logistic regression. p-Value for heterogeneity was calculated using a likelihood ratio test. Results 45% of ovarian tumors were PR(+), 78% were ERα(+) and 45% were ERα(+)/PR(+), while 22% were ERα(–)/PR(–). Postmenopausal status was associated with an increased risk of PR(–) tumors (OR: 2.07; 95%CI: 1.15–3.75; p-heterogeneity=0.01) and age at natural menopause was inversely associated with PR(–) tumors (OR, per 5years: 0.77; 95%CI: 0.61–0.96; p-het=0.01). Increasing duration of postmenopause was differentially associated by PR status (p-het=0.0009). Number of children and tubal ligation were more strongly associated with ERα(–) versus ERα(+) tumors (p-het=0.002 and 0.05, respectively). No differential associations were observed for oral contraceptive or hormone therapy use. Conclusions Postmenopausal women have an increased risk of developing PR(–) ovarian tumors compared to premenopausal women. The associations observed for ovarian cancer differ from those seen for breast cancer suggesting that the biology for tumor development through ERα and PR pathways may differ.

Background: Ovarian cancer survival is poor, particularly for platinum-resistant cases. The previous literature on pre-diagnostic reproductive factors and ovarian cancer survival has been mixed. Therefore, we evaluated pre-diagnostic reproductive and hormonal factors with overall survival and, additionally, platinum-chemotherapy resistance. Methods: We followed 1649 invasive epithelial ovarian cancer cases who were enrolled between 1992 and 2008 for overall mortality within the New England Case-Control Study and abstracted chemotherapy data on a subset (n=449). We assessed pre-diagnostic reproductive and hormonal factors during in-person interviews. We calculated hazard ratios (HRs) using Cox-proportional hazards models. Results: We observed 911 all-cause deaths among 1649 ovarian cancer cases. Self-reported endometriosis and longer duration of hormone therapy use were associated with improved survival (HR: 0.72; 95% confidence interval (CI): 0.54–0.94 and HR, ⩾5 years vs never: 0.70; 95% CI: 0.55–0.90, respectively). Older age at menopause and menarche were associated with worse survival (HR, ⩽50 vs >50 years: 1.23; 95% CI: 1.03–1.46 and HR, 13 vs

Contains fulltext : 170527.pdf (Publisher’s version ) (Closed access) BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. METHODS: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). RESULTS: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA

There have been recent proposals advocating the use of additive gene-environment interaction instead of the widely used multiplicative scale, as a more relevant public health measure. Using gene-environment independence enhances statistical power for testing multiplicative interaction in case-control studies. However, under departure from this assumption, substantial bias in the estimates and inflated type I error in the corresponding tests can occur. In this paper, we extend the empirical Bayes (EB) approach previously developed for multiplicative interaction, which trades off between bias and efficiency in a data-adaptive way, to the additive scale. An EB estimator of the relative excess risk due to interaction is derived, and the corresponding Wald test is proposed with a general regression setting under a retrospective likelihood framework. We study the impact of gene-environment association on the resultant test with case-control data. Our simulation studies suggest that the EB approach uses the gene-environment independence assumption in a data-adaptive way and provides a gain in power compared with the standard logistic regression analysis and better control of type I error when compared with the analysis assuming gene-environment independence. We illustrate the methods with data from the Ovarian Cancer Association Consortium.

Introduction Despite strides in identifying factors that predict risk of ovarian cancer and improvements in ovarian cancer treatment, little is known about factors that predict ovarian cancer survival. Methods We reviewed the literature for analyses of factors before, at, or after diagnosis that may predict survival outcomes, including demographics (e.g., age and race), genetics (e.g., inherited BRCA mutations), hormonal factors (e.g., parity and hormone use), and lifestyle (e.g., physical activity and diet). Results While treatment factors, tumor characteristics and genetic syndromes are predictive of survival, few studies of most hormonal and lifestyle factors have been published; most have evaluated pre-diagnosis factors. For example, we identified eight studies that examined menopausal hormone use prior to diagnosis, reporting a non-significant survival benefit for users compared to non-users, while four studies reported better survival with use after surgery, though only two were significant. Similarly, while increased body size has been extensively studied as potentially associated with reduced survival, other modifiable factors, such as diet and physical activity remain understudied. We identified three studies of pre-diagnosis physical activity and five studies of pre-diagnosis diet, with a suggestive benefit of higher vegetable intake and vigorous physical activity. By contrast, large studies of the impact of race/ethnicity and socioeconomic status (SES) confirm that non-white women and women of lower SES fare more poorly than white women and women of higher SES, respectively. Conclusions Our review of the published literature on predictors of ovarian cancer survival revealed that modifiable lifestyle factors may be related to survival, but that hormonal factors do not strongly predict outcomes in ovarian cancer patients. However, more attention should be paid to women's post-diagnosis survival experience. The dearth of literature on post-diagnosis factors that may improve outcomes makes it difficult to make specific recommendations for survivors.

