High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations

PCAWG Transcriptome Working Group; PCAWG-Structural Variation Working Group; PCAWG Consortium; Yiqun Zhang; Fengju Chen; Nuno A. Fonseca; Yao He; Masashi Fujita; Hidewaki Nakagawa; Zemin Zhang; Alvis Brazma; Samirkumar B. Amin; Philip Awadalla; Peter J. Bailey; Alvis Brazma; Angela N. Brooks; Claudia Calabrese; Aurélien Chateigner; Isidro Cortés-Ciriano; Brian Craft; David Craft; Chad J. Creighton; Natalie R. Davidson; Deniz Demircioğlu; Serap Erkek; Nuno A. Fonseca; Milana Frenkel-Morgenstern; Mary J. Goldman; Liliana Greger; Jonathan Göke; Yao He; Katherine A. Hoadley; Yong Hou; Matthew R. Huska; Andre Kahles; Ekta Khurana; Helena Kilpinen; Jan O. Korbel; Fabien C. Lamaze; Kjong Van Lehmann; Chang Li; Siliang Li; Xiaobo Li; Xinyue Li; Dongbing Liu; Fenglin Liu; Xingmin Liu; Maximillian G. Marin; Julia Markowski; Matthew Meyerson; Tannistha Nandi; Morten Muhlig Nielsen; Akinyemi I. Ojesina; B. F.Francis Ouellette; Qiang Pan-Hammarström; Peter J. Park; Chandra Sekhar Pedamallu; Jakob Skou Pedersen; Marc D. Perry; Gunnar Rätsch; Roland F. Schwarz; Yuichi Shiraishi; Reiner Siebert; Cameron M. Soulette; Stefan G. Stark; Oliver Stegle; Hong Su; Patrick Tan; Bin Tean Teh; Lara Urban; Jian Wang; Sebastian M. Waszak; Kui Wu; Qian Xiang; Heng Xiong; Sergei Yakneen; Huanming Yang; Chen Ye; Christina K. Yung; Fan Zhang; Junjun Zhang; Xiuqing Zhang; Zemin Zhang; Liangtao Zheng; Jingchun Zhu; Shida Zhu; Kadir C. Akdemir; Eva G. Alvarez; Adrian Baez-Ortega; Rameen Beroukhim; Paul C. Boutros; David D.L. Bowtell; Benedikt Brors; Kathleen H. Burns; Peter J. Campbell; Kin Chan; Ken Chen; Isidro Cortés-Ciriano; Ana Dueso-Barroso; Andrew J. Dunford; Paul A. Edwards; Xavier Estivill; Dariush Etemadmoghadam; Lars Feuerbach; J. Lynn Fink; Dale W. Garsed; Mark Gerstein; Dmitry A. Gordenin; David Haan; James E. Haber; Julian M. Hess; Barbara Hutter; Marcin Imielinski; David T.W. Jones; Young Seok Ju; Marat D. Kazanov; Leszek J. Klimczak; Youngil Koh; Jan O. Korbel; Kiran Kumar; Eunjung Alice Lee; Jake June Koo Lee; Yilong Li; Andy G. Lynch; Geoff Macintyre; Florian Markowetz; Iñigo Martincorena; Alexander Martinez-Fundichely; Satoru Miyano; Hidewaki Nakagawa; Fabio C.P. Navarro; Stephan Ossowski; John V. Pearson; Montserrat Puiggròs; Karsten Rippe; Nicola D. Roberts; Steven A. Roberts; Bernardo Rodriguez-Martin; Steven E. Schumacher; Ralph Scully; Mark Shackleton; Nikos Sidiropoulos; Lina Sieverling; Chip Stewart; David Torrents; Jose M.C. Tubio; Izar Villasante; Nicola Waddell; Jeremiah A. Wala; Joachim Weischenfeldt; Lixing Yang; Xiaotong Yao; Sung Soo Yoon; Jorge Zamora; Cheng Zhong Zhang; Chad J. Creighton; Lauri A. Aaltonen; Federico Abascal; Adam Abeshouse; Hiroyuki Aburatani; David J. Adams; Nishant Agrawal; Keun Soo Ahn; Sung Min Ahn; Hiroshi Aikata; Rehan Akbani; Kadir C. Akdemir; Hikmat Al-Ahmadie; Sultan T. Al-Sedairy; Fatima Al-Shahrour; Malik Alawi; Monique Albert; Kenneth Aldape; Ludmil B. Alexandrov; Adrian Ally; Kathryn Alsop; Eva G. Alvarez; Fernanda Amary; Samirkumar B. Amin; Brice Aminou; Ole Ammerpohl; Matthew J. Anderson; Yeng Ang; Davide Antonello; Pavana Anur; Samuel Aparicio; Elizabeth L. Appelbaum; Yasuhito Arai; Axel Aretz; Koji Arihiro; Shun ichi Ariizumi; Joshua Armenia; Laurent Arnould; Sylvia Asa; Li Ding; Lucinda A. Fulton; Robert S. Fulton; Ramaswamy Govindan; Reyka Jayasinghe; Tim Ley; Christopher A. Miller; Francesc Muyas; Johannes Werner

