An APOBEC Cytidine Deaminase Mutagenesis Pattern is Widespread in Human Cancers

Steven A Roberts; Michael S Lawrence; Leszek J Klimczak; Sara A Grimm; David Fargo; Petar Stojanov; Adam Kiezun; Gregory V Kryukov; Scott L Carter; Gordon Saksena; Shawn Harris; Ruchir R Shah; Michael A Resnick; Gad Getz; Dmitry A Gordenin

doi:10.1038/ng.2702

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An APOBEC Cytidine Deaminase Mutagenesis Pattern is Widespread in Human Cancers

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An APOBEC Cytidine Deaminase Mutagenesis Pattern is Widespread in Human Cancers

Steven A Roberts, Michael S Lawrence, Leszek J Klimczak, Sara A Grimm, David Fargo, Petar Stojanov, Adam Kiezun, Gregory V Kryukov, Scott L Carter, Gordon Saksena, …

Nature genetics, Vol.45(9), pp.970-976

09/2013

DOI: https://doi.org/10.1038/ng.2702

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https://hdl.handle.net/2376/100738

PMCID: PMC3789062

PMID: 23852170

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Abstract

Recent studies indicate that a subclass of APOBEC cytidine deaminases, which convert cytosine to uracil during RNA editing and retrovirus or retrotransposon restriction, may induce mutation clusters in human tumors. We show here that throughout cancer genomes APOBEC mutagenesis is pervasive and correlates with APOBEC mRNA levels. Mutation clusters in whole-genome and exome datasets conformed to stringent criteria indicative of an APOBEC mutation pattern. Applying these criteria to 954,247 mutations in 2,680 exomes of 14 cancer types, mostly from TCGA, revealed significant presence of the APOBEC mutation pattern in bladder, cervical, breast, head and neck and lung cancers, reaching 68% of all mutations in some samples. Within breast cancer, the HER2E subtype was clearly enriched with tumors displaying the APOBEC mutation pattern, suggesting this type of mutagenesis is functionally linked with cancer development. The APOBEC mutation pattern also extended to cancer-associated genes, implying that ubiquitous APOBEC mutagenesis is carcinogenic.

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Title: An APOBEC Cytidine Deaminase Mutagenesis Pattern is Widespread in Human Cancers
Creators: Steven A Roberts - Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Durham, NC 27709, USA
Michael S Lawrence - The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Leszek J Klimczak - Integrative Bioinformatics, National Institute of Environmental Health Sciences, Durham, NC 27709, USA
Sara A Grimm - Integrative Bioinformatics, National Institute of Environmental Health Sciences, Durham, NC 27709, USA
David Fargo - Integrative Bioinformatics, National Institute of Environmental Health Sciences, Durham, NC 27709, USA
Petar Stojanov - The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Adam Kiezun - The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Gregory V Kryukov - The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Scott L Carter - The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Gordon Saksena - The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Shawn Harris - SRA International, Inc, Durham, NC 27709, USA
Ruchir R Shah - SRA International, Inc, Durham, NC 27709, USA
Michael A Resnick - Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Durham, NC 27709, USA
Gad Getz - The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Dmitry A Gordenin - Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Durham, NC 27709, USA
Publication Details: Nature genetics, Vol.45(9), pp.970-976
Academic Unit: Molecular Biosciences, School of
Grant note: Z99 ES999999 || ES / National Institute of Environmental Health Sciences : NIEHS
Identifiers: 99900546635901842
Language: English
Resource Type: Journal article