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Cancer Res. 2019 Mar 15. pii: canres.3441.2018. doi: 10.1158/0008-5472.CAN-18-3441. [Epub ahead of print]

Intratumoral genetic and functional heterogeneity in pediatric glioblastoma.

Author information

1
Biochemistry & Molecular Biology, University of Calgary.
2
University of Calgary.
3
Department of Physics, University of Cambridge.
4
Biochemistry and Molecular Biology, University of Calgary.
5
BMB, University of Calgary.
6
Hospital for Sick Children.
7
Oncology, University of Calgary.
8
Brain Tumor Research Centre, Hospital for Sick Children.
9
Developmental and Stem Cell Biology, Hospital for Sick Children.
10
Neurosurgery, Children's Hospital of Philadelphia.
11
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, and Department of Medical Genetics, University of British Columbia.
12
Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency.
13
Genome Sciences Center, British Columbia Cancer Agency.
14
Genome Sciences Centre, BC Cancer.
15
The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children.
16
Princess Margaret Cancer Centre, University Health Network.
17
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children.
18
Pediatrics, University of Calgary.
19
Alberta Children's Hospital.
20
Department of Surgery, Children's Hospital of Philadelphia.
21
Department of Molecular Genetics, Hospital for Sick Children.
22
Oncology, Southern Alberta Cancer Research Institute, University of Calgary.
23
Physics, University of Cambridge.
24
Dept of Pathology and Laboratory Medicine, University of Calgary.
25
Physiology & Pharmacology, Biochemistry & Molecular Biology, University of Calgary marco.gallo@ucalgary.ca.

Abstract

Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand the mechanisms of tumor evolution in this cancer, we performed whole genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones. Clonal composition rapidly evolved at recurrence, with less than 8% of non-synonymous single nucleotide variants being shared in diagnostic-recurrent pairs. To track the origins of the mutational events observed in pGBM, we generated whole genome datasets for two patients and their parents. These trios showed that genetic variants could be (i) somatic, (ii) inherited from a healthy parent, or (iii) de novo in the germlines of pGBM patients. Analysis of variant allele frequencies supported a model of tumor growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to non-dividing cells. Interestingly, radiation and anti-mitotic chemotherapeutics did not increase overall tumor burden upon recurrence. These findings support an important role for slow-cycling stem cell populations in contributing to recurrences, since slow-cycling cell populations are expected to be less prone to genotoxic stress induced by these treatments and therefore would accumulate few mutations. Our results highlight the need for new targeted treatments that account for the complex functional hierarchies and genomic heterogeneity of pGBM.

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