{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:17:59Z","timestamp":1772173079337,"version":"3.50.1"},"reference-count":63,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["Project Grant"],"award-info":[{"award-number":["Project Grant"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004376","name":"Terry Fox Research Institute","doi-asserted-by":"publisher","award":["New Investigator Award"],"award-info":[{"award-number":["New Investigator Award"]}],"id":[{"id":"10.13039\/501100004376","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["Discovery Grant"],"award-info":[{"award-number":["Discovery Grant"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012118","name":"Ontario Institute for Cancer Research","doi-asserted-by":"publisher","award":["Investigator Award"],"award-info":[{"award-number":["Investigator Award"]}],"id":[{"id":"10.13039\/100012118","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Somatic mutations in cancer genomes are associated with DNA replication timing (RT) and chromatin accessibility (CA), however these observations are based on normal tissues and cell lines while primary cancer epigenomes remain uncharacterised. Here we use machine learning to model megabase-scale mutation burden in 2,500 whole cancer genomes and 17 cancer types via a compendium of 900 CA and RT profiles covering primary cancers, normal tissues, and cell lines. CA profiles of primary cancers, rather than those of normal tissues, are most predictive of regional mutagenesis in most cancer types. Feature prioritisation shows that the epigenomes of matching cancer types and organ systems are often the strongest predictors of regional mutation burden, highlighting disease-specific associations of mutational processes. The genomic distributions of mutational signatures are also shaped by the epigenomes of matched cancer and tissue types, with SBS5\/40, carcinogenic and unknown signatures most accurately predicted by our models. In contrast, fewer associations of RT and regional mutagenesis are found. Lastly, the models highlight genomic regions with overrepresented mutations that dramatically exceed epigenome-derived expectations and show a pan-cancer convergence to genes and pathways involved in development and oncogenesis, indicating the potential of this approach for coding and non-coding driver discovery. The association of regional mutational processes with the epigenomes of primary cancers suggests that the landscape of passenger mutations is predominantly shaped by the epigenomes of cancer cells after oncogenic transformation.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010393","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T13:29:36Z","timestamp":1660138176000},"page":"e1010393","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Chromatin accessibility of primary human cancers ties regional mutational processes and signatures with tissues of origin"],"prefix":"10.1371","volume":"18","author":[{"given":"Oliver","family":"Ocsenas","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2299-2309","authenticated-orcid":true,"given":"J\u00fcri","family":"Reimand","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"issue":"7793","key":"pcbi.1010393.ref001","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/s41586-020-1969-6","article-title":"Pan-cancer analysis of whole genomes","volume":"578","author":"ICGC-TCGA Pan-Cancer Analysis of Whole Genomes Consortium","year":"2020","journal-title":"Nature"},{"issue":"7793","key":"pcbi.1010393.ref002","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s41586-019-1907-7","article-title":"The evolutionary history of 2,658 cancers","volume":"578","author":"M Gerstung","year":"2020","journal-title":"Nature"},{"issue":"5","key":"pcbi.1010393.ref003","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/j.cell.2017.09.042","article-title":"Universal Patterns of Selection in Cancer and Somatic Tissues","volume":"171","author":"I Martincorena","year":"2017","journal-title":"Cell"},{"key":"pcbi.1010393.ref004","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41586-020-1965-x","article-title":"Analyses of non-coding somatic drivers in 2,693 cancer whole genomes","volume":"578","author":"E Rheinbay","year":"2020","journal-title":"Nature"},{"key":"pcbi.1010393.ref005","article-title":"Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks","author":"H Zhu","year":"2020","journal-title":"Mol Cell"},{"issue":"7793","key":"pcbi.1010393.ref006","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41586-020-1943-3","article-title":"The repertoire of mutational signatures in human cancer","volume":"578","author":"LB Alexandrov","year":"2020","journal-title":"Nature"},{"issue":"7793","key":"pcbi.1010393.ref007","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41586-019-1913-9","article-title":"Patterns of somatic structural variation in human cancer genomes","volume":"578","author":"Y Li","year":"2020","journal-title":"Nature"},{"issue":"5","key":"pcbi.1010393.ref008","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/j.cell.2020.01.032","article-title":"Passenger Mutations in More Than 2,500 Cancer Genomes: Overall Molecular Functional Impact and Consequences","volume":"180","author":"S Kumar","year":"2020","journal-title":"Cell"},{"issue":"6237","key":"pcbi.1010393.ref009","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1126\/science.aaa6806","article-title":"Tumor evolution. 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