MUTATION-BASED MOLECULAR GLIOMA CLASSIFICATION: PREVALENCE AND ASSOCIATION WITH GERMLINE RISK SNPS

Abstract

BACKGROUND: Specific germline alterations within TERT, EGFR, CCDC26, CDKN2A/B, PHLDB1, TP53 and RTEL1 are associated with development of glioma. While germline variants in TERT are associated with all gliomas, others are associated with specific morphologic and/or molecular subtypes. For example, the RTEL1 region variants are associated with primary glioblastoma and rs55705857 in CCDC26 is associated with 1p/19q co-deleted oligodendrogliomas and with IDH mutant astrocytic gliomas. We hypothesize that germline variants will be associated with specific molecular glioma subtypes recently defined by the Cancer Genome Atlas (TCGA) and other groups. In this study we grouped Mayo Clinic and TCGA high- and low-grade glioma patients into somatic mutation-defined molecular subgroups, regardless of grade, based on three molecular alterations. We then determined if germline polymorphisms are associated with these mutation-based molecular subtypes. METHODS: Five molecular subtypes were defined based on combinations of the following molecular alterations: TERT promoter mutation (TERT mut vs. TERT wt), IDH1/2 mutation (IDH mut vs. IDH wt) and 1p/19q co-deletion (1p19q codel vs. 1p19q noncodel). Germline single nucleotide polymorphisms (SNPs) were evaluated by array analysis of blood-derived DNA (Mayo) and 1K genome imputation (TCGA). RESULTS: 207 Mayo Clinic and 402 TCGA gliomas had both germline SNP and mutation data available. The acquired mutation data defined five molecular subgroups (Table). The prevalence of each of these subtypes were very similar in the Mayo and TCGA cohorts, (Table). In both the Mayo Clinic and TCGA cohorts various SNPs were associated with the development of specific subtypes (Table). Further validation using a UCSF cohort, as well as analyses of grade, subtype and survival are underway. Table Prevalence of Mutation-based Acquired Molecular Glioma Subtypes and Their Germline SNP Associations