title: Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer.
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.
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK. Electronic address: adam.shlien@sickkids.ca.
authors: Adam
authors: A
authors: Shlien
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Keiran
authors: K
authors: Raine
authors: Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors: Fabio
authors: F
authors: Fuligni
authors: Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors: Roland
authors: R
authors: Arnold
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Serena
authors: S
authors: Nik-Zainal
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Serge
authors: S
authors: Dronov
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Lira
authors: L
authors: Mamanova
authors: Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors: Andrej
authors: A
authors: Rosic
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Young Seok
authors: YS
authors: Ju
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Susanna L
authors: SL
authors: Cooke
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Manasa
authors: M
authors: Ramakrishna
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Elli
authors: E
authors: Papaemmanuil
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Helen R
authors: HR
authors: Davies
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Patrick S
authors: PS
authors: Tarpey
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK; Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors: Peter
authors: P
authors: Van Loo
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: David C
authors: DC
authors: Wedge
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: David R
authors: DR
authors: Jones
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Sancha
authors: S
authors: Martin
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: John
authors: J
authors: Marshall
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Elizabeth
authors: E
authors: Anderson
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Claire
authors: C
authors: Hardy
authors: Breakthrough Breast Cancer, The Institute of Cancer Research, London SM2 5NG, UK.
authors: Violetta
authors: V
authors: Barbashina
authors: British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors: Samuel A J R
authors: SA
authors: Aparicio
authors: Department of Pathology, Oslo University Hospital, 0450 Oslo, Norway.
authors: Torill
authors: T
authors: Sauer
authors: Department of Pathology, Oslo University Hospital, 0450 Oslo, Norway.
authors: Øystein
authors: Ø
authors: Garred
authors: Institut Curie, 75005 Paris, France.
authors: Anne
authors: A
authors: Vincent-Salomon
authors: Institut Curie, 75005 Paris, France.
authors: Odette
authors: O
authors: Mariani
authors: Synergie Lyon Cancer, Centre Léon Bérard, 69008 Lyon, France.
authors: Sandrine
authors: S
authors: Boyault
authors: Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Aquila
authors: A
authors: Fatima
authors: 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.
authors: Anita
authors: A
authors: Langerød
authors: Department of Oncology, Lund University, SE-221 00 Lund, Sweden.
authors: Åke
authors: Å
authors: Borg
authors: Synergie Lyon Cancer, Centre Léon Bérard, 69008 Lyon, France.
authors: Gilles
authors: G
authors: Thomas
authors: Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Andrea L
authors: AL
authors: Richardson
authors: 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.
authors: Anne-Lise
authors: AL
authors: Børresen-Dale
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Kornelia
authors: K
authors: Polyak
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors: Michael R
authors: MR
authors: Stratton
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK; Department of Haematology, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK; Department of Haematology, University of Cambridge, Cambridge CB2 1TN, UK. Electronic address: pc8@sanger.ac.uk.
authors: Peter J
authors: PJ
authors: Campbell
mesh_terms: D000465:Algorithms; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003627:Data Interpretation, Statistical; D059472:Exome; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D026723:Polyadenylation; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics; D059467:Transcriptome; D049951:X Chromosome Inactivation
chemical_list: D015514:Oncogene Proteins, Fusion; D011960:Receptors, Estrogen