To describe the clinical characteristics of patients with endosalpingiosis (ES) and examine its association with endometriosis and gynecologic malignancies.We queried the medical record for patients who underwent gynecologic surgery (Gynecologic Surgery Cohort (GSC), n=58,161) from 1998 to 2013 at a single institution for the presence of "endosalpingiosis" (ES). Demographic and clinical characteristics were collected for patients with pathologically confirmed ES (n=838). Within GSC, we compared the frequency of endometriosis and gynecologic malignancies with and without ES. We estimated the expected distribution of ovarian cancer subtypes using cases from the New England Case Control Study (NECC). We used chi-square tests to test for significant differences in frequency distributions and unconditional logistic regression to calculate multivariate odds ratios for the association between ES and ovarian cancer subtypes.We observed concurrent endometriosis (p0.0001), uterine cancer (p0.0001), and ovarian cancer (p0.0001) more frequently in women with ES. Women from the GSC with ES and ovarian cancer were more likely to have serous borderline (OR=10.2, 95% CI=5.1-20.7), clear cell (OR=3.0, 95% CI=1.1-8.0), and invasive mucinous tumors (OR=5.0, 95% CI=1.5-16.6) as compared to ovarian cancer cases from the NECC without ES, after accounting for age, race, menopausal status, parity, tubal ligation, and endometriosis.Women with ES are more likely to also be diagnosed with endometriosis, uterine, and ovarian cancers. Further study is needed to understand these associations so we may appropriately counsel patients with ES diagnosed at time of gynecologic surgery.

Menopausal estrogen-alone therapy (ET) is a well-established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome-wide association studies. The interplay among these loci, ET use and ovarian cancer risk has yet to be evaluated. We analyzed data from 1,414 serous cases, 337 endometrioid cases and 4,051 controls across 10 case–control studies participating in the Ovarian Cancer Association Consortium (OCAC). Conditional logistic regression was used to determine the association between the confirmed susceptibility variants and risk of serous and endometrioid ovarian cancer among ET users and non-users separately and to test for statistical interaction. A splicing variant in TERT, rs10069690, showed a statistically significant interaction with ET use for risk of serous ovarian cancer (pint = 0.013). ET users carrying the T allele had a 51% increased risk of disease (OR = 1.51, 95% CI 1.19–1.91), which was stronger for long-term ET users of 10+ years (OR = 1.85, 95% CI 1.28–2.66, pint = 0.034). Non-users showed essentially no association (OR = 1.08, 95% CI 0.96–1.21). Two additional genomic regions harboring rs7207826 (C allele) and rs56318008 (T allele) also had significant interactions with ET use for the endometrioid histotype (pint = 0.021 and pint = 0.037, respectively). Hence, three confirmed susceptibility variants were identified whose associations with ovarian cancer risk are modified by ET exposure; follow-up is warranted given that these interactions are not adjusted for multiple comparisons. These findings, if validated, may elucidate the mechanism of action of these loci.

Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2: et al., [Objective]: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. [Methods]: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). [Results]: We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. [Conclusions]: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers., The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 — HEALTH-F2-2009-223175). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). Funding for the project was provided by the Wellcome Trust under award 076113. This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA) and SAF2010-20493. Was supported by a grant RD12/00369/0006 and 12/00539 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. Contract grant sponsor: Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285 and 2009SGR290.

Contains fulltext : 171697.pdf (Publisher’s version ) (Closed access) PURPOSE: Socioeconomic status (SES) is a known predictor of survival for several cancers and it has been suggested that SES differences affecting tumour stage at diagnosis may be the most important explanatory factor for this. However, only a limited number of studies have investigated SES differences in tumour stage at diagnosis of ovarian cancer. In a pooled analysis, we investigated whether SES as represented by level of education is predictive for advanced tumour stage at diagnosis of ovarian cancer, overall and by histotype. The effect of cigarette smoking and body mass index (BMI) on the association was also evaluated. METHODS: From 18 case-control studies, we obtained information on 10,601 women diagnosed with epithelial ovarian cancer. Study specific odds ratios (ORs) with corresponding 95% confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio (pOR) using a random effects model. RESULTS: Overall, women who completed high school (pOR 1.15; 95% CI 1.03-1.28). The risk estimates for the different histotypes of ovarian cancer resembled that observed for ovarian cancers combined but did not reach statistical significance. Our results were unchanged when we included BMI and cigarette smoking. CONCLUSION: Lower level of education was associated with an increased risk of advanced tumour stage at diagnosis of ovarian cancer. The observed socioeconomic difference in stage at diagnosis of ovarian cancer calls for further studies on how to reduce this diagnostic delay.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.

Contains fulltext : 171904.pdf (Publisher’s version ) (Closed access) BACKGROUND: In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer. METHODS: We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases). RESULTS: The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01). CONCLUSIONS: Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

Objective To investigate whether galactose-1-phosphate uridyl transferase ( GALT ) variant genotypes were associated with epithelial ovarian cancer risk, and to determine if this association was modified by lactose intake. Design Two prospective cohort studies and a case-control study. Setting Academic institution. Patient(s) A total of 992 cases and 1,050 population-based control samples from a New England case-control study and 240 cases and 900 control samples from the Nurses' Health Studies. Intervention(s) None. Main Outcome Measure(s) Genotyping of the N314D variant and the 4-bp deletion (−119delGTCA) of GALT with the use of the Taqman 5′ nuclease assay. Duarte1 (D1) genotype individuals have a missense mutation (N314D) associated with normal GALT activity unless it occurs together with an associated 4-bp deletion leading to reduced GALT activity (Duarte2 or D2). Result(s) Logistic regression analysis identified no association between D1/D2 genotypes and ovarian cancer risk (pooled risk ratio 1.1 [95% confidence interval (CI) 0.8–1.5] for D1 and 1.0 [95% CI 0.7–1.4] for D2). We did not observe a significant interaction between D1 and D2 genotypes in analyses stratified by level of lactose intake. Conclusion(s) D1 and D2 genotypes do not appear to play a role in the association between galactose intake, possible ovarian dysfunction, and the link with ovarian cancer.

