TY - JOUR
T1 - Analyses of non-coding somatic drivers in 2,658 cancer whole genomes
AU - PCAWG Drivers and Functional Interpretation Working Group
AU - PCAWG Structural Variation Working Group
AU - PCAWG Consortium
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 - 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 - Raphael, Benjamin J.
N1 - Funding Information:
Competing interests The following authors declare that they have competing interests. P.B. receives grant funding from Novartis from an unrelated project; R.B. owns equity in Ampressa Therapeutics and receives grant funding from Novartis; G.G. receives research funds from IBM and Pharmacyclics and is an inventor on patent applications related to MuTect, ABSOLUTE, MutSig, MSMuTect, MSMutSig and POLYSOLVER; B.J.R. is a consultant at and has ownership interest (including stock, patents and so on) in Medley Genomics; O.S. is currently an employee of Cedilla Therapeutics); and Y.L. is currently an employee of Seven Bridges Genomics.
Funding Information:
Acknowledgements We thank the ICGC and TCGA PCAWG Network and the PCAWG steering committee for enabling this work, and for guidance throughout the study. We thank K. Kübler for assistance with meta-cohort generation and R. Heller for discussion on FDR. We are grateful to the PCAWG steering committee, M. Meyerson and E. S. Lander for helpful feedback, and M. Miller for editing this manuscript. Work in the Getz laboratory was partially funded by the GDAC grants (NIH U24CA143845 and NIH U24CA210999), G.G.’s funds at the Broad Institute and MGH. G.G. is also partially supported by the Paul C. Zamecnik Chair in Oncology in MGH. J.S.P. was partially funded by Independent Research Fund Denmark (12-126439 and 7016-00379) and The Danish Cancer Society (R124-A7869). R.B. received funds from the National Institutes of Health (U54CA143798, R01CA188228, R35GM127029, and R01CA215489), the DFCI-Novartis Drug Discovery Program, the Pediatric Low Grade Astrocytoma Foundation, the Cure Starts Now Foundation and The Fund for Innovation in Cancer Informatics. J.W. was partly funded by Independent Research Fund Denmark (4183-00233B and 8020-00282B) and Danish Cancer Society (R147-Rp12977). N.L.-B. acknowledges funding from the European Research Council consolidator grant 682398) and Spanish Ministry of Economy and Competitiveness (SAF2015-66084-R, MINECO/FEDER, UE). We acknowledge the contributions of the many clinical networks across ICGC and TCGA who provided samples and data to the PCAWG Consortium, and the contributions of the Technical Working Group and the Germline Working Group of the PCAWG Consortium for collation, realignment and harmonized variant calling of the cancer genomes used in this study. We thank the patients and their families for their participation in the individual ICGC and TCGA projects.
Publisher Copyright:
© 2020, The Author(s).
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.
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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 -