Analyses of non-coding somatic drivers in 2,658 cancer whole genomes

PCAWG Consortium; PCAWG Drivers and Functional Interpretation Working Group; PCAWG-Structural Variation Working Group; Esther Rheinbay; Morten Muhlig Nielsen; Federico Abascal; Jeremiah A. Wala; Ofer Shapira; Grace Tiao; Henrik Hornshøj; Julian M. Hess; Randi Istrup Juul; Ziao Lin; Lars Feuerbach; Radhakrishnan Sabarinathan; Tobias Madsen; Jaegil Kim; Loris Mularoni; Shimin Shuai; Andrés Lanzós; Carl Herrmann; Yosef E. Maruvka; Ciyue Shen; Samirkumar B. Amin; Pratiti Bandopadhayay; Johanna Bertl; Keith A. Boroevich; John Busanovich; Joana Carlevaro-Fita; Dimple Chakravarty; Calvin Wing Yiu Chan; David Craft; Priyanka Dhingra; Klev Diamanti; Nuno A. Fonseca; Abel Gonzalez-Perez; Qianyun Guo; Mark P. Hamilton; Nicholas J. Haradhvala; Chen Hong; Keren Isaev; Todd A. Johnson; Malene Juul; Andre Kahles; Abdullah Kahraman; Youngwook Kim; Jan Komorowski; Kiran Kumar; Sushant Kumar; Donghoon Lee; Kjong Van Lehmann; Yilong Li; Eric Minwei Liu; Lucas Lochovsky; Keunchil Park; Oriol Pich; Nicola D. Roberts; Gordon Saksena; Steven E. Schumacher; Nikos Sidiropoulos; Lina Sieverling; Nasa Sinnott-Armstrong; Chip Stewart; David Tamborero; Jose M.C. Tubio; Husen M. Umer; Liis Uusküla-Reimand; Claes Wadelius; Lina Wadi; Xiaotong Yao; Cheng Zhong Zhang; Jing Zhang; James E. Haber; Asger Hobolth; Marcin Imielinski; Manolis Kellis; Michael S. Lawrence; Christian von Mering; Hidewaki Nakagawa; Benjamin J. Raphael; Mark A. Rubin; Chris Sander; Lincoln D. Stein; Joshua M. Stuart; Tatsuhiko Tsunoda; David A. Wheeler; Rory Johnson; Jüri Reimand; Mark Gerstein; Ekta Khurana; Peter J. Campbell; Núria López-Bigas; Joachim Weischenfeldt; Rameen Beroukhim; Iñigo Martincorena; Jakob Skou Pedersen; Gad Getz; Gary D. Bader; Jonathan Barenboim; Søren Brunak; Ken Chen; Jung Kyoon Choi; Jordi Deu-Pons; J. Lynn Fink; Joan Frigola; Carlo Gambacorti-Passerini; Dale W. Garsed; Ivo G. Gut; David Haan; Arif O. Harmanci; Mohamed Helmy; Ermin Hodzic; Jose M.G. Izarzugaza; Jong K. Kim; Jan O. Korbel; Erik Larsson; Shantao Li; Xiaotong Li; Shaoke Lou; Kathleen Marchal; Alexander Martinez-Fundichely; Patrick D. McGillivray; William Meyerson; Ferran Muiños; Marta Paczkowska; Kiejung Park; Tirso Pons; Sergio Pulido-Tamayo; Iker Reyes-Salazar; Matthew A. Reyna; Carlota Rubio-Perez; S. Cenk Sahinalp; Leonidas Salichos; Mark Shackleton; Raunak Shrestha; Alfonso Valencia; Miguel Vazquez; Lieven P.C. Verbeke; Jiayin Wang; Jonathan Warrell; Sebastian M. Waszak; Guanming Wu; Jun Yu; Xuanping Zhang; Yan Zhang; Zhongming Zhao; Lihua Zou; Kadir C. Akdemir; Eva G. Alvarez; Adrian Baez-Ortega; Paul C. Boutros; David D.L. Bowtell; Benedikt Brors; Kathleen H. Burns; Kin Chan; Isidro Cortés-Ciriano; Ana Dueso-Barroso; Andrew J. Dunford; Paul A. Edwards; Xavier Estivill; Dariush Etemadmoghadam; Milana Frenkel-Morgenstern; Dmitry A. Gordenin; Barbara Hutter; David T.W. Jones; Young Seok Ju; Marat D. Kazanov; Leszek J. Klimczak; Youngil Koh; Eunjung Alice Lee; Jake June Koo Lee; Andy G. Lynch; Geoff Macintyre; Florian Markowetz; Matthew Meyerson; Satoru Miyano; Fabio C.P. Navarro; Stephan Ossowski; Peter J. Park; John V. Pearson; Montserrat Puiggròs; Karsten Rippe; Steven A. Roberts; Bernardo Rodriguez-Martin; Ralph Scully; David Torrents; Izar Villasante; Nicola Waddell; Lixing Yang; Sung Soo Yoon; Jorge Zamora; Lauri A. Aaltonen; Adam Abeshouse; Hiroyuki Aburatani; Li Ding; Lucinda A. Fulton; Robert S. Fulton; Ramaswamy Govindan; Reyka Jayasinghe; Tim Ley; Christopher A. Miller; David Mutch; Michael C. Wendl

