Cell-of-origin chromatin organization shapes the mutational landscape of cancer View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-02

AUTHORS

Paz Polak, Rosa Karlić, Amnon Koren, Robert Thurman, Richard Sandstrom, Michael S. Lawrence, Alex Reynolds, Eric Rynes, Kristian Vlahoviček, John A. Stamatoyannopoulos, Shamil R. Sunyaev

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. More... »

PAGES

360

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature14221

    DOI

    http://dx.doi.org/10.1038/nature14221

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1012147864

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/25693567


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    310 Department of Informatics, University of Oslo, P.O. Box 1080, Blindern, NO-0316 Oslo, Norway
    311 rdf:type schema:Organization
    312 https://www.grid.ac/institutes/grid.66859.34 schema:alternateName Broad Institute
    313 schema:name Division of Genetics, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    314 The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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