TY - JOUR
T1 - Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer
AU - Shlien, Adam
AU - Raine, Keiran
AU - Fuligni, Fabio
AU - Arnold, Roland
AU - Nik-Zainal, Serena
AU - Dronov, Serge
AU - Mamanova, Lira
AU - Rosic, Andrej
AU - Ju, Young Seok
AU - Cooke, Susanna L
AU - Ramakrishna, Manasa
AU - Papaemmanuil, Elli
AU - Davies, Helen R
AU - Tarpey, Patrick S
AU - Van Loo, Peter
AU - Wedge, David C
AU - Jones, David R
AU - Martin, Sancha
AU - Marshall, John
AU - Anderson, Elizabeth
AU - Hardy, Claire
AU - ICGC Breast Cancer Working Group, Oslo Breast Cancer Research Consortium
AU - Barbashina, Violetta
AU - Aparicio, Samuel A J R
AU - Sauer, Torill
AU - Garred, Øystein
AU - Vincent-Salomon, Anne
AU - Mariani, Odette
AU - Boyault, Sandrine
AU - Fatima, Aquila
AU - Langerød, Anita
AU - Borg, Åke
AU - Thomas, Gilles
AU - Richardson, Andrea L
AU - Børresen-Dale, Anne-Lise
AU - Polyak, Kornelia
AU - Stratton, Michael R
AU - Campbell, Peter J
N1 - Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2016/8/16
Y1 - 2016/8/16
N2 - 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.
AB - 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.
KW - Algorithms
KW - Breast Neoplasms
KW - Data Interpretation, Statistical
KW - Exome
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - High-Throughput Nucleotide Sequencing
KW - Humans
KW - Mutation
KW - Oncogene Proteins, Fusion
KW - Polyadenylation
KW - Receptors, Estrogen
KW - Transcriptome
KW - X Chromosome Inactivation
KW - Journal Article
U2 - 10.1016/j.celrep.2016.07.028
DO - 10.1016/j.celrep.2016.07.028
M3 - Article
C2 - 27498871
SN - 2211-1247
VL - 16
SP - 2032
EP - 2046
JO - Cell Reports
JF - Cell Reports
IS - 7
ER -