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Evidence for APOBEC3B mutagenesis in multiple human cancers

Abstract

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.

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Figure 1: APOBEC3B is upregulated in numerous cancer types.
Figure 2: Mutation types and signatures in 19 human cancers.
Figure 3: Cytosine mutation spectra for 19 cancers.
Figure 4: APOBEC3B expression levels correlate with total mutation loads and kataegis events.

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Acknowledgements

We thank The Cancer Genome Atlas (TCGA) Network for generating the RNA-seq and somatic mutation data and for providing open access, and we thank the Harris laboratory members and S. Kaufmann for comments. M.B.B. was supported by a Department of Defense Breast Cancer Research Program Predoctoral Fellowship (BC101124). This work was supported by grants from the Jimmy V Foundation, the Minnesota Ovarian Cancer Alliance and the US National Institutes of Health (R01 AI064046 and P01 GM091743).

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All authors contributed to the study design, data analysis and manuscript preparation. M.B.B. and N.A.T. analyzed data from TCGA. N.A.T. performed mutation and cluster analysis.

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Correspondence to Reuben S Harris.

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Burns, M., Temiz, N. & Harris, R. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat Genet 45, 977–983 (2013). https://doi.org/10.1038/ng.2701

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