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Genomic basis for RNA alterations revealed by whole-genome analyses of 27 cancer types

PCAWG Transcriptome Core Group, View ORCID ProfileClaudia Calabrese, Natalie R. Davidson, View ORCID ProfileNuno A. Fonseca, Yao He, View ORCID ProfileAndré Kahles, View ORCID ProfileKjong-Van Lehmann, View ORCID ProfileFenglin Liu, View ORCID ProfileYuichi Shiraishi, View ORCID ProfileCameron M. Soulette, Lara Urban, View ORCID ProfileDeniz Demircioğlu, Liliana Greger, View ORCID ProfileSiliang Li, View ORCID ProfileDongbing Liu, View ORCID ProfileMarc D. Perry, Linda Xiang, Fan Zhang, Junjun Zhang, Peter Bailey, Serap Erkek, View ORCID ProfileKatherine A. Hoadley, View ORCID ProfileYong Hou, View ORCID ProfileHelena Kilpinen, Jan O. Korbel, View ORCID ProfileMaximillian G. Marin, View ORCID ProfileJulia Markowski, Tannistha Nandi, View ORCID ProfileQiang Pan-Hammarström, Chandra Sekhar Pedamallu, Reiner Siebert, Stefan G. Stark, View ORCID ProfileHong Su, Patrick Tan, View ORCID ProfileSebastian M. Waszak, Christina Yung, Shida Zhu, PCAWG Transcriptome Working Group, Philip Awadalla, Chad J. Creighton, View ORCID ProfileMatthew Meyerson, B.F. Francis Ouellette, Kui Wu, View ORCID ProfileHuangming Yang, ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network, View ORCID ProfileAlvis Brazma, View ORCID ProfileAngela N. Brooks, View ORCID ProfileJonathan Göke, View ORCID ProfileGunnar Rätsch, View ORCID ProfileRoland F. Schwarz, Oliver Stegle, View ORCID ProfileZemin Zhang
doi: https://doi.org/10.1101/183889
1European Molecular Biology Laboratory, Hinxton, CB10 1SD, UK,
Claudia Calabrese
1European Molecular Biology Laboratory, Hinxton, CB10 1SD, UK,
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Natalie R. Davidson
2ETH Zurich, Zurich, 8092, Switzerland,
3Memorial Sloan Kettering Cancer Center, New York, 10065, USA,
4Weill Cornell Medical College, New York, 10065, USA,
5SIB Swiss Institute of Bioinformatics, LaUSAnne, 1015, Switzerland,
6University Hospital Zurich, Zurich, 8091, Switzerland,
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Nuno A. Fonseca
1European Molecular Biology Laboratory, Hinxton, CB10 1SD, UK,
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Yao He
7Peking University, Beijing, 100871, China,
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André Kahles
2ETH Zurich, Zurich, 8092, Switzerland,
3Memorial Sloan Kettering Cancer Center, New York, 10065, USA,
4Weill Cornell Medical College, New York, 10065, USA,
5SIB Swiss Institute of Bioinformatics, LaUSAnne, 1015, Switzerland,
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Kjong-Van Lehmann
2ETH Zurich, Zurich, 8092, Switzerland,
3Memorial Sloan Kettering Cancer Center, New York, 10065, USA,
5SIB Swiss Institute of Bioinformatics, LaUSAnne, 1015, Switzerland,
6University Hospital Zurich, Zurich, 8091, Switzerland,
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Fenglin Liu
7Peking University, Beijing, 100871, China,
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Yuichi Shiraishi
8The University of Tokyo, Minato-ku, 108-8639, Japan,
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Cameron M. Soulette
9University of California, Santa Cruz, Santa Cruz, 95064, USA,
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Lara Urban
1European Molecular Biology Laboratory, Hinxton, CB10 1SD, UK,
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Deniz Demircioğlu
10National University of Singapore, Singapore, 117417, Singapore,
11Genome Institute of Singapore, Singapore, 138672, Singapore,
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Liliana Greger
1European Molecular Biology Laboratory, Hinxton, CB10 1SD, UK,
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Siliang Li
12BGI-Shenzhen, Shenzhen, 518083, China,
13China National GeneBank-Shenzhen, Shenzhen, 518083, China,
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Dongbing Liu
12BGI-Shenzhen, Shenzhen, 518083, China,
13China National GeneBank-Shenzhen, Shenzhen, 518083, China,
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Marc D. Perry
14Ontario Institute for Cancer Research, Toronto, M5G 0A3, Canada,
15University of California, San Francisco, San Francisco, 94143, USA,
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Linda Xiang
14Ontario Institute for Cancer Research, Toronto, M5G 0A3, Canada,
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Fan Zhang
7Peking University, Beijing, 100871, China,
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Junjun Zhang
14Ontario Institute for Cancer Research, Toronto, M5G 0A3, Canada,
