Genomic basis for RNA alterations in cancer

PCAWG Transcriptome Core Group, PCAWG Transcriptome Working Group, PCAWG Consortium

Research output: Contribution to journalArticlepeer-review

191 Scopus citations


Transcript alterations often result from somatic changes in cancer genomes1. Various forms of RNA alterations have been described in cancer, including overexpression2, altered splicing3 and gene fusions4; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)5. Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed ‘bridged’ fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.

Original languageEnglish
Pages (from-to)129-136
Number of pages8
Issue number7793
StatePublished - 6 Feb 2020

Bibliographical note

Funding Information:
Competing interests M.M. is a scientific advisory board chair of, and consultant for, OrigiMed, receives research funding from Bayer and Ono Pharma, and has patent royalties from LabCorp. G.R. is on the scientific advisory board of Computomics GmbH and receives research funding from Roche Diagnostics and Google. R.S. received honorariums for speaking at meeting organized by Roche and AstraZeneca. All the other authors have no competing interests.

Funding Information:
Acknowledgements Funding for this work was provided by the Damon Runyon Cancer Research Foundation (A.N.B.), European Research Council (RNAEDIT-649019, Q.-P.-H.). C.M.S. was supported by National Institutes of Health (NIH) training grants T32GM008646 and 2R25GM058903. K.-V.L., A.K., N.R.D., S.G.S. and G.R. received core funding from ETH Zurich and MSKCC (New York). This work was also partially supported by SPHN/PHRT Project (106 to G.R.). L.U., R.F.S. and O.S. received support from core funding of the EMBLand the EU Horizon2020 research and innovation programme (grant agreement N635290). R.F.S. and J.M. received support from the Helmholtz Foundation and the Max Delbrueck Center for Molecular Medicine. Y.H., F.L., F.Z. and Z.Z. received support from Beijing Advanced Innovation Centre for Genomics at Peking University, Key Technologies R&D Program (2016YFC0900100), National Natural Science Foundation of China (81573022, 31530036, 91742203). C.C., L.G., N.F. and A.B. received support from core funding of the EMBL and from EU FP7 Programme projects EurocanPlatform (grant agreement 260791) and CAGEKID (241669). J.G. received support from the Agency for Science, Technology and Research (A*STAR). D.D. received support from the Singapore International Graduate Award (SINGA) and A*STAR. We acknowledge the contributions of the many clinical networks across ICGC and TCGA who provided samples and data to the PCAWG Consortium, and the contributions of the Technical Working Group and the Germline Working Group of the PCAWG Consortium for collation, realignment and harmonized variant calling of the cancer genomes used in this study. We thank the patients and their families for their participation in the individual ICGC and TCGA projects.

Publisher Copyright:
© 2020, The Author(s).


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