doi:10.1038/s41467-019-13885-w

High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations

PCAWG Transcriptome Working Group, PCAWG-Structural Variation Working Group, PCAWG Consortium, Yiqun Zhang, Fengju Chen, Nuno A. Fonseca, Yao He, Masashi Fujita, Hidewaki Nakagawa, Zemin Zhang, Alvis Brazma, Samirkumar B. Amin, Philip Awadalla, Peter J. Bailey, Alvis Brazma, Angela N. Brooks, Claudia Calabrese, Aurélien Chateigner, Isidro Cortés-Ciriano, Brian CraftDavid Craft, Chad J. Creighton, Natalie R. Davidson, Deniz Demircioğlu, Serap Erkek, Nuno A. Fonseca, Milana Frenkel-Morgenstern, Mary J. Goldman, Liliana Greger, Jonathan Göke, Yao He, Katherine A. Hoadley, Yong Hou, Matthew R. Huska, Andre Kahles, Ekta Khurana, Helena Kilpinen, Jan O. Korbel, Fabien C. Lamaze, Kjong Van Lehmann, Chang Li, Siliang Li, Xiaobo Li, Xinyue Li, Dongbing Liu, Fenglin Liu, Xingmin Liu, Maximillian G. Marin, Julia Markowski, Matthew Meyerson, Tannistha Nandi, Morten Muhlig Nielsen, Akinyemi I. Ojesina, B. F.Francis Ouellette, Qiang Pan-Hammarström, Peter J. Park, Chandra Sekhar Pedamallu, Jakob Skou Pedersen, Marc D. Perry, Gunnar Rätsch, Roland F. Schwarz, Yuichi Shiraishi, Reiner Siebert, Cameron M. Soulette, Stefan G. Stark, Oliver Stegle, Hong Su, Patrick Tan, Bin Tean Teh, Lara Urban, Jian Wang, Sebastian M. Waszak, Kui Wu, Qian Xiang, Heng Xiong, Sergei Yakneen, Huanming Yang, Chen Ye, Christina K. Yung, Fan Zhang, Junjun Zhang, Xiuqing Zhang, Zemin Zhang, Liangtao Zheng, Jingchun Zhu, Shida Zhu, Kadir C. Akdemir, Eva G. Alvarez, Adrian Baez-Ortega, Rameen Beroukhim, Paul C. Boutros, David D.L. Bowtell, Benedikt Brors, Kathleen H. Burns, Peter J. Campbell, Kin Chan, Ken Chen, Isidro Cortés-Ciriano, Ana Dueso-Barroso, Andrew J. Dunford, Paul A. Edwards, Xavier Estivill, Dariush Etemadmoghadam, Lars Feuerbach, J. Lynn Fink, Dale W. Garsed, Mark Gerstein, Dmitry A. Gordenin, David Haan, James E. Haber, Julian M. Hess, Barbara Hutter, Marcin Imielinski, David T.W. Jones, Young Seok Ju, Marat D. Kazanov, Leszek J. Klimczak, Youngil Koh, Jan O. Korbel, Kiran Kumar, Eunjung Alice Lee, Jake June Koo Lee, Yilong Li, Andy G. Lynch, Geoff Macintyre, Florian Markowetz, Iñigo Martincorena, Alexander Martinez-Fundichely, Satoru Miyano, Hidewaki Nakagawa, Fabio C.P. Navarro, Stephan Ossowski, John V. Pearson, Montserrat Puiggròs, Karsten Rippe, Nicola D. Roberts, Steven A. Roberts, Bernardo Rodriguez-Martin, Steven E. Schumacher, Ralph Scully, Mark Shackleton, Nikos Sidiropoulos, Lina Sieverling, Chip Stewart, David Torrents, Jose M.C. Tubio, Izar Villasante, Nicola Waddell, Jeremiah A. Wala, Joachim Weischenfeldt, Lixing Yang, Xiaotong Yao, Sung Soo Yoon, Jorge Zamora, Cheng Zhong Zhang, Chad J. Creighton, Lauri A. Aaltonen, Federico Abascal, Adam Abeshouse, Hiroyuki Aburatani, David J. Adams, Nishant Agrawal, Keun Soo Ahn, Sung Min Ahn, Hiroshi Aikata, Rehan Akbani, Kadir C. Akdemir, Hikmat Al-Ahmadie, Sultan T. Al-Sedairy, Fatima Al-Shahrour, Malik Alawi, Monique Albert, Kenneth Aldape, Ludmil B. Alexandrov, Adrian Ally, Kathryn Alsop, Eva G. Alvarez, Fernanda Amary, Samirkumar B. Amin, Brice Aminou, Ole Ammerpohl, Matthew J. Anderson, Yeng Ang, Davide Antonello, Pavana Anur, Samuel Aparicio, Elizabeth L. Appelbaum, Yasuhito Arai, Axel Aretz, Koji Arihiro, Shun ichi Ariizumi, Joshua Armenia, Laurent Arnould, Sylvia Asa, Li Ding, Lucinda A. Fulton, Robert S. Fulton, Ramaswamy Govindan, Reyka Jayasinghe, Tim Ley, Christopher A. Miller, Francesc Muyas, Johannes Werner

