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Nat Genet DOI:10.1038/ng.2702

An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers.

Publication TypeJournal Article
Year of Publication2013
AuthorsRoberts, SA, Lawrence, MS, Klimczak, LJ, Grimm, SA, Fargo, D, Stojanov, P, Kiezun, A, Kryukov, GV, Carter, SL, Saksena, G, Harris, S, Shah, RR, Resnick, MA, Getz, G, Gordenin, DA
JournalNat Genet
Volume45
Issue9
Pages970-6
Date Published2013 Sep
ISSN1546-1718
KeywordsAPOBEC-1 Deaminase, Breast Neoplasms, Cell Transformation, Neoplastic, Cytidine Deaminase, Exome, Female, Genome, Human, Genomics, Humans, Male, Mutagenesis, Mutation, Neoplasms, Receptor, ErbB-2, RNA, Messenger
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-mediated mutagenesis is pervasive and correlates with APOBEC mRNA levels. Mutation clusters in whole-genome and exome data sets conformed to the stringent criteria indicative of an APOBEC mutation pattern. Applying these criteria to 954,247 mutations in 2,680 exomes from 14 cancer types, mostly from The Cancer Genome Atlas (TCGA), showed a 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 HER2-enriched subtype was clearly enriched for tumors with the APOBEC mutation pattern, suggesting that this type of mutagenesis is functionally linked with cancer development. The APOBEC mutation pattern also extended to cancer-associated genes, implying that ubiquitous APOBEC-mediated mutagenesis is carcinogenic.

URLhttp://dx.doi.org/10.1038/ng.2702
DOI10.1038/ng.2702
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23852170?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID23852170
PubMed Central IDPMC3789062
Grant ListU54 HG003067 / HG / NHGRI NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
HHSN273201000086U / / PHS HHS / United States
GS-23F-9806H / / PHS HHS / United States
Z01 ES065073 / ES / NIEHS NIH HHS / United States
Z99 ES999999 / / Intramural NIH HHS / United States