Inconsistent results for the role of dairy food intake in relation to ovarian cancer risk may reflect the potential adverse effects of lactose, which has been hypothesized to increase gonadotropin levels, and the beneficial anti-proliferative effects of calcium and vitamin D. Using data from the New England case-control study (1909 cases; 1989 controls) we examined dairy foods and nutrients in relation to risk of ovarian cancer overall, histological subtypes, and rapidly fatal versus less aggressive disease. We used logistic regression and polytomous logistic regression to estimate odds ratios and 95% confidence intervals. In models that were simultaneously adjusted for total (dietary plus supplements) calcium, total vitamin D and lactose, we observed a decreased overall risk of ovarian cancer with high intake of total calcium (Quartile 4 (Q4, >1319 mg/day) vs. Quartile 1 (Q1, 559 IU/day vs. Q1

Background: Telomeres protect chromosomal ends, shorten with cellular division, and signal cellular senescence, but unchecked telomere attrition can lead to telomere dysfunction, upregulation of telomerase, and carcinogenesis. Shorter telomeres in peripheral blood leukocytes (PBL) have been associated with elevated cancer risk. Furthermore, genetic variants in and around the TERT gene have been implicated in carcinogenesis. Methods: We measured relative telomere length (RTL) in PBLs of 911 cases and 948 controls from the New England case–control (NECC) study, a population-based study of ovarian cancer. In addition, we assessed germ line genetic variation in five telomere maintenance genes among 2,112 cases and 2,456 controls from the NECC study and the Nurses' Health Study, a prospective cohort study. ORs and 95% CIs were estimated by logistic regression. Results: Overall, we observed no differences in telomere length between cases and controls. Compared with women with RTL in the longest tertile, women with RTL in the shortest tertile had no increase in risk (OR = 1.01, 95% CI: 0.80–1.28). However, several SNPs in the TERT gene, including rs2736122, rs4246742, rs4975605, rs10069690, rs2736100, rs2853676, and rs7726159, were significantly associated with ovarian cancer risk. We observed a significant gene-level association between TERT and ovarian cancer risk (P = 0.00008). Conclusion: Our observations suggest that genetic variation in the TERT gene may influence ovarian cancer risk, but the association between average telomere length in PBLs and ovarian cancer remains unclear. Impact: The role of telomeres in ovarian carcinogenesis remains unsettled and warrants further investigation. Cancer Epidemiol Biomarkers Prev; 21(3); 504–12. ©2012 AACR.

Previous studies have examined the association between ABO blood group and ovarian cancer risk, with inconclusive results.In eight studies participating in the Ovarian Cancer Association Consortium, we determined ABO blood groups and diplotypes by genotyping 3 SNPs in the ABO locus. Odds ratios and 95 % confidence intervals were calculated in each study using logistic regression; individual study results were combined using random effects meta-analysis.Compared to blood group O, the A blood group was associated with a modestly increased ovarian cancer risk: (OR: 1.09; 95 % CI: 1.01-1.18; p = 0.03). In diplotype analysis, the AO, but not the AA diplotype, was associated with increased risk (AO: OR: 1.11; 95 % CI: 1.01-1.22; p = 0.03; AA: OR: 1.03; 95 % CI: 0.87-1.21; p = 0.76). Neither AB nor the B blood groups were associated with risk. Results were similar across ovarian cancer histologic subtypes.Consistent with most previous reports, the A blood type was associated modestly with increased ovarian cancer risk in this large analysis of multiple studies of ovarian cancer. Future studies investigating potential biologic mechanisms are warranted.

Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10(-4)]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways. ispartof: Journal of Genetics and Genome Research vol:2 issue:2 pages:017- ispartof: location:United States status: published

Inflammatory cytokines, like tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), are elevated in ovarian cancer. Differences in cytokine expression by histologic subytpe or ovarian cancer risk factors can provide useful insight into ovarian cancer risk and etiology. We used ribonucleic acid (RNA) in-situ hybridization to assess TNF-α and IL-6 expression on tissue microarray slides from 78 epithelial ovarian carcinomas (51 serous, 12 endometrioid, 7 clear cell, 2 mucinous, 6 other) from a population-based case control study. Cytokine expression was scored semi-quantitatively and odds ratios (OR) and 95% confidence intervals (CI) were calculated using polytomous logistic regression. TNF-α was expressed in 46% of the tumors while sparse IL-6 expression was seen only 18% of the tumors. For both markers, expression was most common in high grade serous carcinomas followed by endometrioid carcinomas. Parity was associated with a reduced risk of TNF-α positive (OR=0.3, 95% CI: 0.1-0.7 for 3 or more children versus none) but not TNF-α negative tumors (p-heterogeneity=0.02). In contrast, current smoking was associated with a nearly three fold increase in risk of TNF-α negative (OR=2.8, 95% CI: 1.2, 6.6) but not TNF-α positive tumors (p-heterogeneity = 0.06). Our data suggests that TNF-α expression in ovarian carcinoma varies by histologic subtype and provides some support for the role of inflammation in ovarian carcinogenesis. The novel associations detected in our study need to be validated in a larger cohort of patients in future studies.

