Abstract 104: Toenail iron, genetic variation in iron status, and the risk and outcome of glioma .
Authors: Anic Gabriella M. , Thompson Reid C. , Nabors L. Burton , Olson Jeffrey J. , Madden Melissa H. , Browning James E. , Brockman John D. , Forsyth Peter A. , Egan Kathleen M. 
Published: August 2014

Elevated iron stores can trigger overproduction of reactive oxygen species and induce oxidative DNA damage. To our knowledge, no studies have investigated the association of body iron stores with the risk of glioma. In this investigation, we examined single nucleotide polymorphisms (SNPs) identified as markers of iron status in genome-wide association studies, and also measured iron stores in toenail samples in a clinic-based case-control study conducted at medical centers in the southeastern US. Genotyping was performed in 622 newly diagnosed, nonrecurrent glioma cases (including 341 WHO grade IV glioblastomas (GBM); 146 WHO grade II or III astrocytomas, 94 mixed oligoastrocytomas (MOAs) and oligodendrogliomas, and 41 gliomas with unspecified histology) and 628 healthy controls with no history of brain tumors. Illumina GoldenGate and Taqman OpenArray assays were used to genotype oral DNA samples. A total of 24 SNPs associated with markers of iron status were genotyped. Iron levels in toenail samples were measured in 200 glioma cases and 200 controls using neutron-activation analysis. Logistic regression was used to estimate age and gender-adjusted odds ratios (OR) and 95% confidence intervals (CI) for glioma risk according to examined genotypes and toenail iron levels. Proportional hazards regression was used to estimate age and gender-adjusted hazard ratios (HR) for glioma-related death among 320 patients with GBM or high grade astrocytomas all treated with the current standard of care for high grade glioma (eg. surgery, radiation and temozolomide) (248 deaths; median Kaplan-Meier survival: 15.0 months). We observed no overall association with glioma risk or patient outcome for SNPs in ARSB, BTN1A1, C7ORF10, FLJ43390, GHR, GTSCR1, HFE, HIST1H2BJ, KRT18P33, LRRC16, SCGN, SLC17A1, TOPBP1, and WTAP. Among non-GBM astrocytomas, borderline risk associations were observed for rs236918 in PCSK7 (G&gt;C; minor allele frequency (MAF) = 0.11) (per variant allele OR = 0.50; 95% CI: 0.29 to 0.88; p for trend = 0.01) and with rs1049296 in TF (C&gt;T; MAF = 0.17) (recessive model OR = 3.03; 95% CI: 1.11 to 8.27; p = 0.03). Among oligodendrogliomas/MOAs, risk associations were observed for rs4820268 in TMPRSS6 (A&gt;G; MAF = 0.43) (recessive model OR = 1.91; 95% CI: 1.14 to 3.22; p = 0.01) and rs12216125 in TRIM38 (C&gt;T; MAF = 0.35) (dominant model OR = 1.67; 95% CI: 1.03 to 2.72; p = 0.04). No SNPs were associated with the risk of GBM. One SNP, rs972275 in RSPO3 (G&gt;C; MAF = 0.38), was associated with shorter patient survival (dominant model HR = 1.40; 95% CI: 1.06, 1.87; p=0.02). Increasing levels of toenail iron was associated with a non-significant decrease in glioma risk (OR = 0.88; 95% CI: 0.77 to 1.02; p = 0.08). Iron levels were not associated with survival. To our knowledge this is the first report suggesting that genetically determined variation in iron status may affect glioma risk and patient outcome. Further studies are needed to confirm these results.

Citation Format: Gabriella M. Anic, Reid C. Thompson, L. Burton Nabors, Jeffrey J. Olson, Melissa H. Madden, James E. Browning, John D. Brockman, Peter A. Forsyth, Kathleen M. Egan. Toenail iron, genetic variation in iron status, and the risk and outcome of glioma . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 104. doi:10.1158/1538-7445.AM2013-104