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Nature. 2018 Mar 15;555(7696):371-376. doi: 10.1038/nature25795. Epub 2018 Feb 28.

Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours.

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Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
Independent Researcher, Chicago, Illinois 60654, USA.
Oncology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland 20892, USA.
Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland 20892, USA.
Division of Hematology-Oncology, Connecticut Children's Medical Center, Hartford, Connecticut 06106, USA.
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA.
Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois 60208, USA.


Analysis of molecular aberrations across multiple cancer types, known as pan-cancer analysis, identifies commonalities and differences in key biological processes that are dysregulated in cancer cells from diverse lineages. Pan-cancer analyses have been performed for adult but not paediatric cancers, which commonly occur in developing mesodermic rather than adult epithelial tissues. Here we present a pan-cancer study of somatic alterations, including single nucleotide variants, small insertions or deletions, structural variations, copy number alterations, gene fusions and internal tandem duplications in 1,699 paediatric leukaemias and solid tumours across six histotypes, with whole-genome, whole-exome and transcriptome sequencing data processed under a uniform analytical framework. We report 142 driver genes in paediatric cancers, of which only 45% match those found in adult pan-cancer studies; copy number alterations and structural variants constituted the majority (62%) of events. Eleven genome-wide mutational signatures were identified, including one attributed to ultraviolet-light exposure in eight aneuploid leukaemias. Transcription of the mutant allele was detectable for 34% of protein-coding mutations, and 20% exhibited allele-specific expression. These data provide a comprehensive genomic architecture for paediatric cancers and emphasize the need for paediatric cancer-specific development of precision therapies.

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