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The topography of mutational processes in breast cancer genomes

Author:
  • Sandro Morganella
  • Ludmil B. Alexandrov
  • Dominik Glodzik
  • Xueqing Zou
  • Helen Davies
  • Johan Staaf
  • Anieta M. Sieuwerts
  • Arie B. Brinkman
  • Sancha Martin
  • Manasa Ramakrishna
  • Adam Butler
  • Hyung Yong Kim
  • Åke Borg
  • Christos Sotiriou
  • P. Andrew Futreal
  • Peter J. Campbell
  • Paul N. Span
  • Steven Van Laere
  • Sunil R. Lakhani
  • Jorunn E. Eyfjord
  • Alastair M. Thompson
  • Hendrik G. Stunnenberg
  • Marc J. Van De Vijver
  • John W M Martens
  • Anne Lise Børresen-Dale
  • Andrea L. Richardson
  • Gu Kong
  • Gilles Thomas
  • Julian Sale
  • Cristina Rada
  • Michael R. Stratton
  • Ewan Birney
  • Serena Nik-Zainal
Publishing year: 2016-05-02
Language: English
Publication/Series: Nature Communications
Volume: 7
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.

Keywords

  • Cancer and Oncology

Other

Published
  • ISSN: 2041-1723
Åke Borg
Åke Borg
E-mail: ake.borg [at] med.lu.se

Principal investigator

Oncology and Pathology, MV

+46 46 275 25 52

MV 404 C21B2

90

Project manager

Familial Breast Cancer

90

Professor

Oncology and Pathology, MV

MV 404 C21C2

90