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

Abstract

The 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.

Original language	English
Article number	736
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13885-w
State	Published - Dec 1 2020

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10.1038/s41467-019-13885-w

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PCAWG Transcriptome Working Group, PCAWG-Structural Variation Working Group, PCAWG Consortium, Zhang, Y., Chen, F., Fonseca, N. A., He, Y., Fujita, M., Nakagawa, H., Zhang, Z., Brazma, A., Amin, S. B., Awadalla, P., Bailey, P. J., Brazma, A., Brooks, A. N., Calabrese, C., Chateigner, A., Cortés-Ciriano, I., ... Werner, J. (2020). High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations. Nature communications, 11(1), Article 736. https://doi.org/10.1038/s41467-019-13885-w

@article{85606f0b566f4674a51027ea6492a044,

title = "High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations",

abstract = "The 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.",

author = "{PCAWG Transcriptome Working Group} and {PCAWG-Structural Variation Working Group} and {PCAWG Consortium} and Yiqun Zhang and Fengju Chen and Fonseca, {Nuno A.} and Yao He and Masashi Fujita and Hidewaki Nakagawa and Zemin Zhang and Alvis Brazma and Amin, {Samirkumar B.} and Philip Awadalla and Bailey, {Peter J.} and Alvis Brazma and Brooks, {Angela N.} and Claudia Calabrese and Aur{\'e}lien Chateigner and Isidro Cort{\'e}s-Ciriano and Brian Craft and David Craft and Creighton, {Chad J.} and Davidson, {Natalie R.} and Deniz Demircioğlu and Serap Erkek and Fonseca, {Nuno A.} and Milana Frenkel-Morgenstern and Goldman, {Mary J.} and Liliana Greger and Jonathan G{\"o}ke and Yao He and Hoadley, {Katherine A.} and Yong Hou and Huska, {Matthew R.} and Andre Kahles and Ekta Khurana and Helena Kilpinen and Korbel, {Jan O.} and Lamaze, {Fabien C.} and Lehmann, {Kjong Van} and Chang Li and Siliang Li and Xiaobo Li and Xinyue Li and Dongbing Liu and Fenglin Liu and Xingmin Liu and Marin, {Maximillian G.} and Julia Markowski and Matthew Meyerson and Tannistha Nandi and Nielsen, {Morten Muhlig} and Ojesina, {Akinyemi I.} and Ouellette, {B. F.Francis} and Qiang Pan-Hammarstr{\"o}m and Park, {Peter J.} and Pedamallu, {Chandra Sekhar} and Pedersen, {Jakob Skou} and Perry, {Marc D.} and Gunnar R{\"a}tsch and Schwarz, {Roland F.} and Yuichi Shiraishi and Reiner Siebert and Soulette, {Cameron M.} and Stark, {Stefan G.} and Oliver Stegle and Hong Su and Patrick Tan and Teh, {Bin Tean} and Lara Urban and Jian Wang and Waszak, {Sebastian M.} and Kui Wu and Qian Xiang and Heng Xiong and Sergei Yakneen and Huanming Yang and Chen Ye and Yung, {Christina K.