doi:10.1038/s41586-020-1965-x

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes

PCAWG Consortium, PCAWG Drivers and Functional Interpretation Working Group, PCAWG-Structural Variation Working Group, Esther Rheinbay, Morten Muhlig Nielsen, Federico Abascal, Jeremiah A. Wala, Ofer Shapira, Grace Tiao, Henrik Hornshøj, Julian M. Hess, Randi Istrup Juul, Ziao Lin, Lars Feuerbach, Radhakrishnan Sabarinathan, Tobias Madsen, Jaegil Kim, Loris Mularoni, Shimin Shuai, Andrés LanzósCarl Herrmann, Yosef E. Maruvka, Ciyue Shen, Samirkumar B. Amin, Pratiti Bandopadhayay, Johanna Bertl, Keith A. Boroevich, John Busanovich, Joana Carlevaro-Fita, Dimple Chakravarty, Calvin Wing Yiu Chan, David Craft, Priyanka Dhingra, Klev Diamanti, Nuno A. Fonseca, Abel Gonzalez-Perez, Qianyun Guo, Mark P. Hamilton, Nicholas J. Haradhvala, Chen Hong, Keren Isaev, Todd A. Johnson, Malene Juul, Andre Kahles, Abdullah Kahraman, Youngwook Kim, Jan Komorowski, Kiran Kumar, Sushant Kumar, Donghoon Lee, Kjong Van Lehmann, Yilong Li, Eric Minwei Liu, Lucas Lochovsky, Keunchil Park, Oriol Pich, Nicola D. Roberts, Gordon Saksena, Steven E. Schumacher, Nikos Sidiropoulos, Lina Sieverling, Nasa Sinnott-Armstrong, Chip Stewart, David Tamborero, Jose M.C. Tubio, Husen M. Umer, Liis Uusküla-Reimand, Claes Wadelius, Lina Wadi, Xiaotong Yao, Cheng Zhong Zhang, Jing Zhang, James E. Haber, Asger Hobolth, Marcin Imielinski, Manolis Kellis, Michael S. Lawrence, Christian von Mering, Hidewaki Nakagawa, Benjamin J. Raphael, Mark A. Rubin, Chris Sander, Lincoln D. Stein, Joshua M. Stuart, Tatsuhiko Tsunoda, David A. Wheeler, Rory Johnson, Jüri Reimand, Mark Gerstein, Ekta Khurana, Peter J. Campbell, Núria López-Bigas, Joachim Weischenfeldt, Rameen Beroukhim, Iñigo Martincorena, Jakob Skou Pedersen, Gad Getz, Gary D. Bader, Jonathan Barenboim, Søren Brunak, Ken Chen, Jung Kyoon Choi, Jordi Deu-Pons, J. Lynn Fink, Joan Frigola, Carlo Gambacorti-Passerini, Dale W. Garsed, Ivo G. Gut, David Haan, Arif O. Harmanci, Mohamed Helmy, Ermin Hodzic, Jose M.G. Izarzugaza, Jong K. Kim, Jan O. Korbel, Erik Larsson, Shantao Li, Xiaotong Li, Shaoke Lou, Kathleen Marchal, Alexander Martinez-Fundichely, Patrick D. McGillivray, William Meyerson, Ferran Muiños, Marta Paczkowska, Kiejung Park, Tirso Pons, Sergio Pulido-Tamayo, Iker Reyes-Salazar, Matthew A. Reyna, Carlota Rubio-Perez, S. Cenk Sahinalp, Leonidas Salichos, Mark Shackleton, Raunak Shrestha, Alfonso Valencia, Miguel Vazquez, Lieven P.C. Verbeke, Jiayin Wang, Jonathan Warrell, Sebastian M. Waszak, Guanming Wu, Jun Yu, Xuanping Zhang, Yan Zhang, Zhongming Zhao, Lihua Zou, Kadir C. Akdemir, Eva G. Alvarez, Adrian Baez-Ortega, Paul C. Boutros, David D.L. Bowtell, Benedikt Brors, Kathleen H. Burns, Kin Chan, Isidro Cortés-Ciriano, Ana Dueso-Barroso, Andrew J. Dunford, Paul A. Edwards, Xavier Estivill, Dariush Etemadmoghadam, Milana Frenkel-Morgenstern, Dmitry A. Gordenin, Barbara Hutter, David T.W. Jones, Young Seok Ju, Marat D. Kazanov, Leszek J. Klimczak, Youngil Koh, Eunjung Alice Lee, Jake June Koo Lee, Andy G. Lynch, Geoff Macintyre, Florian Markowetz, Matthew Meyerson, Satoru Miyano, Fabio C.P. Navarro, Stephan Ossowski, Peter J. Park, John V. Pearson, Montserrat Puiggròs, Karsten Rippe, Steven A. Roberts, Bernardo Rodriguez-Martin, Ralph Scully, David Torrents, Izar Villasante, Nicola Waddell, Lixing Yang, Sung Soo Yoon, Jorge Zamora, Lauri A. Aaltonen, Adam Abeshouse, Hiroyuki Aburatani, Li Ding, Lucinda A. Fulton, Robert S. Fulton, Ramaswamy Govindan, Reyka Jayasinghe, Tim Ley, Christopher A. Miller, David Mutch, Michael C. Wendl

