Genomic basis for RNA alterations in cancer Journal Article
| Authors: | PCAWG Transcriptome Core Group; Calabrese, C.; Davidson, N. R.; Demircioğlu, D.; Fonseca, N. A.; He, Y.; Kahles, A.; Lehmann, K. V.; Liu, F.; Shiraishi, Y.; Soulette, C. M.; Urban, L.; Greger, L.; Li, S.; Liu, D.; Perry, M. D.; Xiang, Q.; Zhang, F.; Zhang, J.; Bailey, P.; Erkek, S.; Hoadley, K. A.; Hou, Y.; Huska, M. R.; Kilpinen, H.; Korbel, J. O.; Marin, M. G.; Markowski, J.; Nandi, T.; Pan-Hammarström, Q.; Pedamallu, C. S.; Siebert, R.; Stark, S. G.; Su, H.; Tan, P.; Waszak, S. M.; Yung, C.; Zhu, S.; Awadalla, P.; Creighton, C. J.; Meyerson, M.; Ouellette, B. F. F.; Wu, K.; Yang, H.; PCAWG Transcriptome Working Group; Brazma, A.; Brooks, A. N.; Göke, J.; Rätsch, G.; Schwarz, R. F.; Stegle, O.; Zhang, Z.; & PCAWG Consortium |
| Article Title: | Genomic basis for RNA alterations in cancer |
| Abstract: | 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. © 2020, The Author(s). |
| Keywords: | promoter region; single nucleotide polymorphism; somatic mutation; exon; mutation; allele; gene; gene expression; genetic association; intron; gene frequency; genetic variation; transcriptomics; carcinogenesis; rna; gene fusion; scoring system; alternative rna splicing; telomerase reverse transcriptase; genomics; genome; oxidative stress; tumor; interferon regulatory factor 4; rna sequence; heterogeneity; copy number variation; isocitrate dehydrogenase 1; idh1 gene; germline mutation; ctnnb1 gene; tert gene; cancer; human; priority journal; article; whole genome sequencing; nfkbie gene; malignant neoplasm; expression quantitative trait locus; alu repeat; b2m gene; cdk12 gene; eif4g2 gene; erc1 ret1 gene; etv6 ntrk3 gene; exo1 gene; irf4 gene; numb heatr4 gene; pcbp2 gene; splicing associated variant; tekt5 gene; tmprss2 erg gene |
| Journal Title: | Nature |
| Volume: | 578 |
| Issue: | 7793 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-01-01 |
| Start Page: | 129 |
| End Page: | 136 |
| Language: | English |
| DOI: | 10.1038/s41586-020-1970-0 |
| PUBMED: | 32025019 |
| PROVIDER: | scopus |
| PMCID: | PMC7054216 |
| DOI/URL: | |
| Notes: | Erratum issued, see DOI: 10.1038/s41586-022-05596-y -- Article -- Export Date: 2 March 2020 -- Source: Scopus |
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