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dc.contributor.authorPolak, Pazen_US
dc.contributor.authorKarlić, Rosaen_US
dc.contributor.authorKoren, Amnonen_US
dc.contributor.authorThurman, Roberten_US
dc.contributor.authorSandstrom, Richarden_US
dc.contributor.authorLawrence, Michaelen_US
dc.contributor.authorReynolds, Alexen_US
dc.contributor.authorRynes, Ericen_US
dc.contributor.authorVlahoviček, Kristianen_US
dc.contributor.authorStamatoyannopoulos, John A.en_US
dc.contributor.authorSunyaev, Shamil R.en_US
dc.date.accessioned2015-09-01T13:27:59Z
dc.date.issued2015en_US
dc.identifier.citationPolak, P., R. Karlić, A. Koren, R. Thurman, R. Sandstrom, M. Lawrence, A. Reynolds, et al. 2015. “Cell-of-origin chromatin organization shapes the mutational landscape of cancer.” Nature 518 (7539): 360-364. doi:10.1038/nature14221. http://dx.doi.org/10.1038/nature14221.en
dc.identifier.issn0028-0836en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:21462011
dc.description.abstractCancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the genome. Instead, different genomic regions vary by up to 5-fold in the local density of somatic mutations1, posing a fundamental problem for statistical methods of cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape1-5. However, both somatic mutagenesis and epigenomic features are highly cell-type-specific6,7. We investigated the distribution of mutations in multiple samples of diverse cancer types and compared them to cell-type-specific epigenomic features. Here, we show that chromatin accessibility and modification, together with replication timing, explain up to 86% of the variance in mutation rates along cancer genomes. Overwhelmingly, the best predictors of local somatic mutation density are epigenomic features derived from the most likely cell type of origin of the corresponding malignancy. Moreover, we find that cell-of-origin chromatin features are much stronger determinants of cancer mutation profiles than chromatin features of cognate cancer cell lines. We show further that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome. Thus, DNA sequence of a cancer genome encompasses a wealth of information about the identity and epigenomic features of its cell of origin.en
dc.language.isoen_USen
dc.relation.isversionofdoi:10.1038/nature14221en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405175/pdf/en
dash.licenseLAAen_US
dc.titleCell-of-origin chromatin organization shapes the mutational landscape of canceren
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalNatureen
dash.depositing.authorKoren, Amnonen_US
dc.date.available2015-09-01T13:27:59Z
dc.identifier.doi10.1038/nature14221*
dash.authorsorderedfalse
dash.contributor.affiliatedKoren, Amnon
dash.contributor.affiliatedSunyaev, Shamil


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