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


CONCLUSIONS
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.
Cancer Research UK London Research Institute, London, United Kingdom; Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
F
F
Favero
Cancer Research UK London Research Institute, London, United Kingdom; Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London.
N
N
McGranahan
Cancer Research UK London Research Institute, London, United Kingdom.
M
M
Salm
Cancer Research UK London Research Institute, London, United Kingdom; University College London Cancer Institute, London, United Kingdom.
N J
NJ
Birkbak
NantOmics, LLC, Santa Cruz, USA.
J Z
JZ
Sanborn
NantOmics, LLC, Santa Cruz, USA.
S C
SC
Benz
Illumina Ltd, Cambridge.
J
J
Becq
Illumina Ltd, Cambridge.
J F
JF
Peden
Illumina Ltd, Cambridge.
Z
Z
Kingsbury
Illumina Ltd, Cambridge.
R J
RJ
Grocok
Illumina Ltd, Cambridge.
S
S
Humphray
Illumina Ltd, Cambridge.
D
D
Bentley
Cancer Research UK London Research Institute, London, United Kingdom.
B
B
Spencer-Dene
University College London Cancer Institute, London, United Kingdom.
A
A
Gutteridge
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool; Department of Radiation Oncology, Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, United Kingdom.
M
M
Brada
Department of Oncology, University Hospital Zurich, Zürich.
S
S
Roger
Centre of Oncology, University Hospitals of Geneva, Geneva, Switzerland.
P-Y
PY
Dietrich
University College London Cancer Institute, London, United Kingdom.
T
T
Forshew
Cancer Research UK London Research Institute, London, United Kingdom; Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.
M
M
Gerlinger
Cancer Research UK London Research Institute, London, United Kingdom.
A
A
Rowan
Cancer Research UK London Research Institute, London, United Kingdom.
G
G
Stamp
Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
A C
AC
Eklund
Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark; Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology (CHIP@HST), Harvard Medical School, Boston, USA; MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences, 2nd Department of Pathology, Semmelweis University, Budapest,Hungary.
Z
Z
Szallasi
Cancer Research UK London Research Institute, London, United Kingdom; University College London Cancer Institute, London, United Kingdom. Electronic address: charles.swanton@cancer.org.uk.
C
C
Swanton
D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D017024:Chemotherapy, Adjuvant; D002877:Chromosomes, Human; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018450:Disease Progression; D017809:Fatal Outcome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009154:Mutation; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D019635:Neurosurgical Procedures; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D000077204:Temozolomide; D013997:Time Factors; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D047428:Protein Kinase Inhibitors; D003606:Dacarbazine; D000068877:Imatinib Mesylate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D000077204:Temozolomide
double minute chromosome; glioblastoma; intra-tumour heterogeneity; multi-region sequencing