Vitamin D pathway gene variants and prostate cancer risk.
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ABSTRACT:
SUBMITTER: Holt SK
PROVIDER: S-EPMC2743676 | biostudies-literature | 2009 Jun
REPOSITORIES: biostudies-literature
Publications
Vitamin D pathway gene variants and prostate cancer risk.
Holt Sarah K SK Kwon Erika M EM Peters Ulrike U Ostrander Elaine A EA Stanford Janet L JL
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20090519 6
Vitamin D has antiproliferative, antiangiogenic, and apoptotic properties. There is some evidence supporting an association between vitamin D-related gene variants and prostate cancer risk. We report results from this population-based case-control study of genes encoding for the vitamin D receptor (VDR), the vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1), and deactivating enzyme 24-hydroxylase (CYP24A1). Forty-eight tagging single nucleotide polymorphisms (tagSNP) were analyzed in 827 ...[more]
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Project description:Heritability is one of the strongest risk factors of prostate cancer, emphasizing the importance of the genetic contribution towards prostate cancer risk. To date, 86 established prostate cancer risk variants have been identified by genome-wide association studies (GWAS). To determine if these risk variants are located near genes that interact together in biological networks or pathways contributing to prostate cancer initiation or progression, we generated gene sets based on proximity to the 86 prostate cancer risk variants. We took two approaches to generate gene lists. The first strategy included all immediate flanking genes, up- and downstream of the risk variant, regardless of distance from the index variant, and the second strategy included genes closest to the index GWAS marker and to variants in high LD (r2 ?0.8 in Europeans) with the index variant, within a 100 kb window up- and downstream. Pathway mapping of the two gene sets supported the importance of the androgen receptor-mediated signaling in prostate cancer biology. In addition, the hedgehog and Wnt/?-catenin signaling pathways were identified in pathway mapping for the flanking gene set. We also used the HaploReg resource to examine the 86 risk loci and variants high LD (r2 ?0.8) for functional elements. We found that there was a 12.8 fold (p = 2.9 x 10-4) enrichment for enhancer motifs in a stem cell line and a 4.4 fold (p = 1.1 x 10-3) enrichment of DNase hypersensitivity in a prostate adenocarcinoma cell line, indicating that the risk and correlated variants are enriched for transcriptional regulatory motifs. Our pathway-based functional annotation of the prostate cancer risk variants highlights the potential regulatory function that GWAS risk markers, and their highly correlated variants, exert on genes. Our study also shows that these genes may function cooperatively in key signaling pathways in prostate cancer biology.
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