Subclonal architecture, evolutionary trajectories and patterns of inheritance of germline variants in pediatric glioblastoma
Subclonal architecture, evolutionary trajectories and patterns of inheritance of germline variants in pediatric glioblastoma
Abstract 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 patients’ 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.
Gillmor Aaron H、Luu Betty、Marra Marco A、Cavalli Florence MG、Mungall Andrew J、Moore Richard、Pugh Trevor J、Senger Donna L、Narta Kiran、King Jennifer、Dang Ngoc Ha、Hoffman Mary、Dirks Peter B、Taylor Michael D、Kunz Daniel J、Ellestad Katrina、Chan Jennifer A、Coutinho Fiona J、Nikolic Ana、Johnston Michael、Kushida Michelle M、Morrissy A Sorana、Gallo Marco、Simons Benjamin D、Ma Yussanne
Department of Biochemistry and Molecular Biology, University of Calgary||Alberta Children?ˉs Hospital Research Institute, University of Calgary||Charbonneau Cancer Institute, University of CalgaryThe Hospital for Sick Children Research Institute, Arthur and Sonia Labatt Brain Tumour Research CentreCanada?ˉs Michael Smith Genome Sciences CentreThe Hospital for Sick Children Research Institute, Arthur and Sonia Labatt Brain Tumour Research CentreCanada?ˉs Michael Smith Genome Sciences CentreCanada?ˉs Michael Smith Genome Sciences CentrePrincess Margaret Cancer Centre, University Health NetworkAlberta Children?ˉs Hospital Research Institute, University of Calgary||Charbonneau Cancer Institute, University of Calgary||Department of Oncology, University of CalgaryDepartment of Biochemistry and Molecular Biology, University of Calgary||Alberta Children?ˉs Hospital Research Institute, University of Calgary||Charbonneau Cancer Institute, University of CalgaryAlberta Children?ˉs Hospital Research Institute, University of Calgary||Charbonneau Cancer Institute, University of CalgaryAlberta Children?ˉs Hospital Research Institute, University of Calgary||Charbonneau Cancer Institute, University of CalgaryDepartment of Biochemistry and Molecular Biology, University of Calgary||Alberta Children?ˉs Hospital Research Institute, University of Calgary||Charbonneau Cancer Institute, University of CalgaryThe Hospital for Sick Children Research Institute, Arthur and Sonia Labatt Brain Tumour Research Centre||Department of Molecular Genetics, University of TorontoThe Hospital for Sick Children Research Institute, Arthur and Sonia Labatt Brain Tumour Research CentreCavendish Laboratory, Department of Physics, University of Cambridge||The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge||The Wellcome Trust/Medical Research Council Stem Cell Institute, University of CambridgeAlberta Children?ˉs Hospital Research Institute, University of Calgary||Charbonneau Cancer Institute, University of CalgaryAlberta Children?ˉs Hospital Research Institute, University of Calgary||Charbonneau Cancer Institute, University of Calgary||Department of Pathology and Laboratory Medicine, University of Calgary, CalgaryThe Hospital for Sick Children Research Institute, Arthur and Sonia Labatt Brain Tumour Research CentreDepartment of Biochemistry and Molecular Biology, University of Calgary||Alberta Children?ˉs Hospital Research Institute, University of Calgary||Charbonneau Cancer Institute, University of CalgaryAlberta Children?ˉs Hospital Research Institute, University of Calgary||Charbonneau Cancer Institute, University of CalgaryThe Hospital for Sick Children Research Institute, Arthur and Sonia Labatt Brain Tumour Research CentreDepartment of Biochemistry and Molecular Biology, University of Calgary||Alberta Children?ˉs Hospital Research Institute, University of Calgary||Charbonneau Cancer Institute, University of CalgaryDepartment of Biochemistry and Molecular Biology, University of Calgary||Alberta Children?ˉs Hospital Research Institute, University of Calgary||Charbonneau Cancer Institute, University of Calgary||Department of Physiology and Pharmacology, University of CalgaryCavendish Laboratory, Department of Physics, University of Cambridge||The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge||The Wellcome Trust/Medical Research Council Stem Cell Institute, University of CambridgeCanada?ˉs Michael Smith Genome Sciences Centre
肿瘤学基础医学遗传学
Gillmor Aaron H,Luu Betty,Marra Marco A,Cavalli Florence MG,Mungall Andrew J,Moore Richard,Pugh Trevor J,Senger Donna L,Narta Kiran,King Jennifer,Dang Ngoc Ha,Hoffman Mary,Dirks Peter B,Taylor Michael D,Kunz Daniel J,Ellestad Katrina,Chan Jennifer A,Coutinho Fiona J,Nikolic Ana,Johnston Michael,Kushida Michelle M,Morrissy A Sorana,Gallo Marco,Simons Benjamin D,Ma Yussanne.Subclonal architecture, evolutionary trajectories and patterns of inheritance of germline variants in pediatric glioblastoma[EB/OL].(2025-03-28)[2025-08-22].https://www.biorxiv.org/content/10.1101/434241.点此复制
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