Germline polymorphisms in (or near) CDKN2A/B, RTEL1, TERT, and CCDC26 are differentially associated with glioma grade and morphologic subtype

Abstract

BACKGROUND: Two recent genome-wide association studies (GWAS), including one from UCSF/Mayo reported that single nucleotide polymorphisms (SNPs) in (or near) CDKN2A/B, RTEL1, TERT, or CCDC26 are associated with adult glioma development. These reports did not directly determine if the SNP associations are with all adult gliomas or with specific glioma morphologic subtypes or grades. We report a reanalysis of UCSF/Mayo cases stratified by morphologic grade and subtype of glioma. METHODS: Germline DNA from 681 and 582 patients with gliomas from USCF and Mayo, respectively, as well as from 602 and 532 controls from USCF and Mayo, respectively, was analyzed using Illumina SNP platforms. Collectively, the cases included 740 grade 4 glioblastomas (GBM), 220 grade 3 (AA), 104 grade 2 astrocytomas (A2), 81 oligodendrogliomas (O), and 118 mixed oligoastrocytomas (MOA). RESULTS: SNPs in or near CCDC26 (8q24) (e.g. rs 4295627) are associated with the development of O/MOA but not GBM (P = 6.34 null 10-9 and 0.35, respectively). SNPs in or near RTEL1 (20q13, e.g. rs6010620) are associated with the development of GBM but not O/MOA (P = 1.08 null 1028 and 0.17, respectively). A SNP within TERT (5p15, rs2736100) is associated with the development of both GBM and AA, but not O/MOA (P = 2.67 null 10-6, 7.00 null 10-4 and 0.025, respectively). SNPs in or near CDKN2A/B (9p21, e.g. rs2157719) are associated with the development of both GBM and A2/AA, but not O/MOA (P = 2.48 null 10-5, 5.6 null 10-3 and 0.87, respectively). CONCLUSIONS: Germline polymorphisms are likely associated with the development of different morphologic subtypes and histologic grades of glioma. These observations can be used to generate hypotheses concerning the possible mechanisms by which specific SNPs (or alterations in linkage disequilibrium with such SNPs) are associated with glioma development.