Whole genome duplication is an early event leading to aneuploidy in IDH-wild type glioblastoma.

Blandine Boisselier,Philippe Menei,Audrey Rousseau,Marc-Antoine Belaud-Rotureau,Frédéric Dugay,Philippe Guardiola,Emmanuel Garcion,Anne Coutolleau

doi:10.18632/oncotarget.26330

Abstract

Glioblastoma, the most frequent and lethal form of glioma, displays chromosome instability and recurrent somatic copy number alterations (SCNA). Chromothripsis and whole genome duplication (WGD) have been recently identified in cancer. In the present study, we analyzed SCNA and determine the ploidy pattern in 123 IDH-wild-type glioblastomas, using SNP array data. WGD and chromothripsis events were validated using, respectively, FISH and CTLPScanner. WGD was detected in 11.4% glioblastomas (14/123) and was associated with TP53 mutation (p = 0.0068). It was an early event occurring after the recurrent SCNA observed in diffuse high-grade gliomas. Glioblastomas with WGD were more aneuploid compared to glioblastomas without WGD (p < 0.0001). Chromothripsis occurred in 29.3% glioblastomas (36/123) and mostly affected chromosomes 7, 9 and 12, with amplification of oncogenes (EGFR, MDM2/CDK4), and homozygous deletion of tumor suppressor genes (CDKN2A). There was a significant association between chromothripsis and gene rearrangement at a given locus. WGD is an early genetic event significantly associated to TP53 mutation and leading to chromosome instability and aneuploidy in IDH-wild-type glioblastoma. Chromothripsis recurrently targets oncogenes and tumor suppressor genes that are key players in gliomagenesis and tumor progression. The occurrence of chromothripsis points to underlying gene rearrangements (including gene fusions), potential therapeutic targets in glioblastoma.

Highlights

Glioblastoma (GBM) is the most frequent and most aggressive form of diffuse glioma
We studied whole genome duplication (WGD) and CT in a large series of 123 primary IDH-wild-type GBM independent from the TCGA GBM cohort
The frequency is highly variable across tumor types; carcinomas from the ovary, breast, lung, and esophagus have an incidence of genome doubling of about 50% whereas WGD has not been observed in leukemia [7]

Summary

INTRODUCTION

Glioblastoma (GBM) is the most frequent and most aggressive form of diffuse glioma. The prognosis is very poor, with a median overall survival of 15 months after maximum safe resection and radiochemotherapy [1]. Even if somatic CNA (SCNA) have been well described in GBM, general mechanisms leading to massive rearrangements implicating several, if not all, chrs are not well understood. Among these www.oncotarget.com mechanisms, whole genome duplication (WGD) leads to tetraploidization of cells, which may pave the way to aneuploidy [3]. CT is a recently described phenomenon whereby massive chr shattering occurs during a single (mitotic) event [9]. CT has recently been proposed as a novel mechanism for genetic instability and cancer development It has been reported in a broad range of tumors (prostate carcinomas, multiple myelomas, GBM, medulloblastomas, neuroblastomas) [10, 11]. We investigated WGD and CT events in a series of 123 primary IDH-wild-type GBM and correlated the results with the survival data

RESULTS

DISCUSSION

MATERIALS AND METHODS