Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer

Research output: Contribution to journalArticle

Authors

  • Adam Shlien
  • Keiran Raine
  • Fabio Fuligni
  • Roland Arnold
  • Serena Nik-Zainal
  • Serge Dronov
  • Lira Mamanova
  • Andrej Rosic
  • Young Seok Ju
  • Susanna L Cooke
  • Manasa Ramakrishna
  • Elli Papaemmanuil
  • Helen R Davies
  • Patrick S Tarpey
  • Peter Van Loo
  • David C Wedge
  • David R Jones
  • Sancha Martin
  • John Marshall
  • Elizabeth Anderson
  • Claire Hardy
  • ICGC Breast Cancer Working Group, Oslo Breast Cancer Research Consortium
  • Violetta Barbashina
  • Samuel A J R Aparicio
  • Torill Sauer
  • Øystein Garred
  • Anne Vincent-Salomon
  • Odette Mariani
  • Sandrine Boyault
  • Aquila Fatima
  • Anita Langerød
  • Åke Borg
  • Gilles Thomas
  • Andrea L Richardson
  • Anne-Lise Børresen-Dale
  • Kornelia Polyak
  • Michael R Stratton
  • Peter J Campbell

Colleges, School and Institutes

External organisations

  • Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK. Electronic address: adam.shlien@sickkids.ca.
  • Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
  • Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK; Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium.
  • Breakthrough Breast Cancer, The Institute of Cancer Research, London SM2 5NG, UK.
  • British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
  • Department of Pathology, Oslo University Hospital, 0450 Oslo, Norway.
  • Institut Curie, 75005 Paris, France.
  • Synergie Lyon Cancer, Centre Léon Bérard, 69008 Lyon, France.
  • Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, 0379 Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway.
  • Department of Oncology, Lund University, SE-221 00 Lund, Sweden.
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • University of Cambridge

Abstract

Disordered transcriptomes of cancer encompass direct effects of somatic mutation on transcription, coordinated secondary pathway alterations, and increased transcriptional noise. To catalog the rules governing how somatic mutation exerts direct transcriptional effects, we developed an exhaustive pipeline for analyzing RNA sequencing data, which we integrated with whole genomes from 23 breast cancers. Using X-inactivation analyses, we found that cancer cells are more transcriptionally active than intermixed stromal cells. This is especially true in estrogen receptor (ER)-negative tumors. Overall, 59% of substitutions were expressed. Nonsense mutations showed lower expression levels than expected, with patterns characteristic of nonsense-mediated decay. 14% of 4,234 rearrangements caused transcriptional abnormalities, including exon skips, exon reusage, fusions, and premature polyadenylation. We found productive, stable transcription from sense-to-antisense gene fusions and gene-to-intergenic rearrangements, suggesting that these mutation classes drive more transcriptional disruption than previously suspected. Systematic integration of transcriptome with genome data reveals the rules by which transcriptional machinery interprets somatic mutation.

Details

Original languageEnglish
Pages (from-to)2032-46
Number of pages15
JournalCell Reports
Volume16
Issue number7
Early online date4 Aug 2016
Publication statusPublished - 16 Aug 2016

Keywords

  • Algorithms, Breast Neoplasms, Data Interpretation, Statistical, Exome, Female, Gene Expression Regulation, Neoplastic, High-Throughput Nucleotide Sequencing, Humans, Mutation, Oncogene Proteins, Fusion, Polyadenylation, Receptors, Estrogen, Transcriptome, X Chromosome Inactivation, Journal Article