Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers

Research output: Contribution to journalArticle

Abstract

Background

Complex clusters of rearrangements are a challenge in interpretation of cancer genomes. Some clusters of rearrangements demarcate clear amplifications of driver oncogenes but others are less well understood. A detailed analysis of rearrangements within these complex clusters could reveal new insights into selection and underlying mutational mechanisms.
Patients and methods

Here, we systematically investigate rearrangements that are densely clustered in individual tumours in a cohort of 560 breast cancers. Applying an agnostic approach, we identify 21 hotspots where clustered rearrangements recur across cancers.
Results

Some hotspots coincide with known oncogene loci including CCND1, ERBB2, ZNF217, chr8:ZNF703/FGFR1, IGF1R, and MYC. Others contain cancer genes not typically associated with breast cancer: MCL1, PTP4A1, and MYB. Intriguingly, we identify clustered rearrangements that physically connect distant hotspots. In particular, we observe simultaneous amplification of chr8:ZNF703/FGFR1 and chr11:CCND1 where deep analysis reveals that a chr8–chr11 translocation is likely to be an early, critical, initiating event.
Conclusions

We present an overview of complex rearrangements in breast cancer, highlighting a potential new way for detecting drivers and revealing novel mechanistic insights into the formation of two common amplicons.

Details

Authors
  • Dominik Glodzik
  • Colin A Purdie
  • Inga Hansine Rye
  • Peter T Simpson
  • Johan Staaf
  • Paul N. Span
  • Hege Russnes
  • Serena Nik-Zainal
Organisations
External organisations
  • Wellcome Trust Sanger Institute
  • University of Dundee
  • Norwegian Radium Hospital
  • University of Oslo
  • University of Queensland
  • Royal Brisbane and Women's Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Article number30252041
JournalAnnals of Oncology
Publication statusPublished - 2018 Sep 15
Publication categoryResearch
Peer-reviewedYes

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