Objective To determine if phone calls between ET and pregnancy test, decrease stress levels as determined by the Perceived Stress Scale (PSS). Design Randomized controlled trial. Setting Academic medical center. Patient(s) Women undergoing a first fresh cycle of assisted reproductive technology using autologous oocytes with a day 2 or 3 ET. Intervention(s) Phone calls from specialized social workers or standard of care. Main Outcome Measure(s) Primary outcome was the change in PSS score from day of ET compared with 10 days after ET; secondary outcome was perceived patient benefit. Result(s) A total of 131 patients were randomized to the intervention (n = 66) or control (n = 65) group. No differences were seen in the final PSS score or the change in PSS score between groups. At the completion of the study, the intervention group was more likely to report that participating in this study was helpful (65.9% vs. 21.4%), as well as to recommend emotional support during an IVF cycle (95.4% vs. 78.6%). Conclusion(s) Although we observed no significant change in PSS score, first-cycle IVF patients felt that increased emotional support was needed during the waiting period between ET and pregnancy test. Additional research should be conducted to determine the best interventions for this time period.

Folate, methionine, vitamin B(6) and vitamin B(12) may influence carcinogenesis due to their roles in the one-carbon metabolism pathway, which is critical for DNA synthesis, methylation and repair. Low intake of these nutrients has been associated with an increased risk of breast, colon and endometrial cancers. Previous studies that have examined the relation between these nutrients and ovarian cancer risk have been inconsistent and have had limited power to examine the relation by histologic subtype. We investigated the association between folate, methionine, vitamin B(6) , vitamin B(12) and alcohol among 1910 women with ovarian cancer and 1989 controls from a case-control study conducted in eastern Massachusetts and New Hampshire from 1992 to 2008. Diet was assessed via food frequency questionnaire. Participants were asked to recall diet one-year before diagnosis or interview. Logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95% CIs). We also examined whether the associations varied by ovarian cancer histologies using polytomous logistic regression. We observed an inverse association between dietary vitamin B(6) (covariate-adjusted OR = 0.76, 95% CI 0.64-0.92; p(trend) = 0.002) and methionine intake (covariate-adjusted OR = 0.72, 95% CI = 0.60-0.87; p(trend)0.001) and ovarian cancer risk comparing the highest to lowest quartile. The association with dietary vitamin B(6) was strongest for serous borderline (covariate-adjusted OR = 0.49, 95% CI = 0.32-0.77; p(trend) = 0.001) and serous invasive (covariate-adjusted OR = 0.74, 95% CI = 0.58-0.94; p(trend) = 0.012) subtypes. Overall, we observed no significant association between folate and ovarian cancer risk. One-carbon metabolism related nutrients, especially vitamin B(6) and methionine, may lower ovarian cancer risk.

CA125 at presentation of ovarian cancer carries important prognostic significance; but, other than tumor characteristics, little is known about factors that influence CA125 levels. We examined the effect of epidemiologic variables and tumor features on CA125 at diagnosis and their effects on survival.CA125 levels before treatment, tumor features, and questionnaire data from 805 women with ovarian cancer receiving care at Partners Hospitals were recorded. CA125 values were log-normalized and generalized linear, logistic, or Cox proportional hazards models used to identify predictors of CA125 and influence on survival in the subset of women with invasive, nonmucinous tumors.The importance of histology, grade, stage, laterality, and presence of ascites on CA125 level was confirmed. For nonmucinous invasive cancers, Jewish ethnicity, parity, prior breast cancer, and family history of breast or ovarian cancer predicted higher CA125, and greater body mass index (BMI), recurrent yeast infections, colitis, and appendectomy predicted lower CA125. A quadratic model best described the relationship between CA125 and age with lower levels in youngest and oldest women. In multivariate modeling, stage, ascites, and prior breast cancer were the strongest predictors of high CA125 and appendectomy and yeast infections strongest predictors of low CA125. A model with these variables plus CA125 revealed high CA125 remains a predictor of poorer survival.Ovarian tumor features and presence of ascites are key determinants of CA125 at diagnosis, but epidemiologic features such as BMI, parity, prior breast cancer, and history of inflammatory conditions of the genitourinary or gastrointestinal tracts may also play a role.

Folate has been hypothesized to influence carcinogenesis due to its dual role in DNA methylation, which regulates gene expression, and synthesis of purine and thymidylate, which is vital for DNA repair. Thus, we examined ovarian cancer risk in relation to two functional polymorphisms (C677T and A1298C) in the MTHFR gene.We genotyped the C677T (rs1801133) and A1298C (rs1801131) MTHFR polymorphisms in 1642 cases and 2068 controls from three studies, the New England Case Control Study (NEC), Nurses' Health Study (NHS), and Mayo Clinic Ovarian Cancer Case Control Study (MAY).Overall, we observed no association between either SNP and ovarian cancer risk (pooled C677T p(trend)=0.59 and A1298C p(trend)=0.58). Significant associations (C677T p(trend)=0.001, A1298C p(trend)=0.02) between these MTHFR SNPs and serous ovarian cancer risk were observed in the NEC study, but were not replicated in the NHS and MAY studies.MTHFR SNPs C677T and A1298C are not associated with ovarian cancer risk. Our results highlight the need for validation of genetic findings.

