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

Xiaotu Ma
Yu Liu
Yanling Liu
Ludmil B Alexandrov
Michael N Edmonson
Charles Gawad
Xin Zhou
Yongjin Li
Michael C Rusch
John Easton
Robert Huether
Veronica Gonzalez-Pena
Mark R Wilkinson
Leandro C Hermida
Sean Davis
Edgar Sioson
Stanley Pounds
Xueyuan Cao
Rhonda E Ries
Zhaoming Wang
Xiang Chen
Li Dong
Sharon J Diskin
Malcolm A Smith
Jaime M Guidry Auvil
Paul S Meltzer
Ching C Lau, The Jackson Laboratory
Elizabeth J Perlman
John M Maris
Soheil Meshinchi
Stephen P Hunger
Daniela S Gerhard
Jinghui Zhang


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. Nature 2018 Feb 28 [Epub ahead of print]