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

TY - JOUR

T1 - Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome

AU - Favero, F

AU - McGranahan, N

AU - Salm, M

AU - Birkbak, N J

AU - Sanborn, J Z

AU - Benz, S C

AU - Becq, J

AU - Peden, J F

AU - Kingsbury, Z

AU - Grocok, R J

AU - Humphray, S

AU - Bentley, D

AU - Spencer-Dene, B

AU - Gutteridge, A

AU - Brada, M

AU - Roger, S

AU - Dietrich, P-Y

AU - Forshew, T

AU - Gerlinger, M

AU - Rowan, A

AU - Stamp, G

AU - Eklund, A C

AU - Szallasi, Z

AU - Swanton, C

N1 - © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

PY - 2015/5/1

Y1 - 2015/5/1

N2 - BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSION: 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.

AB - BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSION: 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.

KW - Adult

KW - Antineoplastic Agents, Alkylating/therapeutic use

KW - Brain Neoplasms/enzymology

KW - Chemotherapy, Adjuvant

KW - Chromosomes, Human

KW - Cyclin-Dependent Kinase 4/genetics

KW - Dacarbazine/analogs & derivatives

KW - Disease Progression

KW - Fatal Outcome

KW - Female

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Glioblastoma/enzymology

KW - Humans

KW - Imatinib Mesylate/therapeutic use

KW - Isocitrate Dehydrogenase/genetics

KW - Mutation

KW - Neoplasm Grading

KW - Neoplasm Recurrence, Local

KW - Neurosurgical Procedures

KW - Phenotype

KW - Protein Kinase Inhibitors/therapeutic use

KW - Proto-Oncogene Proteins c-kit/genetics

KW - Receptor, Platelet-Derived Growth Factor alpha/genetics

KW - Time Factors

KW - Treatment Outcome

U2 - 10.1093/annonc/mdv127

DO - 10.1093/annonc/mdv127

M3 - Journal article

C2 - 25732040

SN - 0923-7534

VL - 26

SP - 880

EP - 887

JO - Annals of Oncology

JF - Annals of Oncology

IS - 5

ER -