Abstract 2629: Common genetic variants in the vitamin D pathway including genome-wide associated variants in relation to glioma risk and outcome
Authors: Gabriella M. Anic, Reid C. Thompson, L B. Nabors, Jeffrey J. Olson, Melissa H. Madden, James E. Browning, Reed F. Murtagh, Peter A. Forsyth, Kathleen M. Egan
Journal: Cancer Research (2012)

Abstract Experimental and clinical evidence suggest that vitamin D protects against several types of cancer by promoting cell differentiation and apoptosis and by inhibiting cell proliferation and angiogenesis. In vitro evidence supports a similar protective function in glioma; however, no study has examined whether common genetic variants in the vitamin D pathway are related to glioma risk or patient outcome. We evaluated these potential associations in a clinic-based case-control study conducted at medical centers in the southeastern US. Genotyping was performed in 623 newly diagnosed (eg. nonrecurrent) glioma cases (including 343 WHO grade IV glioblastomas (GBM); 148 WHO grade II or III astrocytomas, 95 oligoastrocytomas and oligodendrogliomas, and 37 gliomas with unspecified histology) and 631 healthy controls with no history of brain tumors. A total of 7 candidate tagging single nucleotide polymorphisms (SNPs) were genotyped in the vitamin D receptor (VDR at 12q13) including rs2107301, rs2238135, rs4516035, rs731236 (Taq1), rs1544410 (Bsm1), rs11568820 (Cdx2), and rs2228570 (Fok1). SNPs associated with serum concentrations of 25-hydroxy vitamin D in genome-wide association studies (GWAS) were also evaluated including rs1155563, rs12512631, rs2282679, and rs7041 in GC (4q12-q13), rs10741657 in CYP2R1 (11p15), rs6013897 in CYP24A1 (20q13), rs3829251 in NADSYN1 (11q13), and rs6599638 at C10orf88 (10q26). Genotyping was performed in oral DNA samples using Illumina GoldenGate and Taqman OpenArray assays. Logistic regression was used to estimate age and gender-adjusted odds ratios (OR) and 95% confidence intervals (CI) for glioma risk according to vitamin D genotypes. Proportional hazards regression was used to estimate age and gender-adjusted hazard ratios (HR) for glioma-related death among 439 patients with high grade tumors including GBM and high grade astrocytomas (331 deaths; median Kaplan-Meier survival: 15.0 months). GWAS SNPs in NADSYN1, GC, and C10ORF88 were not associated with glioma risk or patient survival. Risk associations limited to GBM were observed for rs2238135 in the VDR (G&amp;gt;C; minor allele frequency (MAF) = 0.20) (per variant allele OR = 1.31; 95% CI: 1.01 to 1.71; p for trend = 0.04) and for GWAS SNP rs10741657 located near CYP2R1 (G&amp;gt;A; MAF = 0.40) (per variant allele OR = 0.79; 95% CI: 0.63 to 0.98; p for trend = 0.03). The variant allele in CYP24A1 rs6013897 (T&amp;gt;A; MAF = 0.20) was associated with prolonged survival among patients with high grade tumors (per variant allele HR = 0.79; 95% CI: 0.59 to 0.97; p for trend = 0.03) in patients uniformly treated with the current standard of care (surgery, radiation and temozolomide). To our knowledge this is the first report suggesting that genetic variation in vitamin D related genes may be a determinant of glioma risk and outcome. Further studies are needed to confirm these results and identify the putative causal variant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2629. doi:1538-7445.AM2012-2629