Subclonal Architecture, Evolutionary Trajectories and Patterns of Inheritance of Germline Variants in Pediatric Glioblastoma
Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. Intratumoral genetic heterogeneity and mode of tumour evolution have not been systematically addressed for this cancer. Whole-genome sequencing of germline-tumour pairs showed that pGBM is characterized by intratumoral genetic heterogeneity and consequent subclonal architecture. We found that pGBM undergoes extreme evolutionary trajectories, with primary and recurrent tumours having different subclonal compositions. Analysis of variant allele frequencies supported a model of tumour growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to non-dividing cells. pGBM patients’ germlines had subclonal structural variants, some of which underwent dynamic frequency fluctuations during tumour evolution. By sequencing germlines of mother-father-patient trios, we found that inheritance of deleterious germline variants from healthy parents cooperate with de novo germline and somatic events to the tumorigenic process. Our studies, therefore, challenge the current notion that pGBM is a relatively homogeneous molecular entity.
bioRχiv doi: https://doi.org/10.1101/434241
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