A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Research output: Contribution to journalArticle

Abstract

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.

Details

Authors
  • Dominik Glodzik
  • Sandro Morganella
  • Helen R. Davies
  • Peter T Simpson
  • Yilong Li
  • Xueqing Zou
  • Javier Diez-Perez
  • Ludmil B. Alexandrov
  • Marcel Smid
  • Arie B Brinkman
  • Inga Hansine Rye
  • Hege Russnes
  • Keiran Raine
  • Colin A Purdie
  • Sunil R. Lakhani
  • Alastair M Thompson
  • Ewan Birney
  • Hendrik G. Stunnenberg
  • Marc J van de Vijver
  • John W M Martens
  • Anne-Lise Børresen-Dale
  • Andrea L. Richardson
  • Gu Kong
  • Alain Viari
  • Douglas Easton
  • Gerard Evan
  • Peter J. Campbell
  • Michael R. Stratton
  • Serena Nik-Zainal
Organisations
External organisations
  • Wellcome Trust Sanger Institute
  • University of Queensland
  • Los Alamos National Laboratory
  • Erasmus University Medical Center
  • Erasmus University Rotterdam
  • Radboud University Nijmegen
  • Norwegian Radium Hospital
  • University of Oslo
  • Ninewells Hospital and Medical School
  • Royal Brisbane and Women's Hospital
  • University of Texas
  • European Bioinformatics Institute
  • Academic Medical Center of University of Amsterdam (AMC)
  • Brigham and Women's Hospital / Harvard Medical School
  • Dana-Farber Cancer Institute
  • Hanyang University
  • National Institute for Research in Computer Science and Control (INIRA)
  • Centre Léon Bérard
  • University of Cambridge
  • Cambridge University Hospitals NHS Foundation Trust
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Cancer and Oncology
Original languageEnglish
Pages (from-to)341-348
Number of pages8
JournalNature Genetics
Volume49
Issue number3
Publication statusPublished - 2017 Mar 1
Publication categoryResearch
Peer-reviewedYes

Related projects

View all (1)