Abstract 1289: Evaluation of vitamin D receptor regulated genes reveals EGFR polymorphism is associated with high-grade serous ovarian cancer in African American women
Authors: Grant Delores J. , Manichaikul Ani , Peres Lauren C. , Wang Xin-Qun , Schwartz Ann G. , Wu Anna , Peters Edward , Moorman Patricia , Cote Michele L. , Bondy Melissa , Kelemen Linda E. , Barnholtz-Sloan Jill , Keku Temitope O. , Hoyo Cathrine , Berchuck Andrew , Pharoah Paul , Schildkraut Joellen M. ,   African American Cancer Epidemiology Study (AACES) and the Ovarian Cancer Assoc Consortium (OCAC)
Published: July 2017

Few studies have evaluated genetic risk factors for ovarian cancer in African American women. In a previous study with small sample sizes, Vitamin D Receptor (VDR) variants were shown to increase risk of epithelial ovarian cancer (EOC) in that population. This study sought to replicate those findings and assess gene variants from the VDR regulatory pathway. We assessed SNPs (genotyped+imputed) from 5 gene regions which included VDR and genes regulated by VDR, including UGT1A, UGT2B, CYP3A4/5 and EGFR in 755 EOC cases and 1,235 controls among women of African ancestry from the Ovarian Cancer Association Consortium (OCAC). We also performed analyses restricted to 537 patients with HGSOC represented in the overall analysis of EOC. SNPs were genotyped using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set for genotyped and imputed SNPs evaluated at the 5 gene regions (918 SNPs in UGT1A, 6302 SNPs in UGT2B, 410 SNPs in CYP3A4/5, and 824 SNPs in EGFR). Logistic regression was performed using an additive 1 degree of freedom model for genetic inheritance with adjustment for two principal components of ancestry to estimate odds ratios (OR) and 95 % confidence intervals (CI). For each gene region, we applied a gene-specific Bonferroni-threshold for statistical significance defined as 0.05 / number of SNPs examined for that gene. Based on this significance threshold, a statistically significant association with HGSOC was identified in the EGFR region for the imputed SNP, rs114972508 (per allele OR = 2.32, 95% CI = 1.58, 3.40 p=1.6e-05, imputation R-squared=0.89). We further identified suggestive associations (P &lt; 1.0e-06) with EOC for 10 imputed SNPs located within the UGT2B4 gene. We did not replicate previous associations in the 282 SNPs examined in the VDR gene for EOC overall or among HGSOC. In summary, we identified statistically significant association for variants from the EGFR region, and suggestive evidence of association for variants within the UGT2B region in genetic association analyses of ovarian cancer in women of African Ancestry. Data from in vitro experiments suggest that EGFR transcription and proliferative function is suppressed via VDR binding. Thus EGFR association with HGSOC may be a marker of VDR activity. UGT2B4 variants have not been previously explored in ovarian cancer but shown to be nominally associated with breast cancer in women of African ancestry. UGT2B4 enzymes, part of the phase II liver detoxification pathway, are important in the clearance of steroid hormones, bile acid and drug metabolism. Alterations in EGFR and UGT2B4 could perturb enzyme efficacy and proliferation in ovaries and impact susceptibility to ovarian cancer. Future studies will be needed to validate the associations of the imputed SNPs and to determine the impact of EGFR and UGT variants on cancer development.

Citation Format: Delores J. Grant, Ani Manichaikul, Lauren C. Peres, Xin-Qun Wang, Ann G. Schwartz, Anna Wu, Edward Peters, Patricia Moorman, Michele L. Cote, Melissa Bondy, Linda E. Kelemen, Jill Barnholtz-Sloan, Temitope O. Keku, Cathrine Hoyo, Andrew Berchuck, Paul Pharoah, Joellen M. Schildkraut, African American Cancer Epidemiology Study (AACES) and the Ovarian Cancer Assoc Consortium (OCAC). Evaluation of vitamin D receptor regulated genes reveals EGFR polymorphism is associated with high-grade serous ovarian cancer in African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1289. doi:10.1158/1538-7445.AM2017-1289