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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Dokumenter

  • Esther Rheinbay
  • Morten Muhlig Nielsen
  • Federico Abascal
  • Jeremiah A Wala
  • Ofer Shapira
  • Grace Tiao
  • Henrik Hornshøj
  • Julian M Hess
  • Randi Istrup Juul
  • Ziao Lin
  • Lars Feuerbach
  • Radhakrishnan Sabarinathan
  • Tobias Madsen
  • Jaegil Kim
  • Loris Mularoni
  • Shimin Shuai
  • Andrés Lanzós
  • Carl Herrmann
  • Yosef E Maruvka
  • Ciyue Shen
  • Samirkumar B Amin
  • Pratiti Bandopadhayay
  • Johanna Bertl
  • Keith A Boroevich
  • John Busanovich
  • Joana Carlevaro-Fita
  • Dimple Chakravarty
  • Calvin Wing Yiu Chan
  • David Craft
  • Priyanka Dhingra
  • Klev Diamanti
  • Nuno A Fonseca
  • Abel Gonzalez-Perez
  • Qianyun Guo
  • Mark P Hamilton
  • Nicholas J Haradhvala
  • Chen Hong
  • Keren Isaev
  • Todd A Johnson
  • Malene Juul
  • Andre Kahles
  • Abdullah Kahraman
  • Youngwook Kim
  • Jan Komorowski
  • Kiran Kumar
  • Sushant Kumar
  • Donghoon Lee
  • Sidiropoulos, Nikos
  • Weischenfeldt, Joachim Lütken
  • Jakob Skou Pedersen
  • PCAWG Drivers and Functional Interpretation Working Group

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.

OriginalsprogEngelsk
TidsskriftNature
Vol/bind578
Udgave nummer7793
Sider (fra-til)102-111
Antal sider10
ISSN0028-0836
DOI
StatusUdgivet - feb. 2020

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