Abstract
SummaryDisordered 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.
Highlights
Somatic mutation underpins the development of cancer, and most solid tumors have thousands to tens of thousands of point mutations, coupled with tens to hundreds of genomic rearrangements and copy-number changes (Garraway and Lander, 2013; Stratton et al, 2009)
Whole-Genome Sequencing and RNA-Seq from 23 Breast Cancer Samples To understand the inter-relationships between somatic mutation and the transcriptome, we matched RNA sequencing (RNA-seq) data to whole-genome-sequencing data in 23 breast cancer samples
The whole-genome sequencing for the 14 primary breast cancer samples has been described previously (Nik-Zainal et al, 2012a, 2012b), improvements in our bioinformatics algorithm allowed us to update the list of genomic rearrangements (Table S1)
Summary
Somatic mutation underpins the development of cancer, and most solid tumors have thousands to tens of thousands of point mutations, coupled with tens to hundreds of genomic rearrangements and copy-number changes (Garraway and Lander, 2013; Stratton et al, 2009). Altered transcript structure can take many forms, including the creation of fusion genes by genomic rearrangement, interference with RNA splicing at mutated splice sites, alteration of the codon sequence for missense substitutions, and over- or under-expression of genes through copy-number alterations or mutation in regulatory regions. 2032 Cell Reports 16, 2032–2046, August 16, 2016 a 2016 The Authors.
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