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A pan cancer analysis of promoter activity highlights the regulatory role of alternative transcription start sites and their association with noncoding mutations

View ORCID ProfileDeniz Demircioğlu, Martin Kindermans, Tannistha Nandi, Engin Cukuroglu, Claudia Calabrese, Nuno A. Fonseca, Andre Kahles, Kjong Lehmann, Oliver Stegle, PCAWG-3, PCAWG-Network, Alvis Brazma, Angela Brooks, Gunnar Rätsch, Patrick Tan, Jonathan Göke
doi: https://doi.org/10.1101/176487
Deniz Demircioğlu
1Genome Institute of Singapore, Singapore
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  • ORCID record for Deniz Demircioğlu
Martin Kindermans
1Genome Institute of Singapore, Singapore
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Tannistha Nandi
1Genome Institute of Singapore, Singapore
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Engin Cukuroglu
1Genome Institute of Singapore, Singapore
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Claudia Calabrese
3EMBL-EBI, Hinxton, UK
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Nuno A. Fonseca
3EMBL-EBI, Hinxton, UK
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Andre Kahles
4ETH Zürich, Computer Science Dept, Switzerland
5Memorial Sloan Kettering Cancer Center, New York, USA
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Kjong Lehmann
4ETH Zürich, Computer Science Dept, Switzerland
5Memorial Sloan Kettering Cancer Center, New York, USA
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Oliver Stegle
3EMBL-EBI, Hinxton, UK
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Alvis Brazma
3EMBL-EBI, Hinxton, UK
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Angela Brooks
6University of California, Santa Cruz, USA
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Gunnar Rätsch
4ETH Zürich, Computer Science Dept, Switzerland
5Memorial Sloan Kettering Cancer Center, New York, USA
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Patrick Tan
1Genome Institute of Singapore, Singapore
2Duke NUS Medical School
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Jonathan Göke
1Genome Institute of Singapore, Singapore
7National Cancer Centre, Singapore
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ABSTRACT

Most human protein-coding genes are regulated by multiple, distinct promoters, suggesting that the choice of promoter is as important as its level of transcriptional activity. While the role of promoters as driver elements in cancer has been recognized, the contribution of alternative promoters to regulation of the cancer transcriptome remains largely unexplored. Here we show that active promoters can be identified using RNA-Seq data, enabling the analysis of promoter activity in more than 1,000 cancer samples with matched whole genome sequencing data. We find that alternative promoters are a major contributor to tissue-specific regulation of isoform expression and that alternative promoters are frequently deregulated in cancer, affecting known cancer-genes and novel candidates. Noncoding passenger mutations are enriched at promoters of genes with lower regulatory complexity, whereas noncoding driver mutations occur at genes with multiple promoters, often affecting the promoter that shows the highest level of activity. Together our study demonstrates that the landscape of active promoters shapes the cancer transcriptome, opening many opportunities to further explore the interplay of regulatory mechanism and noncoding somatic mutations with transcriptional aberrations in cancer.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 15, 2017.
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A pan cancer analysis of promoter activity highlights the regulatory role of alternative transcription start sites and their association with noncoding mutations
Deniz Demircioğlu, Martin Kindermans, Tannistha Nandi, Engin Cukuroglu, Claudia Calabrese, Nuno A. Fonseca, Andre Kahles, Kjong Lehmann, Oliver Stegle, PCAWG-3, PCAWG-Network, Alvis Brazma, Angela Brooks, Gunnar Rätsch, Patrick Tan, Jonathan Göke
bioRxiv 176487; doi: https://doi.org/10.1101/176487
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A pan cancer analysis of promoter activity highlights the regulatory role of alternative transcription start sites and their association with noncoding mutations
Deniz Demircioğlu, Martin Kindermans, Tannistha Nandi, Engin Cukuroglu, Claudia Calabrese, Nuno A. Fonseca, Andre Kahles, Kjong Lehmann, Oliver Stegle, PCAWG-3, PCAWG-Network, Alvis Brazma, Angela Brooks, Gunnar Rätsch, Patrick Tan, Jonathan Göke
bioRxiv 176487; doi: https://doi.org/10.1101/176487

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