Oncotarget

Research Papers:

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

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

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Oncotarget. 2018; 9:36017-36028. https://doi.org/10.18632/oncotarget.26330

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Abstract

Blandine Boisselier1,2, Frédéric Dugay3, Marc-Antoine Belaud-Rotureau3, Anne Coutolleau4, Emmanuel Garcion2, Philippe Menei5, Philippe Guardiola4 and Audrey Rousseau1,2

1Département de Pathologie Cellulaire et Tissulaire, CHU Angers, Angers, France

2CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France

3Laboratoire de Cytogénétique et Biologie Cellulaire, CHU Rennes, Rennes, France

4SERGOH, CHU Angers, Angers, France

5Département de Neurochirurgie, CHU Angers, Angers, France

Correspondence to:

Audrey Rousseau, email: AuRousseau@chu-angers.fr

Keywords: glioblastoma; whole genome duplication; aneuploidy; chromothripsis; SNP arrays

Received: July 05, 2018     Accepted: October 24, 2018     Published: November 13, 2018

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.


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