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.
| Original language | English |
|---|---|
| Pages (from-to) | 102-111 |
| Number of pages | 10 |
| Journal | Nature |
| Volume | 578 |
| Issue number | 7793 |
| DOIs | |
| State | Published - 6 Feb 2020 |
Bibliographical note
Publisher Copyright:© 2020, The Author(s).
Funding
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. 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.
| Funders | Funder number |
|---|---|
| DFCI-Novartis Drug Discovery Program | |
| GDAC | |
| MINECO/FEDER | |
| MSMutSig | |
| Spanish Ministry of Economy and Competitiveness | SAF2015-66084-R |
| National Institutes of Health | U24CA210999, R01CA215489, R35GM127029, R01CA188228, U54CA143798, U24CA143845 |
| National Human Genome Research Institute | R01HG007069 |
| International Business Machines Corporation | |
| Massachusetts General Hospital | |
| Pediatric Low Grade Astrocytoma Foundation | |
| Cure Starts Now Foundation | 4183-00233B, 8020-00282B, R147-Rp12977 |
| Kræftens Bekæmpelse | R124-A7869 |
| Broad Institute | |
| European Commission | 682398 |
| Danmarks Frie Forskningsfond | 12-126439, 7016-00379 |