CA125 has proven to be the most promising biomarker for ovarian cancer screening. However, results from two large randomized trials comparing screening using CA125 and transvaginal ultrasound (TVU) to usual care have shown no clinically important difference in ovarian cancer mortality. A major limitation of CA125 as an ovarian cancer screening biomarker has been low specificity, which could be due in part to its expression on variety of tissues, including the lung, pancreas, stomach, liver, endometrium, and breast. In addition, CA125 levels vary between individuals based on demographic, reproductive, and lifestyle characteristics. We hypothesize that, independent of ovarian cancer, genetic variation may influence CA125 levels and identification of genetic predictors of CA125 may be used to develop individualized cut-off points, in combination with personal characteristics, to improve the predictive value of CA125 as an ovarian cancer screening biomarker. Furthermore, studies showing that CA125 binds to natural killer cells and monocytes, dampening immune response, suggest that CA125 may contribute to ovarian cancer progression through immune dysregulation. Thus, identifying genetic variants associated with CA125 levels could add another layer of understanding of the biologic role of elevated CA125 in ovarian cancer progression. To test our hypothesis, we evaluated the association between common germline genetic variants across the genome in relation to serum levels of CA125 among 347 women without ovarian cancer recruited as population-based controls in the New England Case Control Study, a population-based study of ovarian cancer that enrolled participants between 1992 and 2008 in eastern Massachusetts and New Hampshire. We used linear regression to identify SNPs associated with CA125 using the Rare variant (RV) test. To account for multiple testing, a p-value threshold of 5x10-8 was used. We adjusted for age and three principal components to account for potential population stratification. While there were no GWAS-significant SNPs, rs12602627 on chromosome 17 was associated with a 75% increase in CA125 per additional variant allele of rs12602627 (p=6.47x10-8). Furthermore, there were two SNPs (rs12602169 and rs73990427) in close proximity that were nearly GWAS significant (p=7.12x10-8 and 8.97x10-8, respectively). rs12602627 explained 8% of the variability of CA125. Monocyte to macrophage differentiation associated (MMD) is the closest gene to rs12602627. MMD encodes a protein expressed in differentiated mature macrophages and is involved in macrophage activation, suggesting it may play an important role in immune response. This is the first GWAS study to assess SNPs directly associated with circulating levels of CA125 in women without ovarian cancer. Validation studies are currently under way. Results from these analyses may provide important insights into genetic determinants of CA125 levels, improved ovarian cancer screening, and better understanding of how CA125 contributes to ovarian cancer pathogenesis and progression. *Coauthors. Citation Format: Naoko Sasamoto, Lai Jiang, Allison F. Vitonis, Raina N. Fichorova, Paul Pharaoh, Daniel W. Cramer, Peter Kraft, Kathryn L. Terry. Genome-wide association study of cancer antigen 125. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B19.

Introduction: Prostaglandin E2 (PGE2) is thought to influence ovarian carcinogenesis by increasing cell proliferation, tumor cell invasiveness, and angiogenesis. PGE-M is the major metabolite of PGE2 and a marker of systemic PGE2 production. Prior research has reported positive associations between urinary PGE-M and risk of colorectal, gastric, lung, pancreatic, and breast cancer; however, this is the first study to evaluate the association between urinary PGE-M and risk of ovarian cancer. Methods: We conducted a prospective case-control study nested in the Nurses’ Health Study (NHS) and NHSII cohorts. We included 194 cases of invasive epithelial ovarian cancer and 387 matched controls. All cases were diagnosed between the time of urine specimen collection (1996-97 NHSII; 2000-2002 NHS) and the end of follow-up (2015). Controls were selected using incidence density sampling and matched to cases on year of birth, menopausal status at collection and diagnosis, date and time of day of collection, hormone therapy use at collection, and fasting status. We measured PGE-M levels using LC/MS methods, and used the PGE-M distribution among controls to identify tertile cutpoints. We estimated the association between prediagnosis urinary PGE-M (in tertiles) and risk of ovarian cancer using conditional logistic regression. Results: We observed a suggestively lower risk of ovarian cancer for those with the highest PGE-M levels in NHS (OR=0.66; 95%CI=0.36-1.21; p-trend=0.15; n=123 cases), and no association in NHSII (OR=1.15; 95%CI=0.50-2.67; p-trend=0.75; n=71 cases). When results from the two cohorts were pooled, we observed nonsignificant, lower odds of ovarian cancer among those in the highest tertile of PGE-M compared to the lowest tertile (OR=0.80; 95%CI=0.50-1.27; p-trend=0.34), particularly after restricting our analysis to study participants who provided first morning urine samples (OR=0.68; 95%CI=0.40-1.14; p-trend=0.13). However, when we examined quartiles, no clear association was observed, although power was limited. Conclusions: Overall, our results suggest that higher prediagnosis PGE-M levels are not associated with an increased risk of ovarian cancer. Further analyses are under way to evaluate the potential for effect modification by menopausal status, BMI, and NSAID use. Citation Format: Mollie E. Barnard, A. Heather Eliassen, Bernard A. Rosner, Kathryn L. Terry, Ginger L. Milne, Shelley S. Tworoger. Urinary PGE-M levels and risk of ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B08.

