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

In a glioblastoma tumour with multi-region sequencing before and after recurrence, we find an IDH1 mutation that is clonal in the primary but lost at recurrence. We also describe the evolution of a double-minute chromosome encoding regulators of the PI3K signalling axis that dominates at recurrence,...

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Bibliographic Details
Published in:	Annals of oncology Vol. 26; no. 5; pp. 880 - 887
Main Authors:	Favero, F., McGranahan, N., Salm, M., Birkbak, N.J., Sanborn, J.Z., Benz, S.C., Becq, J., Peden, J.F., Kingsbury, Z., Grocok, R.J., Humphray, S., Bentley, D., Spencer-Dene, B., Gutteridge, A., Brada, M., Roger, S., Dietrich, P.-Y., Forshew, T., Gerlinger, M., Rowan, A., Stamp, G., Eklund, A.C., Szallasi, Z., Swanton, C.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-05-2015 Oxford University Press
Series:	Editor's choice
Subjects:	Adult Antineoplastic Agents, Alkylating - therapeutic use Brain Neoplasms - enzymology Brain Neoplasms - genetics Brain Neoplasms - pathology Brain Neoplasms - therapy Chemotherapy, Adjuvant Chromosomes, Human Cyclin-Dependent Kinase 4 - genetics Dacarbazine - analogs & derivatives Dacarbazine - therapeutic use Disease Progression double minute chromosome Fatal Outcome Female Genetic Association Studies Genetic Predisposition to Disease glioblastoma Glioblastoma - enzymology Glioblastoma - genetics Glioblastoma - pathology Glioblastoma - therapy Humans Imatinib Mesylate - therapeutic use intra-tumour heterogeneity Isocitrate Dehydrogenase - genetics multi-region sequencing Mutation Neoplasm Grading Neoplasm Recurrence, Local Neurosurgical Procedures Original Phenotype Protein Kinase Inhibitors - therapeutic use Proto-Oncogene Proteins c-kit - genetics Receptor, Platelet-Derived Growth Factor alpha - genetics Temozolomide Time Factors Treatment Outcome double minute chromosome intra-tumour heterogeneity glioblastoma multi-region sequencing
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Summary:	In a glioblastoma tumour with multi-region sequencing before and after recurrence, we find an IDH1 mutation that is clonal in the primary but lost at recurrence. We also describe the evolution of a double-minute chromosome encoding regulators of the PI3K signalling axis that dominates at recurrence, emphasizing the challenges of an evolving and dynamic oncogenic landscape for precision medicine. 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 progressive evolution of the double-minute chromosome converging on the KIT/PDGFRA/PI3K/mTOR axis, superseding the IDH1 mutation in dominance in a mutually exclusive manner at recurrence, consequently the patient was treated with imatinib. Despite rapid sequencing and cancer genome-guided therapy against amplified oncogenes, the disease progressed, and the patient died shortly after. This case sheds light on the dynamic evolution of a GBM tumour, defining the origins of the lethal sub-clone, the macro-evolutionary genomic events dominating the disease at recurrence and the loss of a clonal driver. Even in the era of rapid WGS analysis, cases such as this illustrate the significant hurdles for precision medicine success.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	0923-7534 1569-8041
DOI:	10.1093/annonc/mdv127