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Nature. 2020 Feb;578(7793):102-111. doi: 10.1038/s41586-020-1965-x. Epub 2020 Feb 5.

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

Rheinbay E1,2,3, Nielsen MM4, Abascal F5, Wala JA1,6, Shapira O1,7, Tiao G1, Hornshøj H4, Hess JM1, Juul RI4, Lin Z1,8, Feuerbach L9, Sabarinathan R10,11, Madsen T4, Kim J1, Mularoni L10,11, Shuai S12,13, Lanzós A14,15,16, Herrmann C17,18, Maruvka YE1,2, Shen C19,20, Amin SB21,22, Bandopadhayay P1,7, Bertl J4, Boroevich KA23, Busanovich J1,7, Carlevaro-Fita J14,15,16, Chakravarty D24,25, Chan CWY17,26, Craft D27, Dhingra P28,29, Diamanti K30, Fonseca NA31, Gonzalez-Perez A10,11, Guo Q32, Hamilton MP33, Haradhvala NJ1,2, Hong C9,26, Isaev K12,34, Johnson TA23, Juul M4, Kahles A35, Kahraman A36, Kim Y37, Komorowski J30,38, Kumar K1,7, Kumar S39, Lee D39, Lehmann KV35, Li Y40,41, Liu EM28,29, Lochovsky L42, Park K37, Pich O10,11, Roberts ND41, Saksena G1, Schumacher SE1,7, Sidiropoulos N43, Sieverling L9,26, Sinnott-Armstrong N44, Stewart C1, Tamborero D10,11, Tubio JMC45,46,47, Umer HM30, Uusküla-Reimand L48,49, Wadelius C50, Wadi L12, Yao X51, Zhang CZ52,53, Zhang J39, Haber JE54, Hobolth A32, Imielinski M51,55, Kellis M1,56, Lawrence MS1,2, von Mering C36, Nakagawa H57, Raphael BJ58, Rubin MA59,60,61, Sander C19,20, Stein LD12,13, Stuart JM62, Tsunoda T23,63,64, Wheeler DA65, Johnson R14,16, Reimand J12,34, Gerstein M39,42,66, Khurana E28,29,60,61, Campbell PJ5,41, López-Bigas N10,11,67; PCAWG Drivers and Functional Interpretation Working Group; PCAWG Structural Variation Working Group, Weischenfeldt J68,69, Beroukhim R70,71,72, Martincorena I73, Pedersen JS74,75, Getz G76,77,78,79; PCAWG Consortium.

Collaborators (201)

Abascal F, Amin SB, Bader GD, Bandopadhayay P, Barenboim J, Beroukhim R, Bertl J, Boroevich KA, Brunak S, Campbell PJ, Carlevaro-Fita J, Chakravarty D, Chan CWY, Chen K, Choi JK, Deu-Pons J, Dhingra P, Diamanti K, Feuerbach L, Fink JL, Fonseca NA, Frigola J, Gambacorti-Passerini C, Garsed DW, Gerstein M, Getz G, Guo Q, Gut IG, Haan D, Hamilton MP, Haradhvala NJ, Harmanci AO, Helmy M, Herrmann C, Hess JM, Hobolth A, Hodzic E, Hong C, Hornshøj H, Isaev K, Izarzugaza JMG, Johnson R, Johnson TA, Juul M, Juul RI, Kahles A, Kahraman A, Kellis M, Khurana E, Kim J, Kim JK, Kim Y, Komorowski J, Korbel JO, Kumar S, Lanzós A, Larsson E, Lawrence MS, Lee D, Lehmann KV, Li S, Li X, Lin Z, Liu EM, Lochovsky L, Lou S, Madsen T, Marchal K, Martincorena I, Martinez-Fundichely A, Maruvka YE, McGillivray PD, Meyerson W, Muiños F, Mularoni L, Nakagawa H, Nielsen MM, Paczkowska M, Park K, Park K, Pedersen JS, Pons T, Pulido-Tamayo S, Raphael BJ, Reimand J, Reyes-Salazar I, Reyna MA, Rheinbay E, Rubin MA, Rubio-Perez C, Sahinalp SC, Saksena G, Salichos L, Sander C, Schumacher SE, Shackleton M, Shapira O, Shen C, Shrestha R, Shuai S, Sidiropoulos N, Sieverling L, Sinnott-Armstrong N, Stein LD, Stuart JM, Tamborero D, Tiao G, Tsunoda T, Umer HM, Uusküla-Reimand L, Valencia A, Vazquez M, Verbeke LPC, Wadelius C, Wadi L, Wang J, Warrell J, Waszak SM, Weischenfeldt J, Wheeler DA, Wu G, Yu J, Zhang J, Zhang X, Zhang Y, Zhao Z, Zou L, von Mering C, Akdemir KC, Alvarez EG, Baez-Ortega A, Beroukhim R, Boutros PC, Bowtell DDL, Brors B, Burns KH, Busanovich J, Campbell PJ, Chan K, Chen K, Cortés-Ciriano I, Dueso-Barroso A, Dunford AJ, Edwards PA, Estivill X, Etemadmoghadam D, Feuerbach L, Fink JL, Frenkel-Morgenstern M, 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 JJ, Li Y, Lynch AG, Macintyre G, Markowetz F, Martincorena I, Martinez-Fundichely A, Meyerson M, Miyano S, Nakagawa H, Navarro FCP, Ossowski S, Park PJ, 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.

