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Subclonal architecture, evolutionary trajectories and patterns of inheritance of germline variants in pediatric glioblastoma

By Mary Hoffman, Aaron H Gillmor, Daniel J. Kunz, Michael Johnston, Ana Nikolic, Kiran Narta, Jennifer King, Katrina Ellestad, Ngoc Ha Dang, Florence MG Cavalli, Michelle M Kushida, Fiona J Coutinho, Betty Luu, Yussanne Ma, Andrew J. Mungall, Richard Moore, Marco A. Marra, Michael D Taylor, Trevor J. Pugh, Peter B Dirks, Donna L Senger, Benjamin D. Simons, Jennifer A Chan, A Sorana Morrissy, M. Gallo

Posted 12 Oct 2018
bioRxiv DOI: 10.1101/434241 (published DOI: 10.1158/0008-5472.CAN-18-3441)

Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. Intratumoral genetic heterogeneity and mode of tumor evolution have not been systematically addressed for this cancer. Whole-genome sequencing of germline-tumor 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 tumors having different subclonal compositions. 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. pGBM patient germlines had subclonal structural variants, some of which underwent dynamic frequency fluctuations during tumor 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.

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