} and Fan Zhang and Junjun Zhang and Xiuqing Zhang and Zemin Zhang and Liangtao Zheng and Jingchun Zhu and Shida Zhu and Akdemir, {Kadir C.} and Alvarez, {Eva G.} and Adrian Baez-Ortega and Rameen Beroukhim and Boutros, {Paul C.} and Bowtell, {David D.L.} and Benedikt Brors and Burns, {Kathleen H.} and Campbell, {Peter J.} and Kin Chan and Ken Chen and Isidro Cort{\'e}s-Ciriano and Ana Dueso-Barroso and Dunford, {Andrew J.} and Edwards, {Paul A.} and Xavier Estivill and Dariush Etemadmoghadam and Lars Feuerbach and Fink, {J. Lynn} and Garsed, {Dale W.} and Mark Gerstein and Gordenin, {Dmitry A.} and David Haan and Haber, {James E.} and Hess, {Julian M.} and Barbara Hutter and Marcin Imielinski and Jones, {David T.W.} and Ju, {Young Seok} and Kazanov, {Marat D.} and Klimczak, {Leszek J.} and Youngil Koh and Korbel, {Jan O.} and Kiran Kumar and Lee, {Eunjung Alice} and Lee, {Jake June Koo} and Yilong Li and Lynch, {Andy G.} and Geoff Macintyre and Florian Markowetz and I{\~n}igo Martincorena and Alexander Martinez-Fundichely and Satoru Miyano and Hidewaki Nakagawa and Navarro, {Fabio C.P.} and Stephan Ossowski and Pearson, {John V.} and Montserrat Puiggr{\`o}s and Karsten Rippe and Roberts, {Nicola D.} and Roberts, {Steven A.} and Bernardo Rodriguez-Martin and Schumacher, {Steven E.} and Ralph Scully and Mark Shackleton and Nikos Sidiropoulos and Lina Sieverling and Chip Stewart and David Torrents and Tubio, {Jose M.C.} and Izar Villasante and Nicola Waddell and Wala, {Jeremiah A.} and Joachim Weischenfeldt and Lixing Yang and Xiaotong Yao and Yoon, {Sung Soo} and Jorge Zamora and Zhang, {Cheng Zhong} and Creighton, {Chad J.} and Aaltonen, {Lauri A.} and Federico Abascal and Adam Abeshouse and Hiroyuki Aburatani and Adams, {David J.} and Nishant Agrawal and Ahn, {Keun Soo} and Ahn, {Sung Min} and Hiroshi Aikata and Rehan Akbani and Akdemir, {Kadir C.} and Hikmat Al-Ahmadie and Al-Sedairy, {Sultan T.} and Fatima Al-Shahrour and Malik Alawi and Monique Albert and Kenneth Aldape and Alexandrov, {Ludmil B.} and Adrian Ally and Kathryn Alsop and Alvarez, {Eva G.} and Fernanda Amary and Amin, {Samirkumar B.} and Brice Aminou and Ole Ammerpohl and Anderson, {Matthew J.} and Yeng Ang and Davide Antonello and Pavana Anur and Samuel Aparicio and Appelbaum, {Elizabeth L.} and Yasuhito Arai and Axel Aretz and Koji Arihiro and Ariizumi, {Shun ichi} and Joshua Armenia and Laurent Arnould and Sylvia Asa and Li Ding and Fulton, {Lucinda A.} and Fulton, {Robert S.} and Ramaswamy Govindan and Reyka Jayasinghe and Tim Ley and Miller, {Christopher A.} and Francesc Muyas and Johannes Werner",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-019-13885-w",

