Surrogates of Long-Term Vitamin D Exposure and Ovarian Cancer Risk in Two Prospective Cohort Studies

Experimental evidence and ecologic studies suggest a protective role of vitamin D in ovarian carcinogenesis. However, epidemiologic studies using individual level data have been inconsistent. We evaluated ultraviolet (UV)-B radiation, vitamin D intake, and predicted plasma 25-hydroxyvitamin D [25(OH)D] levels as long-term surrogates of vitamin D exposure within the Nurses’ Health Study (NHS) and NHSII. We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) for risk of overall ovarian cancer and by histologic subtype using Cox proportional hazards models. Between 1976 and 2010 in NHS and 1989 and 2011 in NHSII, we identified a total of 1,225 incident epithelial ovarian cancer cases (NHS: 970, NHSII: 255) over 4,628,648 person-years of follow-up. Cumulative average UV-B exposure was not associated with ovarian cancer risk in NHS (Ptrend = 0.08), but was associated with reduced risk in NHSII (highest vs. lowest category RR = 0.67; 95% CI: 0.50, 0.89; Ptrend < 0.01). When stratified by histologic subtype, UV-B flux was positively associated with risk of serous tumors in NHS (Ptrend < 0.01), but inversely associated in NHSII (Ptrend = 0.01). Adjusted for confounders, ovarian cancer risk was not associated with vitamin D intake from food or supplements or with predicted 25(OH)D levels. Our study does not strongly support a protective role for vitamin D in ovarian cancer risk

A prospective cohort study of dietary indices and incidence of epithelial ovarian cancer

Background: Several dietary indices have been developed to measure overall diet quality, including the Healthy Eating Index-2005 (HEI-2005), which measures adherence to the 2005 Dietary Guidelines from the USDA; the Alternative Healthy Eating Index-2010 (AHEI-2010), which is based on foods and nutrients predictive of chronic disease risk; and the Alternate Mediterranean Diet Score (aMDS), which is an index that characterizes traditional food patterns of Mediterranean countries. Few studies have evaluated diet quality and ovarian cancer risk. Methods: We assessed the associations of the HEI-2005, AHEI-2010, and aMDS with risk of epithelial ovarian cancer prospectively among women in the Nurses’ Health Study. We used Cox proportional hazards models, adjusting for known ovarian cancer risk factors. Results: During 24 years of follow-up, we documented 696 incident epithelial ovarian cancer cases among 82,948 women with diet information. The multivariate adjusted hazard ratios (95% confidence interval; Ptrend) of epithelial ovarian cancer comparing the highest with the lowest quintile were 1.03 (0.80-1.34; 0.77) for the AHEI-2010, 0.85 (0.65-1.12; 0.57) for the HEI-2005, and 0.91 (0.71-1.18; 0.44) for the aMDS. Conclusions: We did not observe any clear association of three diet quality scores with ovarian cancer risk. Further work should other metrics of evaluating diet quality that may be more relevant cancer risk. Electronic supplementary material The online version of this article (doi:10.1186/s13048-014-0112-4) contains supplementary material, which is available to authorized users

Polymorphisms of MUC16 (CA125) and MUC1 (CA15.3) in Relation to Ovarian Cancer Risk and Survival

Objective: To examine single nucleotide polymorphism (SNPs) in MUC16 (CA125) and MUC1 (CA15.3) in relation to ovarian cancer risk and survival. Methods: We genotyped germline variants of MUC16 (rs2547065, rs1559168, rs12984471, rs2121133) and MUC1 (rs2070803, rs4072037, rs1045253) using samples collected from 758 ovarian cancer cases and 788 controls enrolled in the New England Case-Control Study between 2003 and 2008. We calculated age-adjusted odds ratios (OR) and 95% confidence intervals (CIs) for disease risk using unconditional and polytomous logistic regression and hazard ratios (HR) for survival using Cox proportional hazard ratios. In a subset of cases, we compared log-normalized CA125 values by genotype using generalized linear models. Results: Cases homozygous for the variant allele of MUC16 SNP, rs12984471, had poorer overall survival (log-rank p = 0.03) and higher CA125 levels, especially cases over age 65 (p = 0.01). For MUC1 SNP, rs4072037, women homozygous for the G variant had a non-significantly decreased risk for serous invasive types but elevated risk for serous borderline tumors, mucinous borderline and invasive tumors, and endometrioid tumors. Women with the variant allele of MUC16 SNP, rs2547065, especially those who were homozygous had an elevated risk for ovarian cancer; but this association was not confirmed in an independent dataset. Conclusion: This targeted screen of seven polymorphisms of MUC16 and MUC1 genes failed to identify and confirm effects on ovarian cancer risk overall. However, there may be effects of MUC16 rs12984471 on survival and MUC1 rs4072037 on risk for histologic types of ovarian cancer other than invasive serous. Further study is warranted

A Large Cohort Study of Hypothyroidism and Hyperthyroidism in Relation to Gynecologic Cancers

