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Nat Biotechnol. 2014 Jan;32(1):71-5. doi: 10.1038/nbt.2778. Epub 2013 Dec 15.

Reduced local mutation density in regulatory DNA of cancer genomes is linked to DNA repair.

Author information

1
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].
2
1] The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2].
3
Departments of Genome Sciences and Medicine (Oncology), University of Washington, Seattle, Washington, USA.
4
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.
5
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
6
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.
7
Department of Biology, Tufts University, Medford, Massachusetts, USA.

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.

PMID:
24336318
PMCID:
PMC4116484
DOI:
10.1038/nbt.2778
[Indexed for MEDLINE]
Free PMC Article
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