Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types
Publication Date
August 04, 2016
Journal
PLOS Genetics
Authors
Vera B. Kaiser, Martin S. Taylor & Colin A. Semple
Volume
12
Issue
8
Pages
e1006207
DOI
https://dx.plos.org/10.1371/journal.pgen.1006207
Publisher URL
http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1006207
Web of Science
000382394500016
Scopus
84984873593
Mendeley
http://www.mendeley.com/research/mutational-biases-drive-elevated-rates-substitution-regulatory-sites-across-cancer-types
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Mendeley | Further Information

{"title"=>"Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types", "type"=>"journal", "authors"=>[{"first_name"=>"Vera B.", "last_name"=>"Kaiser", "scopus_author_id"=>"15073045300"}, {"first_name"=>"Martin S.", "last_name"=>"Taylor", "scopus_author_id"=>"7406241921"}, {"first_name"=>"Colin A.", "last_name"=>"Semple", "scopus_author_id"=>"7006977465"}], "year"=>2016, "source"=>"PLoS Genetics", "identifiers"=>{"doi"=>"10.1371/journal.pgen.1006207", "sgr"=>"84984873593", "pui"=>"612002705", "scopus"=>"2-s2.0-84984873593", "issn"=>"15537404", "pmid"=>"27490693"}, "id"=>"1973849a-af79-3a31-aedd-47b1766bbac5", "abstract"=>"Disruption of gene regulation is known to play major roles in carcinogenesis and tumour pro-gression. Here, we comprehensively characterize the mutational profiles of diverse tran-scription 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 accumu-late in cancers are typically more disruptive than variants tolerated in extant human popula-tions 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, sug-gesting 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. Author Summary Regulatory regions of the genome are important players in cancer initiation and progres-sion. Here, we study the patterns of mutations accumulating at short DNA segments bound by regulatory proteins (transcription factor binding sites) across many cancer types and in the human population. We find strikingly high rates of mutation at active regula-tory sites across different cancers, relative to matched control sequences. This excess of", "link"=>"http://www.mendeley.com/research/mutational-biases-drive-elevated-rates-substitution-regulatory-sites-across-cancer-types", "reader_count"=>51, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>4, "Researcher"=>13, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>15, "Student > Postgraduate"=>1, "Student > Master"=>5, "Other"=>5, "Student > Bachelor"=>2, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>4, "Researcher"=>13, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>15, "Student > Postgraduate"=>1, "Student > Master"=>5, "Other"=>5, "Student > Bachelor"=>2, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>5, "Biochemistry, Genetics and Molecular Biology"=>15, "Mathematics"=>3, "Agricultural and Biological Sciences"=>22, "Medicine and Dentistry"=>3, "Computer Science"=>3}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>22}, "Computer Science"=>{"Computer Science"=>3}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>15}, "Mathematics"=>{"Mathematics"=>3}, "Unspecified"=>{"Unspecified"=>5}}, "reader_count_by_country"=>{"Canada"=>1, "Japan"=>1, "United Kingdom"=>1, "Germany"=>2}, "group_count"=>1}

Scopus | Further Information

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