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

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

Authors:	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.; Lanzós, A.; Herrmann, C.; Maruvka, Y. E.; Shen, C.; Amin, S. B.; Bandopadhayay, P.; Bertl, J.; Boroevich, K. A.; Busanovich, J.; Carlevaro-Fita, J.; Chakravarty, D.; Chan, C. W. Y.; Craft, D.; Dhingra, P.; Diamanti, K.; Fonseca, N. A.; Gonzalez-Perez, A.; Guo, Q.; Hamilton, M. P.; Haradhvala, N. J.; Hong, C.; Isaev, K.; Johnson, T. A.; Juul, M.; Kahles, A.; Kahraman, A.; Kim, Y.; Komorowski, J.; Kumar, K.; Kumar, S.; Lee, D.; Lehmann, K. V.; Li, Y.; Liu, E. M.; Lochovsky, L.; Park, K.; Pich, O.; Roberts, N. D.; Saksena, G.; Schumacher, S. E.; Sidiropoulos, N.; Sieverling, L.; Sinnott-Armstrong, N.; Stewart, C.; Tamborero, D.; Tubio, J. M. C.; Umer, H. M.; Uusküla-Reimand, L.; Wadelius, C.; Wadi, L.; Yao, X.; Zhang, C. Z.; Zhang, J.; Haber, J. E.; Hobolth, A.; Imielinski, M.; Kellis, M.; Lawrence, M. S.; von Mering, C.; Nakagawa, H.; Raphael, B. J.; Rubin, M. A.; Sander, C.; Stein, L. D.; Stuart, J. M.; Tsunoda, T.; Wheeler, D. A.; Johnson, R.; Reimand, J.; Gerstein, M.; Khurana, E.; Campbell, P. J.; López-Bigas, N.; PCAWG Drivers and Functional Interpretation Working Group; PCAWG Structural Variation Working Group; Weischenfeldt, J.; Beroukhim, R.; Martincorena, I.; Pedersen, J. S.; Getz, G.; & PCAWG Consortium
Contributors:	Abeshouse, A.; Al-Ahmadie, H.; Armenia, J.; Chen, H. W.; Davidson, N. R.; Gao, J.; Ghossein, R.; Giri, D. D.; Gundem, G.; Heins, Z.; Huse, J.; Iacobuzio-Donahue, C. A.; King, T. A.; Kundra, R.; Levine, D. A.; Ochoa, A.; Pastore, A.; Rätsch, G.; Reis-Filho, J.; Reuter, V.; Roehrl, M. H. A.; Sanchez-Vega, F.; Sander, C.; Schultz, N.; Senbabaoglu, Y.; Singer, S.; Socci, N. D.; Stark, S. G.; Vázquez-García, I.; Yellapantula, V. D.; Zhang, H.
Article 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. © 2020, The Author(s).
Keywords:	promoter region; single nucleotide polymorphism; mutation; gene amplification; gene expression; protein; gene locus; genetic variability; genetic transcription; mutational analysis; cancer genetics; oncogene; gene rearrangement; gene identification; gene control; genome; point mutation; genetic screening; genetic code; gene structure; indel mutation; tp53 gene; cancer; human; priority journal; article; whole genome sequencing; malignant neoplasm; akr1c gene; brd4 gene; nfkbiz gene; tob1 gene
Journal Title:	Nature
Volume:	578
Issue:	7793
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2020-02-05
Start Page:	102
End Page:	111
Language:	English
DOI:	10.1038/s41586-020-1965-x
PUBMED:	32025015
PROVIDER:	scopus
PMCID:	PMC7054214
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85079047263&doi=10.1038%2fs41586-020-1965-x&partnerID=40&md5=e721e9bf4ea166561c59c4562c4b0ae0
Notes:	Erratum issued, see DOI: 10.1038/s41586-022-05599-9 -- Article -- Export Date: 2 March 2020 -- Source: Scopus