Intratumoral genetic and functional heterogeneity in pediatric glioblastoma

Cancer Research

March 15, 2019
Hoffman M, Gillmor A, Kunz DJ, Johnston MJ, Nikolic A, Narta K, Zarrei M, King JC, Ellestad K, Dang NH, Cavalli FMG, Kushida M, Coutinho FJ, Zhu Y, Luu B, Ma Y, Mungall AJ, Moore RA, Marra MA, Taylor M, Pugh TJ, Dirks PB, Strother D, Lafay-Cousin L, Resnick AC, Scherer SW, Senger DL, Simons BD, Chan JA, Morrissy AS, Gallo M.



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.