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

371 Scopus citations

Abstract

The discovery of drivers of cancer has traditionally focused on protein-coding genes^1–4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium⁵ of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers^6,7, raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53, in the 3′ untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

Original language	English
Pages (from-to)	102-111
Number of pages	10
Journal	Nature
Volume	578
Issue number	7793
DOIs	https://doi.org/10.1038/s41586-020-1965-x
State	Published - Feb 6 2020

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10.1038/s41586-020-1965-x

Cite this

PCAWG Consortium, PCAWG Drivers and Functional Interpretation Working Group, PCAWG-Structural Variation Working Group, Rheinbay, E., Nielsen, M. M., Abascal, F., Wala, J. A., Shapira, O., Tiao, G., Hornshøj, H., Hess, J. M., Juul, R. I., Lin, Z., Feuerbach, L., Sabarinathan, R., Madsen, T., Kim, J., Mularoni, L., Shuai, S., ... Wendl, M. C. (2020). Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. Nature, 578(7793), 102-111. https://doi.org/10.1038/s41586-020-1965-x

@article{89a27c8c44f64fad9cb5c721a30b9452,

title = "Analyses of non-coding somatic drivers in 2,658 cancer whole genomes",

abstract = "The discovery of drivers of cancer has traditionally focused on protein-coding genes1–4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53, in the 3′ untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.",

