Relation between Established Glioma Risk Variants and DNA Methylation in the Tumor

PLoS One. 2016 Oct 25;11(10):e0163067. doi: 10.1371/journal.pone.0163067. eCollection 2016.

Abstract

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.

MeSH terms

  • Brain Neoplasms / genetics*
  • CpG Islands
  • DNA Methylation*
  • Databases, Genetic
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Glioblastoma / genetics
  • Glioma / genetics*
  • Humans
  • Oligodendroglioma / genetics
  • Pilot Projects
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic
  • RNA, Long Noncoding / genetics*
  • Telomerase / genetics*

Substances

  • CDKN2B antisense RNA, human
  • RNA, Long Noncoding
  • TERT protein, human
  • Telomerase

Grants and funding

This work was supported by Acta Oncologica Foundation through the Royal Swedish Academy of Science (BM salary), the Swedish Cancer Foundation (BM), the Swedish Research council (BM), the Cancer Research Foundation in Northern Sweden (BM), and Umeå University Hospital (cutting edge grant and Umeå University Young Investigator Award; BM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.