23 research outputs found
Author Correction: Genomic basis for RNA alterations in cancer (Nature, (2020), 578, 7793, (129-136), 10.1038/s41586-020-1970-0)
No full textCorrection to: Nature Published online 5 February 2020 In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional minor corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper. An additional affiliation has been added for Aurélien Chateigner (BioForA, French National Institute for Agriculture, Food, and Environment (INRAE), ONF, Orléans, France).</p
Author Correction: High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations
No full textGenomic basis for RNA alterations in cancer
No full textTranscript 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 Correction: High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations
No full textIn the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortiumwere listed in the Supplementary Information; however, these members shouldhave been included in themainpaper.The originalArticle has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. In the PCAWG Transcriptome Working Group, the affiliation ‘BioForA, French National Institute for Agriculture, Food, and Environment (INRAE),ONF,Orléans, France’ for Aurélien Chateignerwas alsomissing. The original Article has been corrected. Additional corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper
High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations [Elektronisk resurs]
No full textThe impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements
High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations.
No full textThe impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements
Genomic basis for RNA alterations in cancer
Full text linkTranscript 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
High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations
Full text linkThe impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements
Abstract SY10-02: Pan-cancer study of recurrent and heterogeneous RNA aberrations and association with whole-genome variants
No full textAbstract
Whole-exome sequencing studies have transformed our understanding of recurrent somatic mutations that contribute to cancer pathogenesis; however, these studies limit our ability to identify cancer-associated mutations to those that cause protein-coding changes. To more comprehensively catalogue cancer-associated gene alterations, we have extensively characterized tumor transcriptomes from 1,220 donors with matched whole-genome sequence data to identify recurrent RNA-level aberrations. Specifically, we created a unified RNA-Seq analysis pipeline including sequence alignment and quality control and subsequently identified gene alterations through outlier detection from estimated gene expression levels, alternative splicing, alternative transcription starts, and allele-specific expression and through identified RNA-edited sites and gene fusions. Our data represent an extensive catalog of RNA aberrations for each gene across 27 cancer types. We have also tested for genetic associations with these RNA phenotypes. Using an integrative analysis approach, we have mapped genome-wide cis and trans effects on individual RNA phenotypes, considering both common germline variants as well as somatic SNVs in gene promoters, enhancers, and intronic and other regions. Many of the regulatory associations we identify are not accessible by exome sequencing, underlining the importance of whole-genome sequence data. Utilizing this RNA-centric view, we have identified genes that are recurrently altered, yet have not been previously characterized as cancer genes or identified through DNA-level driver gene analysis. To identify further supporting evidence that these recurrent alterations are potential drivers, we identified genes with mutually exclusive RNA-level alterations. Our findings reveal new insights into selective advantages of somatic changes and molecular mechanisms of cancer. This work is by the Transcriptome Working Group of the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium and authors are listed in alphabetical order.
Citation Format: Samirkumar Amin, Philip Awadalla, Andrew Biankin, Paul Boutros, Alvis Brazma, Angela Norie Brooks, Claudia Calabrese, David Chang, Aurélien Chateigner, Ken Chen, Zechen Chong, Brian Craft, Chad Creighton, Deniz Demircioğlu, Nuno Fonseca, Milana Frenkel-Morgenstern, Gad Getz, Jonathan Göke, Mary Goldman, Liliana Greger, Syed Haider, Yao He, Katherine Hoadley, Yuan Ji, Andre Kahles, Ekta Khurana, Jan Korbel, Kjong Lehmann, Han Liang, Fenglin Liu, Maximillian Marin, Matthew Meyerson, Akinyemi Ojesina, Francis Ouellette, Chandra Pedamallu, Marc Perry, Gunnar Rätsch, Roland Schwarz, Yuichi Shiraishi, Cameron Soulette, Oliver Stegle, Patrick Tan, Alfonso Valencia, Linda Xiang, Christina Yung, Junjun Zhang, Fan Zhang, Zemin Zhang, Jingchun Zhu. Pan-cancer study of recurrent and heterogeneous RNA aberrations and association with whole-genome variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY10-02. doi:10.1158/1538-7445.AM2017-SY10-02</jats:p
