Abstract 2794: Genetic variations in vitamin D-related pathways and breast cancer risk in African American women
Authors: Yao Song , Hong Chi-Chen , Lunetta Kathryn , Haddad Stephen , Ruiz-Narvaez Edward , Hu Qiang , Zhu Qianqian , Liu Song , Sucheston-Campbell Lara , Haiman Christopher , Olshan Andrew , Palmer Julie , Ambrosone Christine 
Published: August 2015

Abstract
Background: Experimental studies support anti-tumor properties of vitamin D for breast cancer (BC), which have yet to be conclusively demonstrated in epidemiological studies. Common genetic variations in the vitamin D-related pathways have also been studied with BC risk, mostly in populations of European ancestry. Studies in populations of African ancestry (AA), known for a high prevalence of vitamin D deficiency due to high skin pigmentation, have been sparse.
Methods: We examined 69 genes from three vitamin D-related pathways: vitamin D metabolism and signaling, pigmentation synthesis and metabolism, and UV exposure response in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. Tagging single nucleotide polymorphisms (SNPs) were selected and genotyped in a customized Illumina Exome Array, followed by systematic imputation using 1000 Genomes haplotypes. The analytical dataset included 25,295 variants with a minor allele frequency (MAF) of 0.006 or above from the targeted genetic regions in 3,663 breast cancer cases and 4,687 controls. Odds ratios (OR) were derived from multivariable logistic regression models for risk associated with overall BC as well as by estrogen receptor (ER) status (1,983 ER positive and 1,098 ER negative). Case-case analyses were also performed.
Results: Among the three vitamin D-related pathways, genes involved in UV exposure response appear to be the top ones associated with BC risk overall and by ER status. The most significant genes in this pathway included: REV1 for overall BC (OR for the T allele of rs9308822 = 0.86, p = 1e-4), similar for both ER+ and ER- BC; ERCC6 for ER-positive BC (OR for the T allele of rs114723899 = 0.62, p = 4e-5); and DDB2 for ER-negative BC (OR for the G allele of rs4647707 = 1.26, p = 4e-5). For the skin pigmentation pathway, the most significant genes were SLC24A2 with ER-negative BC (top SNP rs4900134 p = 1e-4), and OCA2 associated with ER-negative vs. ER-positive status (top SNP rs144465989 p = 6e-5). For the vitamin D metabolism and signaling pathway, the most significant gene was CASR associated with ER-negative vs. ER-positive status (top SNP rs112594756 p = 7e-5). Only one of the commonly studied VDR SNPs, ApaI or rs7975232, was marginally associated with ER-positive BC (OR = 1.11, p = 0.05) in this study of AA women. Gene-level and pathway-level analyses and for multiple testing correction are ongoing.
Conclusion: In a comprehensive study of vitamin D-related genetic variations in AA women, we found several genes involved in UV exposure response most significantly associated with BC risk overall and by ER status. Because those genes are also involved in DNA damage and repair pathways, findings should be interpreted with caution due to their roles in cutaneous synthesis of vitamin D.
Citation Format: Song Yao, Chi-Chen Hong, Kathryn Lunetta, Stephen Haddad, Edward Ruiz-Narvaez, Qiang Hu, Qianqian Zhu, Song Liu, Lara Sucheston-Campbell, Christopher Haiman, Andrew Olshan, Julie Palmer, Christine Ambrosone. Genetic variations in vitamin D-related pathways and breast cancer risk in African American women. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2794. doi:10.1158/1538-7445.AM2015-2794