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Genomic basis for RNA alterations in cancer

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Item Type:Article
Title:Genomic basis for RNA alterations in cancer
Creators Name:Calabrese, C. and Davidson, N.R. and Demircioğlu, D. and Fonseca, N.A. and He, Y. and Kahles, A. and Lehmann, K.V. and Liu, F. and Shiraishi, Y. and Soulette, C.M. and Urban, L. and Greger, L. and Li, S. and Liu, D. and Perry, M.D. and Xiang, Q. and Zhang, F. and Zhang, J. and Bailey, P. and Erkek, S. and Hoadley, K.A. and Hou, Y. and Huska, M.R. and Kilpinen, H. and Korbel, J.O. and Marin, M.G. and Markowski, J. and Nandi, T. and Pan-Hammarström, Q. and Pedamallu, C.S. and Siebert, R. and Stark, S.G. and Su, H. and Tan, P. and Waszak, S.M. and Yung, C. and Zhu, S. and Awadalla, P. and Creighton, C.J. and Meyerson, M. and Ouellette, B.F.F. and Wu, K. and Yang, H. and Brazma, A. and Brooks, A.N. and Göke, J. and Rätsch, G. and Schwarz, R.F. and Stegle, O. and Zhang, Z.
Abstract:Transcript alterations often result from somatic changes in cancer genomes. Various forms of RNA alterations have been described in cancer, including overexpression, altered splicing and gene fusions; 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). 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.
Keywords:DNA Copy Number Variations, Genomics, Human Genome, Neoplasm DNA, Neoplasms, Neoplastic Gene Expression Regulation, RNA, Transcriptome
Source:Nature
ISSN:0028-0836
Publisher:Nature Publishing Group
Volume:578
Number:7793
Page Range:129-136
Date:6 February 2020
Official Publication:https://doi.org/10.1038/s41586-020-1970-0
PubMed:View item in PubMed

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