Background: Cancer antigen 125 (CA125) is a membrane-bound glycosylated mucin that has been reported to be the most promising biomarker for ovarian cancer screening, although results from two large randomized trials comparing screening using CA125 and transvaginal ultrasound to usual care have shown no clinically significant difference in ovarian cancer mortality. A major limitation of CA125 as an ovarian cancer screening biomarker has been low specificity and variation between individuals by personal characteristics. Identifying personal characteristics that influence CA125 levels could be used to create personalized thresholds for CA125 for each individual, thereby improving its performance as an ovarian cancer screening biomarker. However, reports on factors that influence CA125 among premenopausal women are limited. Methods: We evaluated the association between reproductive and lifestyle factors and CA125 among 828 premenopausal population-based controls enrolled in the New England Case-Control study between 1992 and 2008. CA125 was measured using the CA125II assay at the CERLab at Boston Children's Hospital. We developed a prediction model of log-transformed CA125 using stepwise linear regression with Results: In our univariate analyses, older age and endometriosis were associated with significantly higher CA125 while tubal ligation, hysterectomy, and time since last menstrual period were associated with significantly lower CA125 (p Conclusion: Efforts to validate this CA125 prediction model in an independent cohort of premenopausal women and evaluate whether using the personalized CA125 cutoff based on this prediction model discriminates cases and controls better than the single 35 cutoff are ongoing. Citation Format: Naoko Sasamoto, Ana Babic, Bernard A. Rosner, Allison F. Vitonis, Daniel W. Cramer, Shelley S. Tworoger, Kathryn L. Terry. Prediction model of CA125 among premenopausal women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2205.

Introduction: Sexually transmitted infections (STIs) including bacterial infections Chlamydia trachomatis and Mycoplasma genitalium and infections with the human papillomavirus (HPV), and the herpes simplex virus type 2 (HSV-2), may induce persistent changes in the female genital tract increasing risk of epithelial ovarian cancer (OC). For example, C. trachomatis and M. genitalium infections are associated with pelvic inflammatory disease (PID), salpingitis, and tubal factor infertility. STI-induced tubal pathologies may be relevant to OC development given mounting evidence showing that a proportion of OCs originate in the fallopian tube. Epidemiologic data on STIs and OC risk are sparse. Methods: A case-control study was nested in the Nurses' Health Study (NHS) and NHSII including 338 cases individually matched to 338 controls. Antibodies indicating past infection with C. trachomatis (pGP3), M. genitalium (MgPa N-Terminus + rMgPa), HPV (E6+E7 oncoproteins of types 16, 18, and 45), and HSV-2 (mgGunique) were measured using validated serological multiplex assays in pre-diagnosis plasma samples. Multivariable conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals [CI] comparing seropositive vs. seronegative for the individual infections for OC overall, as well as invasive OC and invasive serous OC. We further cross-classified the infections, comparing women seropositive for C. trachomatis plus any other STI to women seronegative for all STIs. Results: Study participants were median age 60 years (range: 34-81) at blood collection. The majority were parous (87%) and ever oral contraceptive users (54%), and 19% reported tubal ligation. Of the 338 OC cases, 257 were diagnosed with invasive disease and 156 were diagnosed with invasive serous disease. Cases were diagnosed median 7 years (range: 0.1-25) after blood collection. Seropositivity was observed in 20% of cases (12% of controls) for C. trachomatis, 5% (3%) for M. genitalium and 12% (9%) for HSV-2. Prevalence of infection with HPV ranged from 4% of cases (4% of controls) for HPV18 E6+E7 to 14% (14%) for HPV16 E6+E7. C. trachomatis infection was associated with increased risk of OC overall (RR: 1.98 [1.21-3.26]), invasive OC (1.81 [1.12-2.93]) and invasive serous OC (2.14 [1.23-3.75]). We observed no association between the other STIs and OC risk. Seropositivity to C. trachomatis plus any other STI was associated with a 3-fold increased risk of OC, relative to seronegativity to all infections (3.19 [1.41-7.21]). Discussion: We provide the first large-scale epidemiologic study on common STIs and OC risk, and show a significant positive association between C. trachomatis infection and OC, and a potentially synergistic effect of infection with multiple STIs. These results suggest STI prevention efforts, including vaccine development, represent an opportunity to reduce OC risk. Citation Format: Renee Turzanski Fortner, Kathryn L. Terry, Noemi Bender, Tim Waterboer, Shelley S. Tworoger. Sexually transmitted infections and risk of epithelial ovarian cancer: Results from the Nurses' Health Studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4941.