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Peter Bailey
16University of Glasgow, Glasgow, G61 1BD, UK,
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Serap Erkek
17European Molecular Biology Laboratory, Heidelberg, 69117, Germany,
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Katherine A. Hoadley
18The University of North Carolina at Chapel Hill, Chapel Hill, 27599, USA,
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Yong Hou
12BGI-Shenzhen, Shenzhen, 518083, China,
13China National GeneBank-Shenzhen, Shenzhen, 518083, China,
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Helena Kilpinen
19University College London, London, WC1N 1EH, UK,
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Jan O. Korbel
17European Molecular Biology Laboratory, Heidelberg, 69117, Germany,
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Maximillian G. Marin
9University of California, Santa Cruz, Santa Cruz, 95064, USA,
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Julia Markowski
20Berlin Institute for Medical Systems Biology, Max Delbruck Center for Molecular Medicine, Berlin, 13125, Germany,
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Tannistha Nandi
11Genome Institute of Singapore, Singapore, 138672, Singapore,
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Qiang Pan-Hammarström
12BGI-Shenzhen, Shenzhen, 518083, China,
21Karolinska Institutet, Stockholm, 14186, Sweden,
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Chandra Sekhar Pedamallu
22Broad Institute, Cambridge, 02142, USA,
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Reiner Siebert
23Ulm University & Ulm University Medical Center, Ulm, 89081, Germany,
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Stefan G. Stark
2ETH Zurich, Zurich, 8092, Switzerland,
3Memorial Sloan Kettering Cancer Center, New York, 10065, USA,
5SIB Swiss Institute of Bioinformatics, LaUSAnne, 1015, Switzerland,
6University Hospital Zurich, Zurich, 8091, Switzerland,
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Hong Su
12BGI-Shenzhen, Shenzhen, 518083, China,
13China National GeneBank-Shenzhen, Shenzhen, 518083, China,
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Patrick Tan
11Genome Institute of Singapore, Singapore, 138672, Singapore,
24DUKe-NUS Medical School, Singapore, 169857, Singapore,
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Sebastian M. Waszak
17European Molecular Biology Laboratory, Heidelberg, 69117, Germany,
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Christina Yung
14Ontario Institute for Cancer Research, Toronto, M5G 0A3, Canada,
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Shida Zhu
12BGI-Shenzhen, Shenzhen, 518083, China,
13China National GeneBank-Shenzhen, Shenzhen, 518083, China,
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Philip Awadalla
14Ontario Institute for Cancer Research, Toronto, M5G 0A3, Canada,
25University of Toronto, Toronto, M8G 0A8, Canada,
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Chad J. Creighton
26Baylor College of Medicine, Houston, 77030, USA,
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Matthew Meyerson
22Broad Institute, Cambridge, 02142, USA,
27Dana-Farber Cancer Institute, Boston, 02215, USA,
28Harvard Medical School, Boston, 02115, USA,
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B.F. Francis Ouellette
29University of Toronto, Toronto, M5G 0A3, Canada,
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Kui Wu
12BGI-Shenzhen, Shenzhen, 518083, China,
13China National GeneBank-Shenzhen, Shenzhen, 518083, China,
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Huangming Yang
12BGI-Shenzhen, Shenzhen, 518083, China,
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Alvis Brazma
1European Molecular Biology Laboratory, Hinxton, CB10 1SD, UK,
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  • For correspondence: brazma@ebi.ac.uk anbrooks@ucsc.edu Gunnar.Ratsch@ratschlab.org
Angela N. Brooks
9University of California, Santa Cruz, Santa Cruz, 95064, USA,
22Broad Institute, Cambridge, 02142, USA,
27Dana-Farber Cancer Institute, Boston, 02215, USA,
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  • For correspondence: brazma@ebi.ac.uk anbrooks@ucsc.edu Gunnar.Ratsch@ratschlab.org
Jonathan Göke
11Genome Institute of Singapore, Singapore, 138672, Singapore,
30National Cancer Centre Singapore, Singapore, 169610, Singapore,
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Gunnar Rätsch
2ETH Zurich, Zurich, 8092, Switzerland,
3Memorial Sloan Kettering Cancer Center, New York, 10065, USA,
