title: Cell-of-origin chromatin organization shapes the mutational landscape of cancer.
abstract: Cancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the human genome. Instead, different human genomic regions vary by up to fivefold in the local density of cancer somatic mutations, posing a fundamental problem for statistical methods used in cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape. However, both somatic mutagenesis and epigenomic features are highly cell-type-specific. We investigated the distribution of mutations in multiple independent 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. 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 matched cancer cell lines. Furthermore, we show that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome. Thus, the DNA sequence of a cancer genome encompasses a wealth of information about the identity and epigenomic features of its cell of origin.
authors.affiliation: Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115.|The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Paz
authors.initials: P
authors.lastname: Polak
authors.affiliation: Bioinformatics Group, Department of Molecular Biology, Division of Biology, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia.
authors.forename: Rosa
authors.initials: R
authors.lastname: Karlić
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.|The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Amnon
authors.initials: A
authors.lastname: Koren
authors.affiliation: Departments of Genome Sciences and Medicine (Oncology), University of Washington, Seattle, WA 98195, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Thurman
authors.affiliation: Departments of Genome Sciences and Medicine (Oncology), University of Washington, Seattle, WA 98195, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Sandstrom
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lawrence
authors.affiliation: Departments of Genome Sciences and Medicine (Oncology), University of Washington, Seattle, WA 98195, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Reynolds
authors.affiliation: Departments of Genome Sciences and Medicine (Oncology), University of Washington, Seattle, WA 98195, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Rynes
authors.affiliation: Bioinformatics Group, Department of Molecular Biology, Division of Biology, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia.|Department of Informatics, University of Oslo, P.O. Box 1080, Blindern, NO-0316 Oslo, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Vlahoviček
authors.affiliation: Departments of Genome Sciences and Medicine (Oncology), University of Washington, Seattle, WA 98195, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
authors.affiliation: Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115.|The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Shamil R
authors.initials: SR
authors.lastname: Sunyaev
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D042522:DNA Replication Timing; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D009928:Organ Specificity / Q000235:genetics
chemical_list: D002843:Chromatin