Background:. Thyroid status may influence tumorigenesis of gynecologic cancers, yet epidemiologic studies of this relationship are limited and inconsistent. Methods:. We evaluated the association of self-reported history of physician-diagnosed hypothyroidism and hyperthyroidism with medical-record confirmed endometrial (EC; all invasive adenocarcinomas) and ovarian cancer (OC; epithelial ovarian or peritoneal cancers) in Nurses' Health Study (NHS) from 1976 to 2010 and NHSII from 1989 to 2011. Cox proportional hazard models were used to estimate multivariable rate ratios (RRs) and 95% confidence intervals based on pooled cohort data. Results:. We confirmed 1314 incident cases of EC and 1150 cases of OC. Neither a history of hypothyroidism nor hyperthyroidism was significantly associated with risk of EC or OC. However, having a history of hypothyroidism for 8+ years (median) was nonsignificantly inversely associated with EC (RR = 0.81; 95% CI = 0.63–1.04; P-trend with history duration = 0.11) and OC (RR = 0.87, 95% CI = 0.66–1.15; P-trend = 0.13). Having a history of hyperthyroidism for 6+ years (median) was non-significantly positively associated with EC (RR = 1.69; 95% CI = 0.86–3.30; P-trend = 0.12) but not OC (RR = 1.12; 95% CI = 0.46–2.72; P-trend = 0.95). Conclusions:. A history of hypothyroidism or hyperthyroidism was not significantly associated with risk of EC or OC

Evidence of Differential Effects of Vitamin D Receptor Variants on Epithelial Ovarian Cancer Risk by Predicted Vitamin D Status

Introduction: Experimental studies suggest vitamin D inhibits ovarian carcinogenesis. Yet, epidemiologic studies of ovarian cancer risk and lifestyle correlates of vitamin D status, plasma 25-hydroxyvitamin D [25(OH)D], or vitamin D receptor (VDR) variants have been inconsistent. Objective: To evaluate VDR genetic associations by high vs. low predicted 25(OH)D, scores derived from known determinants of plasma 25(OH)D. To assess ovarian cancer associations with variants identified in genome-wide association studies (GWAS) of plasma 25(OH)D. Methods: We genotyped up to seven VDR and eight 25(OH)D GWAS variants in the Nurses’ Health Studies (562 cases, 1,553 controls) and New England Case–Control study (1,821 cases, 1,870 controls). We estimated haplotype scores using expectation-maximization-based algorithms. We used unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CI). We combined study results using DerSimonian and Laird meta-analysis. Results: Ovarian cancer risk increased per A allele of rs7975232 (VDR; OR = 1.12, 95% CI = 1.01–1.25) among all women. When stratified by predicted 25(OH)D, ovarian cancer was associated with rs731236 (VDR; per C allele OR = 1.31) and rs7975232 (OR = 1.38) among women with high predicted 25(OH)D, but not among women with low levels (P ≤ 0.009). We also observed heterogeneity by predicted 25(OH)D for the ovarian cancer association with VDR 3′ end haplotypes (P = 0.009). Of 25(OH)D-associated GWAS loci, rs7041 was associated with reduced ovarian cancer risk (per T allele OR = 0.92, 95% CI = 0.85-0.99), which did not differ by predicted 25(OH)D status. Conclusion: Our study suggests an influence of VDR 3′ end variants on ovarian cancer risk may be observed in women with high predicted 25(OH)D, which remained even after taking multiple comparisons into consideration. Future studies are needed to confirm our results and explore further the relation between vitamin D exposure, genetic variants, and ovarian cancer risk

Examining the common aetiology of serous ovarian cancers and basal-like breast cancers using double primaries

Background: The somatic molecular profiles of basal-like breast cancers and high-grade serous ovarian cancers share many similarities, leading to the hypothesis that they have similar aetiologies, in which case they should occur together in the same patient more often than expected. Methods: We identified 545 women with double independent primary cancers of the breast and ovary reported to the California Cancer Registry from 1999 to 2013 and examined the coincidence of subtype combinations. Results: For most subtype combinations the observed frequencies were similar to their expected frequencies, but in 103 observed cases vs 43.8 expected (O/E=2.35; 95% CI 1.90–2.81) a triple-negative breast tumour (typically basal-like) was matched with a serous ovarian tumour (typically high-grade). Conclusions: The results provide compelling evidence that basal-like breast cancer and high-grade serous ovarian cancer share a much more similar aetiology than breast and ovarian cancers more broadly. Further research is needed to clarify the influence of germ-line BRCA1 mutations and other risk factors on these results

Recreational physical activity and breast cancer risk by menopausal status and tumor hormone receptor status: results from the Nurses’ Health Studies

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BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Periodontal bone loss and risk of epithelial ovarian cancer

Periodontitis, a chronic inflammatory response to pathogenic bacteria in the oral microbiome, is common among adults. It is associated with several medical conditions, including cardiovascular diseases, and potentially with esophageal, lung, oral and pancreatic cancer. One of the proposed mechanisms behind these associations is systemic inflammation, which has also been implicated in ovarian cancer etiology. The aim of this study was to evaluate association between ovarian cancer and periodontal bone loss