language = "English",

volume = "11",

journal = "Nature communications",

issn = "2041-1723",

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PCAWG Transcriptome Working Group, PCAWG-Structural Variation Working Group, PCAWG Consortium, Zhang, Y, Chen, F, Fonseca, NA, He, Y, Fujita, M, Nakagawa, H, Zhang, Z, Brazma, A, Amin, SB, Awadalla, P, Bailey, PJ, Brazma, A, Brooks, AN, Calabrese, C, Chateigner, A, Cortés-Ciriano, I, Craft, B, Craft, D, Creighton, CJ, Davidson, NR, Demircioğlu, D, Erkek, S, Fonseca, NA, Frenkel-Morgenstern, M, Goldman, MJ, Greger, L, Göke, J, He, Y, Hoadley, KA, Hou, Y, Huska, MR, Kahles, A, Khurana, E, Kilpinen, H, Korbel, JO, Lamaze, FC, Lehmann, KV, Li, C, Li, S, Li, X, Li, X, Liu, D, Liu, F, Liu, X, Marin, MG, Markowski, J, Meyerson, M, Nandi, T, Nielsen, MM, Ojesina, AI, Ouellette, BFF, Pan-Hammarström, Q, Park, PJ, Pedamallu, CS, Pedersen, JS, Perry, MD, Rätsch, G, Schwarz, RF, Shiraishi, Y, Siebert, R, Soulette, CM, Stark, SG, Stegle, O, Su, H, Tan, P, Teh, BT, Urban, L, Wang, J, Waszak, SM, Wu, K, Xiang, Q, Xiong, H, Yakneen, S, Yang, H, Ye, C, Yung, CK, Zhang, F, Zhang, J, Zhang, X, Zhang, Z, Zheng, L, Zhu, J, Zhu, S, Akdemir, KC, Alvarez, EG, Baez-Ortega, A, Beroukhim, R, Boutros, PC, Bowtell, DDL, Brors, B, Burns, KH, Campbell, PJ, Chan, K, Chen, K, Cortés-Ciriano, I, Dueso-Barroso, A, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Feuerbach, L, Fink, JL, Garsed, DW, Gerstein, M, Gordenin, DA, Haan, D, Haber, JE, Hess, JM, Hutter, B, Imielinski, M, Jones, DTW, Ju, YS, Kazanov, MD, Klimczak, LJ, Koh, Y, Korbel, JO, Kumar, K, Lee, EA, Lee, JJK, Li, Y, Lynch, AG, Macintyre, G, Markowetz, F, Martincorena, I, Martinez-Fundichely, A, Miyano, S, Nakagawa, H, Navarro, FCP, Ossowski, S, Pearson, JV, Puiggròs, M, Rippe, K, Roberts, ND, Roberts, SA, Rodriguez-Martin, B, Schumacher, SE, Scully, R, Shackleton, M, Sidiropoulos, N, Sieverling, L, Stewart, C, Torrents, D, Tubio, JMC, Villasante, I, Waddell, N, Wala, JA, Weischenfeldt, J, Yang, L, Yao, X, Yoon, SS, Zamora, J, Zhang, CZ, Creighton, CJ, Aaltonen, LA, Abascal, F, Abeshouse, A, Aburatani, H, Adams, DJ, Agrawal, N, Ahn, KS, Ahn, SM, Aikata, H, Akbani, R, Akdemir, KC, Al-Ahmadie, H, Al-Sedairy, ST, Al-Shahrour, F, Alawi, M, Albert, M, Aldape, K, Alexandrov, LB, Ally, A, Alsop, K, Alvarez, EG, Amary, F, Amin, SB, Aminou, B, Ammerpohl, O, Anderson, MJ, Ang, Y, Antonello, D, Anur, P, Aparicio, S, Appelbaum, EL, Arai, Y, Aretz, A, Arihiro, K, Ariizumi, SI, Armenia, J, Arnould, L, Asa, S, Ding, L , Fulton, LA , Fulton, RS , Govindan, R , Jayasinghe, R , Ley, T , Miller, CA , Muyas, F & Werner, J 2020, 'High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations', Nature communications, vol. 11, no. 1, 736. https://doi.org/10.1038/s41467-019-13885-w

