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Evidence of differential effects of vitamin d receptor variants on epithelial ovarian cancer risk by predicted vitamin d status.

ABSTRACT: 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.

SUBMITTER: Prescott J

PROVIDER: S-EPMC4202710 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Evidence of differential effects of vitamin d receptor variants on epithelial ovarian cancer risk by predicted vitamin d status.

Prescott Jennifer J Bertrand Kimberly A KA Reid Brett M BM Permuth-Wey Jennifer J De Vivo Immaculata I Cramer Daniel W DW Terry Kathryn L KL Tworoger Shelley S SS

Frontiers in oncology 20141020

<h4>Introduction</h4>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.<h4>Objective</h4>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 ...[more]

PMID: 25368842

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Project description:BackgroundDue to the presence of both classical estrogen receptor (ERα) and another ER subtype (ERβ) in ovarian cancer, hormonal treatment is an attractive option. However, response to tamoxifen in ovarian cancer is modest. The presence of ERβ variants further complicated the issue. We have recently shown that specifically targeting ER subtypes using selective ER modulators showed opposing functions of ER subtypes on cell growth. In the present study, the clinical significance of ERα and ERβ variants (β1, β2 and β5) and the functional effects of ERβ2 and ERβ5 in ovarian cancer was investigated.MethodsERα, ERβ1, ERβ2 and ERβ5 expression were evaluated by immunohistochemistry in 106 ovarian cancer tissues. The association between ERs expression and clinicopathological parameters or prognosis was analyzed. Ectopic expression of ERβ2 and ERβ5 followed by functional assays were performed in ovarian cancer cell lines in order to detect their effects on cell invasion and proliferation.ResultsWe found significantly higher nuclear (n)ERα and nERβ5 and lower cytoplasmic (c)ERα expression in advanced cancers. Significantly lower ERβ1 expression was also detected in high grade cancers. Significant loss of nERα and cERβ2 expression were observed in clear cell histological subtypes. Higher nERβ5 and lower cERβ5 expression were associated with serous/clear cell subtypes, poor disease-free and overall survival. Positive cERα and higher cERβ1 expression were significantly associated with better disease-free and overall survival. Furthermore, we found nERβ5 as an independent prognostic factor for overall survival. Functionally, overexpression of ERβ5 enhanced ovarian cancer cell migration, invasion and proliferation via FAK/c-Src activation whereas ERβ2 induced cell migration and invasion.ConclusionsSince tamoxifen binds to both ERα and ERβ1 which appear to bear opposing oncogenic roles, the histotypes-specific expression pattern of ERs indicates that personalized treatment for women based on ERs expression using selective estrogen receptor modulators may improve response rate. This study also suggests nERβ5 as a potential prognostic marker and therapeutic target in ovarian cancer.

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Evidence of differential effects of vitamin d receptor variants on epithelial ovarian cancer risk by predicted vitamin d status.

Publications

Evidence of differential effects of vitamin d receptor variants on epithelial ovarian cancer risk by predicted vitamin d status.

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