title: Reduced local mutation density in regulatory DNA of cancer genomes is linked to DNA repair.
abstract: Carcinogenesis and neoplastic progression are mediated by the accumulation of somatic mutations. Here we report that the local density of somatic mutations in cancer genomes is highly reduced specifically in accessible regulatory DNA defined by DNase I hypersensitive sites. This reduction is independent of any known factors influencing somatic mutation density and is observed in diverse cancer types, suggesting a general mechanism. By analyzing individual cancer genomes, we show that the reduced local mutation density within regulatory DNA is linked to intact global genome repair machinery, with nearly complete abrogation of the hypomutation phenomenon in individual cancers that possess mutations in components of the nucleotide excision repair system. Together, our results connect chromatin structure, gene regulation and cancer-associated somatic mutation.
authors: 1] Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [4].
authors: Paz
authors: P
authors: Polak
authors: 1] The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2].
authors: Michael S
authors: MS
authors: Lawrence
authors: Departments of Genome Sciences and Medicine (Oncology), University of Washington, Seattle, Washington, USA.
authors: Eric
authors: 0000000174448981
authors: E
authors: Haugen
authors: 1] Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Nina
authors: N
authors: Stoletzki
authors: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Petar
authors: P
authors: Stojanov
authors: Departments of Genome Sciences and Medicine (Oncology), University of Washington, Seattle, Washington, USA.
authors: Robert E
authors: RE
authors: Thurman
authors: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [4] Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Levi A
authors: LA
authors: Garraway
authors: Department of Biology, Tufts University, Medford, Massachusetts, USA.
authors: Sergei
authors: S
authors: Mirkin
authors: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Gad
authors: G
authors: Getz
authors: Departments of Genome Sciences and Medicine (Oncology), University of Washington, Seattle, Washington, USA.
authors: John A
authors: JA
authors: Stamatoyannopoulos
authors: 1] Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Shamil R
authors: SR
authors: Sunyaev
mesh_terms: D063646:Carcinogenesis; D004247:DNA / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D003850:Deoxyribonuclease I / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D004247:DNA; D003850:Deoxyribonuclease I