High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations. / PCAWG Transcriptome Working Group; PCAWG-Structural Variation Working Group; PCAWG Consortium et al.
In: Nature communications, Vol. 11, No. 1, 736, 01.12.2020.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations

AU - PCAWG Transcriptome Working Group

AU - PCAWG-Structural Variation Working Group

AU - PCAWG Consortium

AU - Zhang, Yiqun

AU - Chen, Fengju

AU - Fonseca, Nuno A.

AU - He, Yao

AU - Fujita, Masashi

AU - Nakagawa, Hidewaki

AU - Zhang, Zemin

AU - Brazma, Alvis

AU - Amin, Samirkumar B.

AU - Awadalla, Philip

AU - Bailey, Peter J.

AU - Brazma, Alvis

AU - Brooks, Angela N.

AU - Calabrese, Claudia

AU - Chateigner, Aurélien

AU - Cortés-Ciriano, Isidro

AU - Craft, Brian

AU - Craft, David

AU - Creighton, Chad J.

AU - Davidson, Natalie R.

AU - Demircioğlu, Deniz

AU - Erkek, Serap

AU - Fonseca, Nuno A.

AU - Frenkel-Morgenstern, Milana

AU - Goldman, Mary J.

AU - Greger, Liliana

AU - Göke, Jonathan

AU - He, Yao

AU - Hoadley, Katherine A.

AU - Hou, Yong

AU - Huska, Matthew R.

AU - Kahles, Andre

AU - Khurana, Ekta

AU - Kilpinen, Helena

AU - Korbel, Jan O.

AU - Lamaze, Fabien C.

AU - Lehmann, Kjong Van

AU - Li, Chang

AU - Li, Siliang

AU - Li, Xiaobo

AU - Li, Xinyue

AU - Liu, Dongbing

AU - Liu, Fenglin

AU - Liu, Xingmin

AU - Marin, Maximillian G.

AU - Markowski, Julia

AU - Meyerson, Matthew

AU - Nandi, Tannistha

AU - Nielsen, Morten Muhlig

AU - Ojesina, Akinyemi I.

AU - Ouellette, B. F.Francis

AU - Pan-Hammarström, Qiang

AU - Park, Peter J.

AU - Pedamallu, Chandra Sekhar

AU - Pedersen, Jakob Skou

AU - Perry, Marc D.

AU - Rätsch, Gunnar

AU - Schwarz, Roland F.

AU - Shiraishi, Yuichi

AU - Siebert, Reiner

AU - Soulette, Cameron M.

AU - Stark, Stefan G.

AU - Stegle, Oliver

AU - Su, Hong

AU - Tan, Patrick

AU - Teh, Bin Tean

AU - Urban, Lara

AU - Wang, Jian

AU - Waszak, Sebastian M.

AU - Wu, Kui

AU - Xiang, Qian

AU - Xiong, Heng

AU - Yakneen, Sergei

AU - Yang, Huanming

AU - Ye, Chen

AU - Yung, Christina K.

AU - Zhang, Fan

AU - Zhang, Junjun

AU - Zhang, Xiuqing

AU - Zhang, Zemin

AU - Zheng, Liangtao

AU - Zhu, Jingchun

AU - Zhu, Shida

AU - Akdemir, Kadir C.

AU - Alvarez, Eva G.

AU - Baez-Ortega, Adrian

AU - Beroukhim, Rameen

AU - Boutros, Paul C.

AU - Bowtell, David D.L.

AU - Brors, Benedikt

AU - Burns, Kathleen H.

AU - Campbell, Peter J.

