Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • 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
  • Violetta Barbashina
  • Samuel A J R Aparicio
  • Torill Sauer
  • Øystein Garred
  • Anne Vincent-Salomon
  • Odette Mariani
  • Sandrine Boyault
  • Aquila Fatima
  • Anita Langerød
  • Gilles Thomas
  • Andrea L. Richardson
  • Anne Lise Børresen-Dale
  • Kornelia Polyak
  • Michael R. Stratton
  • Peter J. Campbell
Enheter & grupper
Externa organisationer
  • Wellcome Trust Sanger Institute
  • Catholic University of Leuven
  • University of Cambridge
  • Oslo university hospital
  • Addenbrooke's Hospital
  • Hospital for Sick Children, Toronto
  • Institute of Cancer Research London
  • British Columbia Cancer Agency
  • Curie Institute, Paris
  • Centre Léon Bérard
  • Dana-Farber Cancer Institute
  • University of Oslo
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
Sidor (från-till)2032-2046
Antal sidor15
TidskriftCell Reports
Volym16
Utgivningsnummer7
StatusPublished - 2016 aug 16
PublikationskategoriForskning
Peer review utfördJa