Objective Together, steroidogenic acute regulator (StAR) and the cholesterol side chain cleavage enzyme (P450scc), which is encoded by CYP11A1 , mediate the initial and rate-limiting step in steroidogenesis. Given the role of estrogens in endometrial carcinogenesis, we hypothesized that genetic variation in StAR and CYP11A1 genes may influence endometrial cancer risk. Methods We genotyped four CYP11A1 tagging single nucleotide polymorphisms (SNPs) and two StAR SNPs in endometrial cancer case–control studies nested within the Nurses' Health Study (553 cases and 1339 controls) and the Women's Health Study (137 cases and 411 controls). We calculated odds ratios and 95% confidence intervals using conditional and unconditional logistic regression adjusted for endometrial cancer risk factors to examine the association between SNPs/haplotypes and endometrial cancer. Results We observed an increased risk for women carrying the variant allele for rs4555110 (odds ratio (OR)=1.3, 95% confidence interval (CI)=1.1–1.7), rs3825944 (OR=1.4, 95% CI=1.1–1.8), and rs7173655 (OR=1.3, 95% CI=1.0–1.7) CYP11A1 SNPs but no significant associations with CYP11A1 haplotypes. CYP11A1 SNPs were not predictive of plasma estradiol levels. We observed no associations between StAR SNPs and endometrial cancer risk. Conclusions Genetic variants in CYP11A1 may influence endometrial cancer risk or may be markers for causal variants elsewhere. Polymorphisms in StAR are not associated with endometrial cancer risk, but further research is needed.

Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92-1.07). When a recessive model was fit, the results were unchanged. Test for hetero geneity of the odds ratios revealed consistency across the 14 replication sites but significant differences compared with the original study population (P = 0.03). This study underscores the need for replication of putative findings in genetic association studies. Cancer Epidemiol Biomarkers Prev; 19(2); 600–4

Motor units discharge at variable rates and thereby produce spike trains that are inherently nonstationary. For signal analysis techniques that assume data stationarity, such as those for detecting and quantifying coherence and short-term synchronization (STS), nonstationarity presents a potential source of inaccuracy. If coherence and STS indices are sensitive to the level of nonstationarity, broad application of these techniques to nonstationary spike trains could diminish the validity of previous and future motor unit synchronization studies. To address this concern, spike trains taken from intramuscular EMG recorded in two hand muscles during a 2-min, submaximal isometric task were checked for significant nonstationarity using the Mann-Kendall test. Linear regressions were then performed for coherence and STS indices against the mean spike train nonstationarity strength for all physiological spike train pairs (n=92). Peak coherence, coherence index, k'-1, and CIS were used to quantify synchronization, whereas two indices (StIn and StatAv) were used to quantify nonstationarity. To extend the scope and power of this study, an integrate-to-fire model was used to create a much larger pool of simulated spike train pairs (n=2520) with predetermined synchronization and stationarity strengths and discharge properties that closely approximated those of the physiological pool. Regressions for both physiological and simulated pairs revealed that coherence, STS, and their indices were insensitive to stationarity. Therefore, motor unit spike train coherence and STS measurements should be robust across all synchronization and nonstationarity levels typical for steady submaximal tasks. Additionally, this finding should hold for all spike trains with similar levels of synchronization and nonstationarity, regardless of origin.

Conflicting reports regarding the relationship between breast-feeding and ovarian cancer risk suggest a possible influence of patterns of breast-feeding. We used logistic regression to examine breast-feeding in a large population of parous women who participated in a case-control study of ovarian cancer in New Hampshire and MA, USA. Risk of ovarian cancer was reduced in parous women who ever breast-fed (OR: 0.75; 95% CI: 0.62, 0.92), but evidence was limited for an influence of duration of breast-feeding and the number of children breast-fed. Compared to never breast-feeding, inverse associations were seen for breast-feeding all children (OR: 0.72; 95% CI: 0.58, 0.91) and for breast-feeding some children when the last born child was breast-fed (OR: 0.58; 95% CI: 0.37, 0.91). There was little evidence of reduced risk for those who breast-fed some children when the last born child was not breast-fed (OR: 0.91; 95% CI: 0.66, 1.26). Similar findings were noted in women with exactly two children and in those with two or more children. The protective influence of breast-feeding on ovarian cancer risk may be limited to women who breast-feed their last born child. These findings, which require confirmation by future studies, imply that breast-feeding resets pregnancy-related states that mediate ovarian cancer risk.

Insulin-like growth factor (IGF) 1 and its binding proteins foster cellular proliferation and inhibit apoptosis. In vitro studies show that IGF1 increases ovarian cell growth and invasive potential, suggesting a role for the IGF1 pathway in ovarian cancer etiology. We evaluated genetic variation in the IGF1, IGFBP1 and IGFBP3 genes in relation to ovarian cancer risk by genotyping 29 haplotype-tagging single nucleotide polymorphisms in 1173 cases and 1201 controls from the New England Case–Control (NECC) study and 296 cases and 854 controls from the Nurses’ Health Study (NHS). The association of haplotypes and single nucleotide polymorphisms (SNPs) with ovarian cancer was estimated using unconditional (NECC) and conditional (NHS) logistic regression. Additionally, we evaluated the association of SNPs with IGF1, IGF-binding protein (IGFBP) 3 and IGFBP2 plasma levels (n = 380 NHS controls). Our data suggest a decreased risk for women carrying haplotype 2C of the IGF1 gene [odds ratios (ORs) = 0.82, 95% confidence intervals (CIs) = 0.69–0.98] and an increased risk for women carrying haplotype 1D (OR = 1.41, 95% CI = 1.03–1.94) or 2D (OR = 1.20, 95% CI = 1.01–1.41) in the binding proteins. When evaluated individually, three SNPs in the IGFBPs (rs10228265, rs4988515 and rs2270628) were associated with increased ovarian cancer risk, and several IGF1 (rs11111285, rs1996656 and rs1019731) and IGFBP3 (rs2270628, rs2854746 and rs2854744) SNPs were significantly associated with IGF1, IGFBP3 and IGFBP2 plasma levels. Some haplotypes and SNPs in the IGF pathway genes may be associated with ovarian cancer risk; however, these results need to be confirmed. Of particular interest was the IGFBP3 SNP rs2270628, which was associated with both increased IGF1 plasma levels and higher ovarian cancer risk.