AU - Chan, Kin

AU - Chen, Ken

AU - Cortés-Ciriano, Isidro

AU - Dueso-Barroso, Ana

AU - Dunford, Andrew J.

AU - Edwards, Paul A.

AU - Estivill, Xavier

AU - Etemadmoghadam, Dariush

AU - Feuerbach, Lars

AU - Fink, J. Lynn

AU - Garsed, Dale W.

AU - Gerstein, Mark

AU - Gordenin, Dmitry A.

AU - Haan, David

AU - Haber, James E.

AU - Hess, Julian M.

AU - Hutter, Barbara

AU - Imielinski, Marcin

AU - Jones, David T.W.

AU - Ju, Young Seok

AU - Kazanov, Marat D.

AU - Klimczak, Leszek J.

AU - Koh, Youngil

AU - Korbel, Jan O.

AU - Kumar, Kiran

AU - Lee, Eunjung Alice

AU - Lee, Jake June Koo

AU - Li, Yilong

AU - Lynch, Andy G.

AU - Macintyre, Geoff

AU - Markowetz, Florian

AU - Martincorena, Iñigo

AU - Martinez-Fundichely, Alexander

AU - Miyano, Satoru

AU - Nakagawa, Hidewaki

AU - Navarro, Fabio C.P.

AU - Ossowski, Stephan

AU - Pearson, John V.

AU - Puiggròs, Montserrat

AU - Rippe, Karsten

AU - Roberts, Nicola D.

AU - Roberts, Steven A.

AU - Rodriguez-Martin, Bernardo

AU - Schumacher, Steven E.

AU - Scully, Ralph

AU - Shackleton, Mark

AU - Sidiropoulos, Nikos

AU - Sieverling, Lina

AU - Stewart, Chip

AU - Torrents, David

AU - Tubio, Jose M.C.

AU - Villasante, Izar

AU - Waddell, Nicola

AU - Wala, Jeremiah A.

AU - Weischenfeldt, Joachim

AU - Yang, Lixing

AU - Yao, Xiaotong

AU - Yoon, Sung Soo

AU - Zamora, Jorge

AU - Zhang, Cheng Zhong

AU - Creighton, Chad J.

AU - Aaltonen, Lauri A.

AU - Abascal, Federico

AU - Abeshouse, Adam

AU - Aburatani, Hiroyuki

AU - Adams, David J.

AU - Agrawal, Nishant

AU - Ahn, Keun Soo

AU - Ahn, Sung Min

AU - Aikata, Hiroshi

AU - Akbani, Rehan

AU - Akdemir, Kadir C.

AU - Al-Ahmadie, Hikmat

AU - Al-Sedairy, Sultan T.

AU - Al-Shahrour, Fatima

AU - Alawi, Malik

AU - Albert, Monique

AU - Aldape, Kenneth

AU - Alexandrov, Ludmil B.

AU - Ally, Adrian

AU - Alsop, Kathryn

AU - Alvarez, Eva G.

AU - Amary, Fernanda

AU - Amin, Samirkumar B.

AU - Aminou, Brice

AU - Ammerpohl, Ole

AU - Anderson, Matthew J.

AU - Ang, Yeng

AU - Antonello, Davide

AU - Anur, Pavana

AU - Aparicio, Samuel

AU - Appelbaum, Elizabeth L.

AU - Arai, Yasuhito

AU - Aretz, Axel

AU - Arihiro, Koji

AU - Ariizumi, Shun ichi

AU - Armenia, Joshua

AU - Arnould, Laurent

AU - Asa, Sylvia

AU - Ding, Li

AU - Fulton, Lucinda A.

AU - Fulton, Robert S.

AU - Govindan, Ramaswamy

AU - Jayasinghe, Reyka

AU - Ley, Tim

AU - Miller, Christopher A.

AU - Muyas, Francesc

AU - Werner, Johannes

PY - 2020/12/1

Y1 - 2020/12/1

N2 - The 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.

AB - The 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.

UR - http://www.scopus.com/inward/record.url?scp=85079031729&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-13885-w

DO - 10.1038/s41467-019-13885-w

M3 - Article

C2 - 32024823

AN - SCOPUS:85079031729

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 736

ER -

High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations

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