author = "{PCAWG Consortium} and {PCAWG Drivers and Functional Interpretation Working Group} and {PCAWG-Structural Variation Working Group} and Esther Rheinbay and Nielsen, {Morten Muhlig} and Federico Abascal and Wala, {Jeremiah A.} and Ofer Shapira and Grace Tiao and Henrik Hornsh{\o}j and Hess, {Julian M.} and Juul, {Randi Istrup} and Ziao Lin and Lars Feuerbach and Radhakrishnan Sabarinathan and Tobias Madsen and Jaegil Kim and Loris Mularoni and Shimin Shuai and Andr{\'e}s Lanz{\'o}s and Carl Herrmann and Maruvka, {Yosef E.} and Ciyue Shen and Amin, {Samirkumar B.} and Pratiti Bandopadhayay and Johanna Bertl and Boroevich, {Keith A.} and John Busanovich and Joana Carlevaro-Fita and Dimple Chakravarty and Chan, {Calvin Wing Yiu} and David Craft and Priyanka Dhingra and Klev Diamanti and Fonseca, {Nuno A.} and Abel Gonzalez-Perez and Qianyun Guo and Hamilton, {Mark P.} and Haradhvala, {Nicholas J.} and Chen Hong and Keren Isaev and Johnson, {Todd A.} and Malene Juul and Andre Kahles and Abdullah Kahraman and Youngwook Kim and Jan Komorowski and Kiran Kumar and Sushant Kumar and Donghoon Lee and Lehmann, {Kjong Van} and Yilong Li and Liu, {Eric Minwei} and Lucas Lochovsky and Keunchil Park and Oriol Pich and Roberts, {Nicola D.} and Gordon Saksena and Schumacher, {Steven E.} and Nikos Sidiropoulos and Lina Sieverling and Nasa Sinnott-Armstrong and Chip Stewart and David Tamborero and Tubio, {Jose M.C.} and Umer, {Husen M.} and Liis Uusk{\"u}la-Reimand and Claes Wadelius and Lina Wadi and Xiaotong Yao and Zhang, {Cheng Zhong} and Jing Zhang and Haber, {James E.} and Asger Hobolth and Marcin Imielinski and Manolis Kellis and Lawrence, {Michael S.} and {von Mering}, Christian and Hidewaki Nakagawa and Raphael, {Benjamin J.} and Rubin, {Mark A.} and Chris Sander and Stein, {Lincoln D.} and Stuart, {Joshua M.} and Tatsuhiko Tsunoda and Wheeler, {David A.} and Rory Johnson and J{\"u}ri Reimand and Mark Gerstein and Ekta Khurana and Campbell, {Peter J.} and N{\'u}ria L{\'o}pez-Bigas and Joachim Weischenfeldt and Rameen Beroukhim and I{\~n}igo Martincorena and Pedersen, {Jakob Skou} and Gad Getz and Bader, {Gary D.} and Jonathan Barenboim and S{\o}ren Brunak and Ken Chen and Choi, {Jung Kyoon} and Jordi Deu-Pons and Fink, {J. Lynn} and Joan Frigola and Carlo Gambacorti-Passerini and Garsed, {Dale W.} and Gut, {Ivo G.} and David Haan and Harmanci, {Arif O.} and Mohamed Helmy and Ermin Hodzic and Izarzugaza, {Jose M.G.} and Kim, {Jong K.} and Korbel, {Jan O.} and Erik Larsson and Shantao Li and Xiaotong Li and Shaoke Lou and Kathleen Marchal and Alexander Martinez-Fundichely and McGillivray, {Patrick D.} and William Meyerson and Ferran Mui{\~n}os and Marta Paczkowska and Kiejung Park and Tirso Pons and Sergio Pulido-Tamayo and Iker Reyes-Salazar and Reyna, {Matthew A.} and Carlota Rubio-Perez and Sahinalp, {S. Cenk} and Leonidas Salichos and Mark Shackleton and Raunak Shrestha and Alfonso Valencia and Miguel Vazquez and Verbeke, {Lieven P.C.} and Jiayin Wang and Jonathan Warrell and Waszak, {Sebastian M.} and Guanming Wu and Jun Yu and Xuanping Zhang and Yan Zhang and Zhongming Zhao and Lihua Zou and Akdemir, {Kadir C.} and Alvarez, {Eva G.} and Adrian Baez-Ortega and Boutros, {Paul C.} and Bowtell, {David D.L.} and Benedikt Brors and Burns, {Kathleen H.} and Kin Chan 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 Milana Frenkel-Morgenstern and Gordenin, {Dmitry A.} and Barbara Hutter and Jones, {David T.W.} and Ju, {Young Seok} and Kazanov, {Marat D.} and Klimczak, {Leszek J.} and Youngil Koh and Lee, {Eunjung Alice} and Lee, {Jake June Koo} and Lynch, {Andy G.} and Geoff Macintyre and Florian Markowetz and Matthew Meyerson and Satoru Miyano and Navarro, {Fabio C.P.} and Stephan Ossowski and Park, {Peter J.} and Pearson, {John V.} and Montserrat Puiggr{\`o}s and Karsten Rippe and Roberts, {Steven A.} and Bernardo Rodriguez-Martin and Ralph Scully and David Torrents and Izar Villasante and Nicola Waddell and Lixing Yang and Yoon, {Sung Soo} and Jorge Zamora and Aaltonen, {Lauri A.} and Adam Abeshouse and Hiroyuki Aburatani 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 David Mutch and Wendl, {Michael C.}",

