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Whole genome sequencing with linked reads of pediatric glioblastoma samples

Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand 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. In order to track the origins of the mutational events we 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) arose 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 to accumulate few mutations. Our results highlight the need for new targeted treatments that account for the complex functional hierarchies and genomic heterogeneity of pGBM.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001005212 HiSeq X Ten 26
Publications Citations
Intratumoral Genetic and Functional Heterogeneity in Pediatric Glioblastoma.
Cancer Res 79: 2019 2111-2123
21
Ancestry and frequency of genetic variants in the general population are confounders in the characterization of germline variants linked to cancer.
BMC Med Genet 21: 2020 92
1
Copy-scAT: Deconvoluting single-cell chromatin accessibility of genetic subclones in cancer.
Sci Adv 7: 2021 eabg6045
11