Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome

Annals of Oncology : Official Journal of the European Society for Medical Oncology
F FaveroCharles Swanton

Abstract

Glioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches. We describe a 35-year-old female patient with recurrent GBM following surgical removal of the primary tumour, adjuvant treatment with temozolomide and a 3-year disease-free period. Rapid whole-genome sequencing (WGS) of three separate tumour regions at recurrence was carried out and interpreted relative to WGS of two regions of the primary tumour. We found extensive mutational and copy-number heterogeneity within the primary tumour. We identified a TP53 mutation and two focal amplifications involving PDGFRA, KIT and CDK4, on chromosomes 4 and 12. A clonal IDH1 R132H mutation in the primary, a known GBM driver event, was detectable at only very low frequency in the recurrent tumour. After sub-clonal diversification, evidence was found for a whole-genome doubling event and a translocation between the amplified regions of PDGFRA, KIT and CDK4, encoded within a double-minute chromosome also incorporating miR26a-2. The WGS analysis uncovered ...Continue Reading

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Citations

Oct 13, 2015·Nature Reviews. Cancer·Francesc Castro-GinerIan Tomlinson
Mar 1, 2016·Gastroenterology·Nicolai Juul Birkbak, Jesper B Andersen
Apr 14, 2017·Annals of Oncology : Official Journal of the European Society for Medical Oncology·M A QaziS K Singh
May 17, 2018·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Deepika SirohiDaniel J Luthringer
Jan 30, 2019·International Journal of Cancer. Journal International Du Cancer·Eszter NémethDávid Szüts
Sep 17, 2017·Proceedings of the National Academy of Sciences of the United States of America·Tali MazorJoseph F Costello
Jun 26, 2020·Cancers·Kambiz AfrasiabiYi-Hong Zhou
Nov 23, 2018·BMC Molecular Biology·Jean-Michel LeméePhilippe Menei
Jul 16, 2017·International Journal of Cancer. Journal International Du Cancer·Mehmet BaysanHoward A Fine
Jun 21, 2015·Cancer Discovery·Charles SwantonReuben S Harris
Aug 9, 2021·Progress in Biophysics and Molecular Biology·Krishna DasariJeffrey P Townsend

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Methods Mentioned

BETA
PCR
flow cytometry
biopsies

Software Mentioned

cBIO
DPpackage R package
ANNOVAR
R
VarScan2
Sequenza

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