4Weill Cornell Medical College, New York, 10065, USA,
5SIB Swiss Institute of Bioinformatics, LaUSAnne, 1015, Switzerland,
6University Hospital Zurich, Zurich, 8091, Switzerland,
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  • For correspondence: brazma@ebi.ac.uk anbrooks@ucsc.edu Gunnar.Ratsch@ratschlab.org
Roland F. Schwarz
1European Molecular Biology Laboratory, Hinxton, CB10 1SD, UK,
20Berlin Institute for Medical Systems Biology, Max Delbruck Center for Molecular Medicine, Berlin, 13125, Germany,
31German Cancer Consortium (DKTK),
32German Cancer Research Center (DKFZ), Heidelberg, Germany
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Oliver Stegle
1European Molecular Biology Laboratory, Hinxton, CB10 1SD, UK,
17European Molecular Biology Laboratory, Heidelberg, 69117, Germany,
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Zemin Zhang
7Peking University, Beijing, 100871, China,
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Abstract

We present the most comprehensive catalogue of cancer-associated gene alterations through characterization of tumor transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes project. Using matched whole-genome sequencing data, we attributed RNA alterations to germline and somatic DNA alterations, revealing likely genetic mechanisms. We identified 444 associations of gene expression with somatic non-coding single-nucleotide variants. We found 1,872 splicing alterations associated with somatic mutation in intronic regions, including novel exonization events associated with Alu elements. Somatic copy number alterations were the major driver of total gene and allele-specific expression (ASE) variation. Additionally, 82% of gene fusions had structural variant support, including 75 of a novel class called “bridged” fusions, in which a third genomic location bridged two different genes. Globally, we observe transcriptomic alteration signatures that differ between cancer types and have associations with DNA mutational signatures. Given this unique dataset of RNA alterations, we also identified 1,012 genes significantly altered through both DNA and RNA mechanisms. Our study represents an extensive catalog of RNA alterations and reveals new insights into the heterogeneous molecular mechanisms of cancer gene alterations.

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Genomic basis for RNA alterations revealed by whole-genome analyses of 27 cancer types
PCAWG Transcriptome Core Group, Claudia Calabrese, Natalie R. Davidson, Nuno A. Fonseca, Yao He, André Kahles, Kjong-Van Lehmann, Fenglin Liu, Yuichi Shiraishi, Cameron M. Soulette, Lara Urban, Deniz Demircioğlu, Liliana Greger, Siliang Li, Dongbing Liu, Marc D. Perry, Linda Xiang, Fan Zhang, Junjun Zhang, Peter Bailey, Serap Erkek, Katherine A. Hoadley, Yong Hou, Helena Kilpinen, Jan O. Korbel, Maximillian G. Marin, Julia Markowski, Tannistha Nandi, Qiang Pan-Hammarström, Chandra Sekhar Pedamallu, Reiner Siebert, Stefan G. Stark, Hong Su, Patrick Tan, Sebastian M. Waszak, Christina Yung, Shida Zhu, PCAWG Transcriptome Working Group, Philip Awadalla, Chad J. Creighton, Matthew Meyerson, B.F. Francis Ouellette, Kui Wu, Huangming Yang, ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network, Alvis Brazma, Angela N. Brooks, Jonathan Göke, Gunnar Rätsch, Roland F. Schwarz, Oliver Stegle, Zemin Zhang
bioRxiv 183889; doi: https://doi.org/10.1101/183889
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Genomic basis for RNA alterations revealed by whole-genome analyses of 27 cancer types
PCAWG Transcriptome Core Group, Claudia Calabrese, Natalie R. Davidson, Nuno A. Fonseca, Yao He, André Kahles, Kjong-Van Lehmann, Fenglin Liu, Yuichi Shiraishi, Cameron M. Soulette, Lara Urban, Deniz Demircioğlu, Liliana Greger, Siliang Li, Dongbing Liu, Marc D. Perry, Linda Xiang, Fan Zhang, Junjun Zhang, Peter Bailey, Serap Erkek, Katherine A. Hoadley, Yong Hou, Helena Kilpinen, Jan O. Korbel, Maximillian G. Marin, Julia Markowski, Tannistha Nandi, Qiang Pan-Hammarström, Chandra Sekhar Pedamallu, Reiner Siebert, Stefan G. Stark, Hong Su, Patrick Tan, Sebastian M. Waszak, Christina Yung, Shida Zhu, PCAWG Transcriptome Working Group, Philip Awadalla, Chad J. Creighton, Matthew Meyerson, B.F. Francis Ouellette, Kui Wu, Huangming Yang, ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network, Alvis Brazma, Angela N. Brooks, Jonathan Göke, Gunnar Rätsch, Roland F. Schwarz, Oliver Stegle, Zemin Zhang
bioRxiv 183889; doi: https://doi.org/10.1101/183889

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