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Genomic basis for RNA alterations in cancer

Calabrese, Claudia ; Davidson, Natalie R ; Demircioğlu, Deniz ; Fonseca, Nuno A ; He, Yao ; Kahles, André ; Lehmann, Kjong-Van ; Liu, Fenglin ; Shiraishi, Yuichi and Soulette, Cameron M , et al. (2020) In Nature 578(7793). p.129-136
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... (More)

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.

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Contribution to journal
publication status
published
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keywords
DNA Copy Number Variations, DNA, Neoplasm, Gene Expression Regulation, Neoplastic, Genome, Human, Genomics, Humans, Neoplasms/genetics, RNA/genetics, Transcriptome
in
Nature
volume
578
issue
7793
pages
129 - 136
publisher
Nature Publishing Group
external identifiers
  • scopus:85079073184
  • pmid:32025019
ISSN
0028-0836
DOI
10.1038/s41586-020-1970-0
language
English
LU publication?
yes
id
ff94e0df-eb42-4aa5-a54d-a958094e2bb6
date added to LUP
2023-03-29 17:01:45
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2024-04-18 20:27:39
@article{ff94e0df-eb42-4aa5-a54d-a958094e2bb6,
  abstract     = {{<p>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.</p>}},
  author       = {{Calabrese, Claudia and Davidson, Natalie R and Demircioğlu, Deniz and Fonseca, Nuno A and He, Yao and Kahles, André and Lehmann, Kjong-Van and Liu, Fenglin and Shiraishi, Yuichi and Soulette, Cameron M and Urban, Lara and Greger, Liliana and Li, Siliang and Liu, Dongbing and Perry, Marc D and Xiang, Qian and Zhang, Fan and Zhang, Junjun and Bailey, Peter and Erkek, Serap and Hoadley, Katherine A and Hou, Yong and Huska, Matthew R and Kilpinen, Helena and Korbel, Jan O and Marin, Maximillian G and Markowski, Julia and Nandi, Tannistha and Pan-Hammarström, Qiang and Pedamallu, Chandra Sekhar and Siebert, Reiner and Stark, Stefan G and Su, Hong and Tan, Patrick and Waszak, Sebastian M and Yung, Christina and Zhu, Shida and Awadalla, Philip and Creighton, Chad J and Meyerson, Matthew and Ouellette, B F Francis and Wu, Kui and Yang, Huanming and Brazma, Alvis and Brooks, Angela N and Göke, Jonathan and Rätsch, Gunnar and Schwarz, Roland F and Stegle, Oliver and Zhang, Zemin}},
  issn         = {{0028-0836}},
  keywords     = {{DNA Copy Number Variations; DNA, Neoplasm; Gene Expression Regulation, Neoplastic; Genome, Human; Genomics; Humans; Neoplasms/genetics; RNA/genetics; Transcriptome}},
  language     = {{eng}},
  number       = {{7793}},
  pages        = {{129--136}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{Genomic basis for RNA alterations in cancer}},
  url          = {{http://dx.doi.org/10.1038/s41586-020-1970-0}},
  doi          = {{10.1038/s41586-020-1970-0}},
  volume       = {{578}},
  year         = {{2020}},
}