Recent genome-wide scans identified several novel breast cancer risk alleles, including variants of the FGFR2, MAP3K1 and LSP1 genes, and a study of associations between these alleles and characteristics of breast cancer patients reported a borderline significant correlation between the number of FGFR2 minor alleles and family history of breast/ovarian cancer. Given these results and similarities in the etiology of breast and ovarian cancer, we examined the association between 7 novel breast cancer susceptibility alleles and epithelial ovarian cancer risk in 2 large study populations. Our analysis included 1,173 cases and 1,201 controls from a New England-based Case–Control study and 210 cases and 603 controls from the prospective Nurses' Health Study. We used logistic regression to estimate the odds ratio (OR) for individuals heterozygous or homozygous for the minor allele at each locus, compared to individuals with the wild-type genotype. We examined the associations separately in each population and, after testing for heterogeneity in the results, pooled the estimates using a random effects model. There was no clear association between these polymorphisms and ovarian cancer risk in either population. The pooled per allele OR for FGFR2 was 1.06 (95% confidence interval (CI) = 0.95–1.18) for rs1219648 and 1.04 (95% CI = 0.93–1.15) for rs2981582. We had more than 80% power to detect a log-additive OR of 1.16–1.18 per allele at the alpha = 0.05 level in the pooled analysis. Our results do not provide strong support for an association between these breast cancer susceptibility alleles and epithelial ovarian cancer risk. © 2008 Wiley-Liss, Inc.

The Ovarian Cancer Association Consortium selected 7 candidate single nucleotide polymorphisms (SNPs), for which there is evidence from previous studies of an association with variation in ovarian cancer or breast cancer risks. The SNPs selected for analysis were F31I (rs2273535) in AURKA, N372H (rs144848) in BRCA2, rs2854344 in intron 17 of RB1, rs2811712 5' flanking CDKN2A, rs523349 in the 3' UTR of SRD5A2, D302H (rs1045485) in CASP8 and L10P (rs1982073) in TGFB1. Fourteen studies genotyped 4,624 invasive epithelial ovarian cancer cases and 8,113 controls of white non-Hispanic origin. A marginally significant association was found for RB1 when all studies were included [ordinal odds ratio (OR) 0.88 (95% confidence interval (CI) 0.79-1.00) p = 0.041 and dominant OR 0.87 (95% CI 0.76-0.98) p = 0.025]; when the studies that originally suggested an association were excluded, the result was suggestive although no longer statistically significant (ordinal OR 0.92, 95% CI 0.79-1.06). This SNP has also been shown to have an association with decreased risk in breast cancer. There was a suggestion of an association for AURKA, when one study that caused significant study heterogeneity was excluded [ordinal OR 1.10 (95% CI 1.01-1.20) p = 0.027; dominant OR 1.12 (95% CI 1.01-1.24) p = 0.03]. The other 5 SNPs in BRCA2, CDKN2A, SRD5A2, CASP8 and TGFB1 showed no association with ovarian cancer risk; given the large sample size, these results can also be considered to be informative. These null results for SNPs identified from relatively large initial studies shows the importance of replicating associations by a consortium approach.

Mouse double-minute 2 homologue (MDM2) is a key negative regulator of p53, a tumor suppressor gene that initiates cell cycle arrest and apoptosis in response to DNA damage and other cellular stresses. A T > G polymorphism found in the promoter region of MDM2 (SNP309) increases MDM2 expression and thereby attenuates p53 activity. We genotyped the MDM2 polymorphism SNP309 in endometrial cancer case-control studies nested within the Nurses' Health Study (454 cases and 1,132 controls) and the Women's Health Study (137 cases and 411 controls). Due to a significant difference in genotype distribution by ethnicity, we restricted our analyses to Caucasians. We calculated odds ratios and 95% confidence intervals using conditional and unconditional logistic regression adjusted for age at menarche, parity and age at first birth, postmenopausal hormone use at diagnosis, age at menopause and menopausal status at diagnosis, first-degree family history of colon cancer, body mass index at diagnosis, and cigarette smoking status at diagnosis. Women with a heterozygous genotype had no greater risk whereas those with a homozygous variant genotype had a greater risk than women with a wild-type genotype for the MDM2 SNP309 (covariate-adjusted odds ratio, 1.87; 95% confidence interval, 1.29-2.73) for endometrial cancer. We observed no association between age at diagnosis and genotype. Women carrying two copies of the MDM2 SNP309 variant may be at greater risk of endometrial cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(4):983–6)