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

year = "2020",

month = feb,

day = "6",

doi = "10.1038/s41586-020-1965-x",

language = "English",

volume = "578",

pages = "102--111",

journal = "Nature",

issn = "0028-0836",

number = "7793",

}

PCAWG Consortium, PCAWG Drivers and Functional Interpretation Working Group, PCAWG-Structural Variation Working Group, Rheinbay, E, Nielsen, MM, Abascal, F, Wala, JA, Shapira, O, Tiao, G, Hornshøj, H, Hess, JM, Juul, RI, Lin, Z, Feuerbach, L, Sabarinathan, R, Madsen, T, Kim, J, Mularoni, L, Shuai, S, Lanzós, A, Herrmann, C, Maruvka, YE, Shen, C, Amin, SB, Bandopadhayay, P, Bertl, J, Boroevich, KA, Busanovich, J, Carlevaro-Fita, J, Chakravarty, D, Chan, CWY, Craft, D, Dhingra, P, Diamanti, K, Fonseca, NA, Gonzalez-Perez, A, Guo, Q, Hamilton, MP, Haradhvala, NJ, Hong, C, Isaev, K, Johnson, TA, Juul, M, Kahles, A, Kahraman, A, Kim, Y, Komorowski, J, Kumar, K, Kumar, S, Lee, D, Lehmann, KV, Li, Y, Liu, EM, Lochovsky, L, Park, K, Pich, O, Roberts, ND, Saksena, G, Schumacher, SE, Sidiropoulos, N, Sieverling, L, Sinnott-Armstrong, N, Stewart, C, Tamborero, D, Tubio, JMC, Umer, HM, Uusküla-Reimand, L, Wadelius, C, Wadi, L, Yao, X, Zhang, CZ, Zhang, J, Haber, JE, Hobolth, A, Imielinski, M, Kellis, M, Lawrence, MS, von Mering, C, Nakagawa, H, Raphael, BJ, Rubin, MA, Sander, C, Stein, LD, Stuart, JM, Tsunoda, T, Wheeler, DA, Johnson, R, Reimand, J, Gerstein, M, Khurana, E, Campbell, PJ, López-Bigas, N, Weischenfeldt, J, Beroukhim, R, Martincorena, I, Pedersen, JS, Getz, G, Bader, GD, Barenboim, J, Brunak, S, Chen, K, Choi, JK, Deu-Pons, J, Fink, JL, Frigola, J, Gambacorti-Passerini, C, Garsed, DW, Gut, IG, Haan, D, Harmanci, AO, Helmy, M, Hodzic, E, Izarzugaza, JMG, Kim, JK, Korbel, JO, Larsson, E, Li, S, Li, X, Lou, S, Marchal, K, Martinez-Fundichely, A, McGillivray, PD, Meyerson, W, Muiños, F, Paczkowska, M, Park, K, Pons, T, Pulido-Tamayo, S, Reyes-Salazar, I, Reyna, MA, Rubio-Perez, C, Sahinalp, SC, Salichos, L, Shackleton, M, Shrestha, R, Valencia, A, Vazquez, M, Verbeke, LPC, Wang, J, Warrell, J, Waszak, SM, Wu, G, Yu, J, Zhang, X, Zhang, Y, Zhao, Z, Zou, L, Akdemir, KC, Alvarez, EG, Baez-Ortega, A, Boutros, PC, Bowtell, DDL, Brors, B, Burns, KH, Chan, K, Cortés-Ciriano, I, Dueso-Barroso, A, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Frenkel-Morgenstern, M, Gordenin, DA, Hutter, B, Jones, DTW, Ju, YS, Kazanov, MD, Klimczak, LJ, Koh, Y, Lee, EA, Lee, JJK, Lynch, AG, Macintyre, G, Markowetz, F, Meyerson, M, Miyano, S, Navarro, FCP, Ossowski, S, Park, PJ, Pearson, JV, Puiggròs, M, Rippe, K, Roberts, SA, Rodriguez-Martin, B, Scully, R, Torrents, D, Villasante, I, Waddell, N, Yang, L, Yoon, SS, Zamora, J, Aaltonen, LA, Abeshouse, A, Aburatani, H, Ding, L , Fulton, LA , Fulton, RS , Govindan, R , Jayasinghe, R , Ley, T , Miller, CA , Mutch, D & Wendl, MC 2020, 'Analyses of non-coding somatic drivers in 2,658 cancer whole genomes', Nature, vol. 578, no. 7793, pp. 102-111. https://doi.org/10.1038/s41586-020-1965-x

