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Nat Biotechnol DOI:10.1038/nbt.2778

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

Publication TypeJournal Article
Year of Publication2014
AuthorsPolak, P, Lawrence, MS, Haugen, E, Stoletzki, N, Stojanov, P, Thurman, RE, Garraway, LA, Mirkin, S, Getz, G, Stamatoyannopoulos, JA, Sunyaev, SR
JournalNat Biotechnol
Volume32
Issue1
Pages71-5
Date Published2014 Jan
ISSN1546-1696
KeywordsCarcinogenesis, Deoxyribonuclease I, DNA, DNA Repair, Gene Expression Regulation, Neoplastic, Genome, Human, Humans, Mutation, Neoplasms, Regulatory Sequences, Nucleic Acid
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.

URLhttp://dx.doi.org/10.1038/nbt.2778
DOI10.1038/nbt.2778
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24336318?dopt=Abstract

Alternate JournalNat. Biotechnol.
PubMed ID24336318
PubMed Central IDPMC4116484
Grant ListR01MH101244 / MH / NIMH NIH HHS / United States
U54HG004592 / HG / NHGRI NIH HHS / United States
U54 CA143874 / CA / NCI NIH HHS / United States
U54CA143874 / CA / NCI NIH HHS / United States
R01 MH101244 / MH / NIMH NIH HHS / United States
HG007010 / HG / NHGRI NIH HHS / United States