Distinct germ line polymorphisms underlie glioma morphologic heterogeneity

Abstract

Two recent genome-wide association studies reported that single nucleotide polymorphisms (SNPs) in (or near) TERT (5p15), CCDC26 (8q24), CDKN2A/B (9p21), PHLDB1 (11q23), and RTEL1 (20q13) are associated with infiltrating glioma. From these reports, it was not clear whether the single nucleotide polymorphism associations predispose to glioma in general or whether they are specific to certain glioma grades or morphologic subtypes. To identify hypothesized associations between susceptibility loci and tumor subtype, we genotyped two case-control groups composed of the spectrum of infiltrating glioma subtypes and stratified the analyses by type. We report that specific germ line polymorphisms are associated with different glioma subtypes. CCDC26 (8q24) region polymorphisms are strongly associated with oligodendroglial tumor risk (rs4295627, odds ratio [OR] = 2.05, P = 8.3 × 10(-11)) but not glioblastoma risk. The opposite is true of RTEL (20q13) region polymorphisms, which are significantly associated with glioblastoma (rs2297440, OR = 0.56, P = 4.6 × 10(-10)) but not oligodendroglial tumor. The SNPs in or near CCDC26 (8q24) are associated with oligodendroglial tumors regardless of combined 1p and 19q deletion status; however, the association is greatest for those with combined deletion (rs4295627, OR = 2.77, P = 2.6 × 10(-9)). These observations generate hypotheses concerning the possible mechanisms by which specific SNPs (or alterations in linkage disequilibrium with such SNPs) are associated with glioma development.

Figure 1. Glioma Risk Stratified by Chromosomal Region and Morphology Type, Oligodendroglioma Grade and 1p/19q Codeletion Status

The single SNP within each region that was most strongly associated is illustrated. For comparative purposes, some SNP-associated risks (and their 95% confidence limits) have been inverted (see Supplemental Tables 2 and 3). P-values are given for case-control comparisons significant after correction for multiple testing. (MOA=mixed oligoastrocytoma, Oligo=oligodendroglioma, GBM=glioblastoma, AA=anaplastic astrocytoma, A2=astrocytoma grade 2, codel=codeleted)

Figure 2. Fine mapping of loci within the 8q24 region by tumor histologic type

−Log₁₀(p) values for 89 SNPs across the 8q24 region stratified by glioma morphologic subtype. Combined Mayo Clinic and UCSF data are shown. Mayo Clinic glioma cases (N=582) and controls (N=532), and UCSF oligodendroglioma (oligo) and mixed oligoastrocytoma (MOA) cases (N=191) and controls (N=192) were genotyped using the Illumina VeraCode platform. UCSF astrocytic glioma cases (N=673) and controls (602) were evaluated by the Illumina 370duo platform. For these latter gliomas, only 28 SNPs are illustrated. Arrows indicate the SNPs reported by Shete et al[3]. The recombination rate (in cM/mbase) across the region from HapMap release 27 (http://hapmap.ncbi.nlm.nih.gov/) is also shown.