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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Esther Rheinbay, Broad Institute, Massachusetts General Hospital, Boston, Harvard Medical School
  • ,
  • Morten Muhlig Nielsen
  • Federico Abascal, Wellcome Sanger Institute
  • ,
  • Jeremiah A. Wala, Broad Institute, Harvard University
  • ,
  • Ofer Shapira, Broad Institute, Dana-Farber Cancer Institute
  • ,
  • Grace Tiao, Broad Institute
  • ,
  • Henrik Hornshøj
  • ,
  • Julian M. Hess, Broad Institute
  • ,
  • Randi Istrup Juul
  • Ziao Lin, Broad Institute, Harvard University
  • ,
  • Lars Feuerbach, German Cancer Research Center, Heidelberg
  • ,
  • Radhakrishnan Sabarinathan, Institute for Research in Biomedicine, Pompeu Fabra University
  • ,
  • Tobias Madsen
  • ,
  • Jaegil Kim, Broad Institute
  • ,
  • Loris Mularoni, Institute for Research in Biomedicine, Pompeu Fabra University
  • ,
  • Shimin Shuai, Ontario Institute for Cancer Research
  • ,
  • Andrés Lanzós, University of Bern
  • ,
  • Carl Herrmann, German Cancer Research Center, Heidelberg, Heidelberg University 
  • ,
  • Yosef E. Maruvka, Broad Institute, Massachusetts General Hospital, Boston
  • ,
  • Ciyue Shen, Harvard Medical School
  • ,
  • Samirkumar B. Amin, University of Texas MD Anderson Cancer Center, Baylor College of Medicine
  • ,
  • Pratiti Bandopadhayay
  • ,
  • Johanna Bertl
  • ,
  • Keith A. Boroevich
  • ,
  • John Busanovich, Broad Institute, Dana-Farber Cancer Institute
  • ,
  • Joana Carlevaro-Fita, University of Bern
  • ,
  • Dimple Chakravarty, University of Texas MD Anderson Cancer Center, Icahn School of Medicine at Mount Sinai
  • ,
  • Calvin Wing Yiu Chan, German Cancer Research Center, Heidelberg, Heidelberg University 
  • ,
  • David Craft, Massachusetts General Hospital, Boston
  • ,
  • Priyanka Dhingra, Cornell University
  • ,
  • Klev Diamanti, Uppsala Universitet
  • ,
  • Nuno A. Fonseca, European Bioinformatics Institute
  • ,
  • Abel Gonzalez-Perez, Institute for Research in Biomedicine, Pompeu Fabra University
  • ,
  • Qianyun Guo
  • ,
  • Mark P. Hamilton, Baylor College of Medicine
  • ,
  • Nicholas J. Haradhvala, Broad Institute, Massachusetts General Hospital, Boston
  • ,
  • Chen Hong, German Cancer Research Center, Heidelberg, Heidelberg University 
  • ,
  • Cheng Zhong Zhang, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School
  • ,
  • Asger Hobolth
  • Jakob Skou Pedersen
  • PCAWG Consortium

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 languageEnglish
JournalNature
Volume578
Issue7793
Pages (from-to)102-111
Number of pages10
ISSN0028-0836
DOIs
Publication statusPublished - 2020

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