Dnar-01. Chromothripsis, One Major Genetic Instability Factor in Glioblastoma, Is Rare in Idh-Mutant Gliomas

Abstract

INTRODUCTION Adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas, and IDH-wildtype glioblastomas (GBM). GBM display genomic instability, which is favored by two genetic events leading to massive chromosomal alterations: chromothripsis (CT) and whole-genome duplication (WGD). Those events are scarcely described in IDH-mutant gliomas. The better prognosis of IDH-mutant gliomas may be in part related to their greater genomic stability compared to GBM. METHODS Pangenomic profiles of 301 adult diffuse gliomas were analyzed at initial diagnosis by SNP arrays, including 196 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 oligodendrogliomas). We further analyzed 16 IDH-mutant recurrent gliomas (11 astrocytomas and 5 oligodendrogliomas). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening. Survival data were compared using Kaplan-Meier method and categorical variables using Chi2 test. RESULTS At initial diagnosis, 37 GBM (18.8%) displayed CT (mainly affecting chromosomes 12, 9 and 7) versus five IDH-mutant gliomas (4.8%) (p = 0.0007). The latter were all high-grade astrocytomas. No oligodendroglioma or grade 2 astrocytoma displayed CT. There was a trend towards higher occurrence of CT in GBM versus high-grade IDH-mutant astrocytomas (p = 0.0589). WGD was detected at initial diagnosis in 18 GBM (9.2%) and 9 IDH-mutant gliomas (of any subtype and grade; 8.6%). Over 75% of chromosomal losses occurred after WGD. Neither CT nor WGD was associated with overall survival in GBM. At recurrence, one grade 4 IDH-mutant astrocytoma displayed CT and another one, WGD with CT. CONCLUSION CT is rare in IDH-mutant gliomas compared to GBM. The absence of CT in oligodendrogliomas and grade 2 astrocytomas may contribute to their greater genomic stability and better prognosis. CT occurrence in high-grade IDH-mutant astrocytomas may underlie aggressive biological behavior. WGD is a rare early event occurring equally in IDH-mutant gliomas and GBM.