Author information

1
The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
2
Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.
3
Harvard Medical School, Boston, MA, USA.
4
Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark.
5
Wellcome Trust Sanger Institute, Hinxton, UK.
6
Bioinformatics and Integrative Genomics, Harvard University, Cambridge, MA, USA.
7
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
8
Harvard University, Cambridge, MA, USA.
9
Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
10
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
11
Research Program on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain.
12
Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
13
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
14
Department for BioMedical Research, University of Bern, Bern, Switzerland.
15
Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
16
Department of Medical Oncology, Bern University Hospital, University of Bern, Bern, Switzerland.
17
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
18
Bioquant Center, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany.
19
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
20
cBio Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
21
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
22
Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX, USA.
23
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
24
Department of Genitourinary Medical Oncology - Research, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
25
Department of Urology, Icahn school of Medicine at Mount Sinai, New York, NY, USA.
26
Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
27
Department of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
28
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
29
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
30
Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
31
European Bioinformatics Institute, European Molecular Biology Laboratory, Hinxton, UK.
32
Bioinformatics Research Centre (BiRC), Aarhus University, Aarhus, Denmark.
33
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
34
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
35
Division of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
36
Institute of Molecular Life Sciences and Swiss Institute of Bioinformatics, University of Zurich, Zurich, Switzerland.
37
Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
38
Institute of Computer Science, Polish Academy of Sciences, Warsaw, Poland.
39
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
40
SBGD Inc, Cambridge, MA, USA.
41
Department of Haematology, University of Cambridge, Cambridge, UK.
42
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
43
Biotech Research & Innovation Centre (BRIC), The Finsen Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
44
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
45
Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
46
Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
47
The Biomedical Research Centre (CINBIO), Universidade de Vigo, Vigo, Spain.
48
Genetics and Genome Biology Program, SickKids Research Institute, Toronto, Ontario, Canada.
49
Department of Gene Technology, Tallinn University of Technology, Tallinn, Estonia.
50
Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
51
New York Genome Center, New York, NY, USA.
52
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
53
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
54
Department of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA, USA.
55
Department of Pathology and Laboratory Medicine, and Englander Institute for Precision Medicine, and Institute for Computational Biomedicine, and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
56
MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA.
57
Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
58
Department of Computer Science, Princeton University, Princeton, NJ, USA.
59
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
60
Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
61
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
62
Center for Biomolecular Science and Engineering, University of California at Santa Cruz, Santa Cruz, CA, USA.
63
Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
64
Laboratory for Medical Science Mathematics, Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
65
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
66
Department of Computer Science, Yale University, New Haven, CT, USA.
67
Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
68
Biotech Research & Innovation Centre (BRIC), The Finsen Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. joachim.weischenfeldt@bric.ku.dk.
69
Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. joachim.weischenfeldt@bric.ku.dk.
70
The Broad Institute of MIT and Harvard, Cambridge, MA, USA. rameen@broadinstitute.org.
71
Bioinformatics and Integrative Genomics, Harvard University, Cambridge, MA, USA. rameen@broadinstitute.org.
72
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. rameen@broadinstitute.org.
73
Wellcome Trust Sanger Institute, Hinxton, UK. im3@sanger.ac.uk.
74
Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark. jakob.skou@clin.au.dk.
75
Bioinformatics Research Centre (BiRC), Aarhus University, Aarhus, Denmark. jakob.skou@clin.au.dk.
76
The Broad Institute of MIT and Harvard, Cambridge, MA, USA. gadgetz@broadinstitute.org.
77
Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA. gadgetz@broadinstitute.org.
78
Harvard Medical School, Boston, MA, USA. gadgetz@broadinstitute.org.
79
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. gadgetz@broadinstitute.org.

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.

PMID:
32025015
DOI:
10.1038/s41586-020-1965-x

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