TY - JOUR

T1 - Analyses of non-coding somatic drivers in 2,658 cancer whole genomes

AU - PCAWG Consortium

AU - PCAWG Drivers and Functional Interpretation Working Group

AU - PCAWG-Structural Variation Working Group

AU - Rheinbay, Esther

AU - Nielsen, Morten Muhlig

AU - Abascal, Federico

AU - Wala, Jeremiah A.

AU - Shapira, Ofer

AU - Tiao, Grace

AU - Hornshøj, Henrik

AU - Hess, Julian M.

AU - Juul, Randi Istrup

AU - Lin, Ziao

AU - Feuerbach, Lars

AU - Sabarinathan, Radhakrishnan

AU - Madsen, Tobias

AU - Kim, Jaegil

AU - Mularoni, Loris

AU - Shuai, Shimin

AU - Lanzós, Andrés

AU - Herrmann, Carl

AU - Maruvka, Yosef E.

AU - Shen, Ciyue

AU - Amin, Samirkumar B.

AU - Bandopadhayay, Pratiti

AU - Bertl, Johanna

AU - Boroevich, Keith A.

AU - Busanovich, John

AU - Carlevaro-Fita, Joana

AU - Chakravarty, Dimple

AU - Chan, Calvin Wing Yiu

AU - Craft, David

AU - Dhingra, Priyanka

AU - Diamanti, Klev

AU - Fonseca, Nuno A.

AU - Gonzalez-Perez, Abel

AU - Guo, Qianyun

AU - Hamilton, Mark P.

AU - Haradhvala, Nicholas J.

AU - Hong, Chen

AU - Isaev, Keren

AU - Johnson, Todd A.

AU - Juul, Malene

AU - Kahles, Andre

AU - Kahraman, Abdullah

AU - Kim, Youngwook

AU - Komorowski, Jan

AU - Kumar, Kiran

AU - Kumar, Sushant

AU - Lee, Donghoon

AU - Lehmann, Kjong Van

AU - Li, Yilong

AU - Liu, Eric Minwei

AU - Lochovsky, Lucas

AU - Park, Keunchil

AU - Pich, Oriol

AU - Roberts, Nicola D.

AU - Saksena, Gordon

AU - Schumacher, Steven E.

AU - Sidiropoulos, Nikos

AU - Sieverling, Lina

AU - Sinnott-Armstrong, Nasa

AU - Stewart, Chip

AU - Tamborero, David

AU - Tubio, Jose M.C.

AU - Umer, Husen M.

AU - Uusküla-Reimand, Liis

AU - Wadelius, Claes

AU - Wadi, Lina

AU - Yao, Xiaotong

AU - Zhang, Cheng Zhong

AU - Zhang, Jing

AU - Haber, James E.

AU - Hobolth, Asger

AU - Imielinski, Marcin

AU - Kellis, Manolis

AU - Lawrence, Michael S.

AU - von Mering, Christian

AU - Nakagawa, Hidewaki

AU - Raphael, Benjamin J.

AU - Rubin, Mark A.

AU - Sander, Chris

AU - Stein, Lincoln D.

AU - Stuart, Joshua M.

AU - Tsunoda, Tatsuhiko

AU - Wheeler, David A.

AU - Johnson, Rory

AU - Reimand, Jüri

AU - Gerstein, Mark

AU - Khurana, Ekta

AU - Campbell, Peter J.

AU - López-Bigas, Núria

AU - Weischenfeldt, Joachim

AU - Beroukhim, Rameen

AU - Martincorena, Iñigo

AU - Pedersen, Jakob Skou

AU - Getz, Gad

AU - Bader, Gary D.

