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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.

SUBMITTER: Shlien A 

PROVIDER: S-EPMC4987284 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer.

Shlien Adam A   Raine Keiran K   Fuligni Fabio F   Arnold Roland R   Nik-Zainal Serena S   Dronov Serge S   Mamanova Lira L   Rosic Andrej A   Ju Young Seok YS   Cooke Susanna L SL   Ramakrishna Manasa M   Papaemmanuil Elli E   Davies Helen R HR   Tarpey Patrick S PS   Van Loo Peter P   Wedge David C DC   Jones David R DR   Martin Sancha S   Marshall John J   Anderson Elizabeth E   Hardy Claire C   Barbashina Violetta V   Aparicio Samuel A J R SA   Sauer Torill T   Garred Øystein Ø   Vincent-Salomon Anne A   Mariani Odette O   Boyault Sandrine S   Fatima Aquila A   Langerød Anita A   Borg Åke Å   Thomas Gilles G   Richardson Andrea L AL   Børresen-Dale Anne-Lise AL   Polyak Kornelia K   Stratton Michael R MR   Campbell Peter J PJ  

Cell reports 20160804 7


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  ...[more]

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