Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types

Disruption of gene regulation is known to play major roles in carcinogenesis and tumour progression. Here, we comprehensively characterize the mutational profiles of diverse transcription factor binding sites (TFBSs) across 1,574 completely sequenced cancer genomes encompassing 11 tumour types. We a...

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Bibliographic Details
Published in:PLoS genetics 2016-08, Vol.12 (8), p.e1006207
Main Authors: Kaiser, Vera B, Taylor, Martin S, Semple, Colin A
Format: Article
Language:English
Subjects:
Binding sites
Binding sites (Biochemistry)
Binding Sites - genetics
Biology and Life Sciences
Cancer
Carcinogenesis
Carcinogenesis - genetics
CCCTC-Binding Factor
Consortia
Datasets
Funding
Gene Expression Regulation, Neoplastic
Gene mutation
Genes
Genetic aspects
Genetic regulation
Genome, Human
Genomes
Health aspects
Humans
Identification and classification
Medicine and Health Sciences
Mutation
Mutation - genetics
Neoplasms - genetics
Neoplasms - metabolism
Protein Binding
Regulatory Sequences, Nucleic Acid
Repressor Proteins - genetics
Repressor Proteins - metabolism
Research and Analysis Methods
Studies
Transcription factors
Transcription Factors - genetics
Transcription Factors - metabolism
Tumors
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Summary:Disruption of gene regulation is known to play major roles in carcinogenesis and tumour progression. Here, we comprehensively characterize the mutational profiles of diverse transcription factor binding sites (TFBSs) across 1,574 completely sequenced cancer genomes encompassing 11 tumour types. We assess the relative rates and impact of the mutational burden at the binding sites of 81 transcription factors (TFs), by comparing the abundance and patterns of single base substitutions within putatively functional binding sites to control sites with matched sequence composition. There is a strong (1.43-fold) and significant excess of mutations at functional binding sites across TFs, and the mutations that accumulate in cancers are typically more disruptive than variants tolerated in extant human populations at the same sites. CTCF binding sites suffer an exceptionally high mutational load in cancer (3.31-fold excess) relative to control sites, and we demonstrate for the first time that this effect is seen in essentially all cancer types with sufficient data. The sub-set of CTCF sites involved in higher order chromatin structures has the highest mutational burden, suggesting a widespread breakdown of chromatin organization. However, we find no evidence for selection driving these distinctive patterns of mutation. The mutational load at CTCF-binding sites is substantially determined by replication timing and the mutational signature of the tumor in question, suggesting that selectively neutral processes underlie the unusual mutation patterns. Pervasive hyper-mutation within transcription factor binding sites rewires the regulatory landscape of the cancer genome, but it is dominated by mutational processes rather than selection.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1006207