{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:20:27Z","timestamp":1772173227893,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010733","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T00:00:00Z","timestamp":1671062400000}}],"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T00:00:00Z","timestamp":1670198400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["P30 CA008748"],"award-info":[{"award-number":["P30 CA008748"]}]},{"name":"National Cancer Institute","award":["R25 CA233208"],"award-info":[{"award-number":["R25 CA233208"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Cancer genomes harbor a catalog of somatic mutations. The type and genomic context of these mutations depend on their causes and allow their attribution to particular mutational signatures. Previous work has shown that mutational signature activities change over the course of tumor development, but investigations of genomic region variability in mutational signatures have been limited. Here, we expand upon this work by constructing regional profiles of mutational signature activities over 2,203 whole genomes across 25 tumor types, using data aggregated by the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium. We present GenomeTrackSig as an extension to the TrackSig R package to construct regional signature profiles using optimal segmentation and the expectation-maximization (EM) algorithm. We find that 426 genomes from 20 tumor types display at least one change in mutational signature activities (changepoint), and 306 genomes contain at least one of 54 recurrent changepoints shared by seven or more genomes of the same tumor type. Five recurrent changepoint locations are shared by multiple tumor types. Within these regions, the particular signature changes are often consistent across samples of the same type and some, but not all, are characterized by signatures associated with subclonal expansion. The changepoints we found cannot strictly be explained by gene density, mutation density, or cell-of-origin chromatin state. We hypothesize that they reflect a confluence of factors including evolutionary timing of mutational processes, regional differences in somatic mutation rate, large-scale changes in chromatin state that may be tissue type-specific, and changes in chromatin accessibility during subclonal expansion. These results provide insight into the regional effects of DNA damage and repair processes, and may help us localize genomic and epigenomic changes that occur during cancer development.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010733","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T13:32:15Z","timestamp":1670247135000},"page":"e1010733","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Regional mutational signature activities in cancer genomes"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4118-4902","authenticated-orcid":true,"given":"Caitlin","family":"Timmons","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2760-6999","authenticated-orcid":true,"given":"Quaid","family":"Morris","sequence":"additional","affiliation":[]},{"given":"Caitlin 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