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Assessing the Gene Regulatory Landscape in 1,188 Human Tumors

View ORCID ProfileC Calabrese, View ORCID ProfileK Lehmann, View ORCID ProfileL Urban, F Liu, S Erkek, View ORCID ProfileNA Fonseca, View ORCID ProfileA Kahles, View ORCID ProfileH Kilpinen, View ORCID ProfileJ Markowski, PCAWG Group 3, View ORCID ProfileSM Waszak, View ORCID ProfileJO Korbel, View ORCID ProfileZ Zhang, View ORCID ProfileA Brazma, View ORCID ProfileG Rätsch, View ORCID ProfileRF Schwarz, View ORCID ProfileO Stegle
doi: https://doi.org/10.1101/225441
C Calabrese
1European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
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K Lehmann
2Department of Computer Science, ETH Zürich, Switzerland
3Memorial Sloan Kettering Cancer Center, New York, USA
4University Hospital Zurich, Switzerland
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L Urban
1European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
5European Molecular Biology Laboratory, Heidelberg, Germany
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F Liu
7Beijing Advanced Innovation Center for Genomics and College of Life Sciences, Peking University, China
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S Erkek
5European Molecular Biology Laboratory, Heidelberg, Germany
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NA Fonseca
1European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
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A Kahles
2Department of Computer Science, ETH Zürich, Switzerland
3Memorial Sloan Kettering Cancer Center, New York, USA
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H Kilpinen
10UCL Great Ormond Street Institute of Child Health, University College London, UK
11Wellcome Trust Sanger Institute, Hinxton, UK
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J Markowski
6Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany
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SM Waszak
5European Molecular Biology Laboratory, Heidelberg, Germany
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JO Korbel
5European Molecular Biology Laboratory, Heidelberg, Germany
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Z Zhang
7Beijing Advanced Innovation Center for Genomics and College of Life Sciences, Peking University, China
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A Brazma
1European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
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G Rätsch
2Department of Computer Science, ETH Zürich, Switzerland
3Memorial Sloan Kettering Cancer Center, New York, USA
4University Hospital Zurich, Switzerland
8Department of Biology, ETH Zürich, Switzerland
9Weill Cornell Medical College, New York, USA
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RF Schwarz
1European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
6Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany
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O Stegle
1European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
5European Molecular Biology Laboratory, Heidelberg, Germany
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Abstract

Cancer is characterised by somatic genetic variation, but the effect of the majority of non-coding somatic variants and the interface with the germline genome are still unknown. We analysed the whole genome and RNA-Seq data from 1,188 human cancer patients as provided by the Pan-cancer Analysis of Whole Genomes (PCAWG) project to map cis expression quantitative trait loci of somatic and germline variation and to uncover the causes of allele-specific expression patterns in human cancers. The availability of the first large-scale dataset with both whole genome and gene expression data enabled us to uncover the effects of the non-coding variation on cancer. In addition to confirming known regulatory effects, we identified novel associations between somatic variation and expression dysregulation, in particular in distal regulatory elements. Finally, we uncovered links between somatic mutational signatures and gene expression changes, including TERT and LMO2, and we explained the inherited risk factors in APOBEC-related mutational processes. This work represents the first large-scale assessment of the effects of both germline and somatic genetic variation on gene expression in cancer and creates a valuable resource cataloguing these effects.

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Posted November 29, 2017.
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Assessing the Gene Regulatory Landscape in 1,188 Human Tumors
C Calabrese, K Lehmann, L Urban, F Liu, S Erkek, NA Fonseca, A Kahles, H Kilpinen, J Markowski, PCAWG Group 3, SM Waszak, JO Korbel, Z Zhang, A Brazma, G Rätsch, RF Schwarz, O Stegle
bioRxiv 225441; doi: https://doi.org/10.1101/225441
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Assessing the Gene Regulatory Landscape in 1,188 Human Tumors
C Calabrese, K Lehmann, L Urban, F Liu, S Erkek, NA Fonseca, A Kahles, H Kilpinen, J Markowski, PCAWG Group 3, SM Waszak, JO Korbel, Z Zhang, A Brazma, G Rätsch, RF Schwarz, O Stegle
bioRxiv 225441; doi: https://doi.org/10.1101/225441

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