Evidence for APOBEC3B mutagenesis in multiple human cancers

By Michael B. Burns, N. Temiz, Reuben S. Harris. Nature Genetics, 2013

741 citations recorded by the source corpus.

Thousands of somatic mutations accrue in most human cancers, and their causes are largely unknown. We recently showed that the DNA cytidine deaminase APOBEC3B accounts for up to half of the mutational load in breast carcinomas expressing this enzyme. Here we address whether APOBEC3B is broadly responsible for mutagenesis in multiple tumor types. We analyzed gene expression data and mutation patterns, distributions and loads for 19 different cancer types, with over 4,800 exomes and 1,000,000 somatic mutations. Notably, APOBEC3B is upregulated, and its preferred target sequence is frequently mutated and clustered in at least six distinct cancers: bladder, cervix, lung (adenocarcinoma and squamous cell carcinoma), head and neck, and breast. Interpreting these findings in the light of previous genetic, cellular and biochemical studies, the most parsimonious conclusion from these global analyses is that APOBEC3B-catalyzed genomic uracil lesions are responsible for a large proportion of both dispersed and clustered mutations in multiple distinct cancers.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a912a7d32b37cbb14cb017bb82f495127c1bd05e

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In Cancer Research

1. Charles Swanton
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Citations in the corpus

• Spatial and temporal diversity in genomic instability processes defines lung cancer evolution (2014, background): “Moreover, while both exogenous mutational processes, such as smoking (10-12) and endogenous processes, such as upregulation of APOBEC cytidine deaminases (13-15), have been found to contribute to the large mutational burden in NSCLC, the temporal dynamics of these processes and their contribution to”
• Chromothripsis and kataegis induced by telomere crisis (2015, neutral): “Second, the clusters exhibited a pronounced preference for C>T and C>G mutations occurring in a TpC context (Figures 6E and 6F), the classic signature of APOBEC3A/B activity (Roberts et al., 2013; Burns et al., 2013a; Burns et al., 2013b; reviewed in Roberts andGordenin, 2014).”
• Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. (2015, background): “…in 15 cancer types, has been linked to the endogenous activity of apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases and is characterized by C > T and C > Gmutations at TpC sites (Alexandrov et al., 2013; Burns et al., 2013; Roberts et al., 2013).”