Dataset Information

Circadian pathway genes in relation to glioma risk and outcome.

ABSTRACT: There is growing evidence that circadian disruption may alter risk and aggressiveness of cancer. We evaluated common genetic variants in the circadian gene pathway for associations with glioma risk and patient outcome in a US clinic-based case-control study.Subjects were genotyped for 17 candidate single nucleotide polymorphisms in ARNTL, CRY1, CRY2, CSNK1E, KLHL30, NPAS2, PER1, PER3, CLOCK, and MYRIP. Unconditional logistic regression was used to estimate age and gender-adjusted odds ratios (OR) and 95 % confidence intervals (CI) for glioma risk under three inheritance models (additive, dominant, and recessive). Proportional hazards regression was used to estimate hazard ratios for glioma-related death among 441 patients with high-grade tumors. Survival associations were validated using The Cancer Genome Atlas (TCGA) dataset.A variant in PER1 (rs2289591) was significantly associated with overall glioma risk (per variant allele OR 0.80; 95 % CI 0.66-0.97; p trend = 0.027). The variant allele for CLOCK rs11133391 under a recessive model increased risk of oligodendroglioma (OR 2.41; 95 % CI 1.31-4.42; p = 0.005), though not other glioma subtypes (p for heterogeneity = 0.0033). The association remained significant after false discovery rate adjustment (p = 0.008). Differential associations by gender were observed for MYRIP rs6599077 and CSNK1E rs1534891 though differences were not significant after adjustment for multiple testing. No consistent mortality associations were identified. Several of the examined genes exhibited differential expression in glioblastoma multiforme versus normal brain in TCGA data (MYRIP, ARNTL, CRY1, KLHL30, PER1, CLOCK, and PER3), and expression of NPAS2 was significantly associated with a poor patient outcome in TCGA patients.This exploratory analysis provides some evidence supporting a role for circadian genes in the onset of glioma and possibly the outcome of glioma.

SUBMITTER: Madden MH

PROVIDER: S-EPMC3947318 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Circadian pathway genes in relation to glioma risk and outcome.

Madden Melissa H MH Anic Gabriella M GM Thompson Reid C RC Nabors L Burton LB Olson Jeffrey J JJ Browning James E JE Monteiro Alvaro N AN Egan Kathleen M KM

Cancer causes & control : CCC 20131018 1

<h4>Purpose</h4>There is growing evidence that circadian disruption may alter risk and aggressiveness of cancer. We evaluated common genetic variants in the circadian gene pathway for associations with glioma risk and patient outcome in a US clinic-based case-control study.<h4>Methods</h4>Subjects were genotyped for 17 candidate single nucleotide polymorphisms in ARNTL, CRY1, CRY2, CSNK1E, KLHL30, NPAS2, PER1, PER3, CLOCK, and MYRIP. Unconditional logistic regression was used to estimate age and ...[more]

PMID: 24135790

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Project description:Genome-wide association studies and candidate gene studies have identified several genetic variants that increase glioma risk. The majority of these variants are non-coding and the mechanisms behind the increased risk in carriers are not known. In this study, we hypothesize that some of the established glioma risk variants induce aberrant DNA methylation in the developing tumor, either locally (gene-specific) or globally (genome-wide). In a pilot data set including 77 glioma patients, we used Illumina beadchip technology to analyze genetic variants in blood and DNA methylation in matched tumor samples. To validate our findings, we used data from the Cancer Genome Atlas, including 401 glioblastoma patients. Consensus clustering identified the glioma CpG island methylator phenotype (gCIMP) and two additional subgroups with distinct patterns of global DNA methylation. In the pilot dataset, gCIMP was associated with two genetic variants in CDKN2B-AS1, rs1412829 and rs4977756 (9p21.3, p = 8.1 x 10-7 and 4.8 x 10-5, respectively). The association was in the same direction in the TCGA dataset, although statistically significant only when combining individuals with AG and GG genotypes. We also investigated the relation between glioma risk variants and DNA methylation in the promoter region of genes located within 30 kb of each variant. One association in the pilot dataset, between the TERT risk variant rs2736100 and lower methylation of cg23827991 (in TERT; p = 0.001), was confirmed in the TCGA dataset (p = 0.001). In conclusion, we found an association between rs1412829 and rs4977756 (9p21.3, CDKN2B-AS1) and global DNA methylation pattern in glioma, for which a trend was seen also in the TCGA glioblastoma dataset. We also found an association between rs2736100 (in TERT) and levels of methylation at cg23827991 (localized in the same gene, 3.3 kbp downstream of the risk variant), which was validated in the TCGA dataset. Except for this one association, we did not find strong evidence for gene-specific DNA methylation mediated by glioma risk variants.

Dataset Information

Circadian pathway genes in relation to glioma risk and outcome.

Publications

Circadian pathway genes in relation to glioma risk and outcome.

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