AU - Barenboim, Jonathan

AU - Brunak, Søren

AU - Chen, Ken

AU - Choi, Jung Kyoon

AU - Deu-Pons, Jordi

AU - Fink, J. Lynn

AU - Frigola, Joan

AU - Gambacorti-Passerini, Carlo

AU - Garsed, Dale W.

AU - Gut, Ivo G.

AU - Haan, David

AU - Harmanci, Arif O.

AU - Helmy, Mohamed

AU - Hodzic, Ermin

AU - Izarzugaza, Jose M.G.

AU - Kim, Jong K.

AU - Korbel, Jan O.

AU - Larsson, Erik

AU - Li, Shantao

AU - Li, Xiaotong

AU - Lou, Shaoke

AU - Marchal, Kathleen

AU - Martinez-Fundichely, Alexander

AU - McGillivray, Patrick D.

AU - Meyerson, William

AU - Muiños, Ferran

AU - Paczkowska, Marta

AU - Park, Kiejung

AU - Pons, Tirso

AU - Pulido-Tamayo, Sergio

AU - Reyes-Salazar, Iker

AU - Reyna, Matthew A.

AU - Rubio-Perez, Carlota

AU - Sahinalp, S. Cenk

AU - Salichos, Leonidas

AU - Shackleton, Mark

AU - Shrestha, Raunak

AU - Valencia, Alfonso

AU - Vazquez, Miguel

AU - Verbeke, Lieven P.C.

AU - Wang, Jiayin

AU - Warrell, Jonathan

AU - Waszak, Sebastian M.

AU - Wu, Guanming

AU - Yu, Jun

AU - Zhang, Xuanping

AU - Zhang, Yan

AU - Zhao, Zhongming

AU - Zou, Lihua

AU - Akdemir, Kadir C.

AU - Alvarez, Eva G.

AU - Baez-Ortega, Adrian

AU - Boutros, Paul C.

AU - Bowtell, David D.L.

AU - Brors, Benedikt

AU - Burns, Kathleen H.

AU - Chan, Kin

AU - Cortés-Ciriano, Isidro

AU - Dueso-Barroso, Ana

AU - Dunford, Andrew J.

AU - Edwards, Paul A.

AU - Estivill, Xavier

AU - Etemadmoghadam, Dariush

AU - Frenkel-Morgenstern, Milana

AU - Gordenin, Dmitry A.

AU - Hutter, Barbara

AU - Jones, David T.W.

AU - Ju, Young Seok

AU - Kazanov, Marat D.

AU - Klimczak, Leszek J.

AU - Koh, Youngil

AU - Lee, Eunjung Alice

AU - Lee, Jake June Koo

AU - Lynch, Andy G.

AU - Macintyre, Geoff

AU - Markowetz, Florian

AU - Meyerson, Matthew

AU - Miyano, Satoru

AU - Navarro, Fabio C.P.

AU - Ossowski, Stephan

AU - Park, Peter J.

AU - Pearson, John V.

AU - Puiggròs, Montserrat

AU - Rippe, Karsten

AU - Roberts, Steven A.

AU - Rodriguez-Martin, Bernardo

AU - Scully, Ralph

AU - Torrents, David

AU - Villasante, Izar

AU - Waddell, Nicola

AU - Yang, Lixing

AU - Yoon, Sung Soo

AU - Zamora, Jorge

AU - Aaltonen, Lauri A.

AU - Abeshouse, Adam

AU - Aburatani, Hiroyuki

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 - Mutch, David

AU - Wendl, Michael C.

PY - 2020/2/6

Y1 - 2020/2/6

N2 - The discovery of drivers of cancer has traditionally focused on protein-coding genes1–4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53, in the 3′ untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

AB - The discovery of drivers of cancer has traditionally focused on protein-coding genes1–4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53, in the 3′ untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

UR - http://www.scopus.com/inward/record.url?scp=85079047263&partnerID=8YFLogxK

U2 - 10.1038/s41586-020-1965-x

DO - 10.1038/s41586-020-1965-x

M3 - Article

C2 - 32025015

AN - SCOPUS:85079047263

SN - 0028-0836

VL - 578

SP - 102

EP - 111

JO - Nature

JF - Nature

IS - 7793

ER -

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes

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