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Jul 15, 2013

Genomic Data Analyses Implicate Immune Proteins in Mutagenesis Across Multiple Cancers

  • A group of proteins involved in innate immunity known as apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) cytidine deaminases may also contribute to mutagenesis in several types of cancer.

    Having previously determined that APOBEC3B accounts for up to half of the mutational load in breast tumors that expressed this enzyme, scientists at the University of Minnesota set out to determine whether the same DNA cytidine deaminase is involved in mutagenesis across multiple tumor types. To accomplish this, Minnesota’s Reuben Harris, Ph.D., and his colleagues analyzed gene expression data and mutation patterns for 19 cancer types, investigating more than 4,800 exomes and 1 million s omatic 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,” Dr. Harris et al. report in Nature Genetics. “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,” the scientists add.

    Elsewhere in the same journal, the National Institute of Environmental Health Sciences’ Dmitry Gordenin, Ph.D., and his colleagues present an examination of 954,247 mutations in 2,680 exomes from 14 cancer types, which they say show APOBEC-mediated mutagenesis is pervasive throughout cancer genomes. Dr. Gordenin et al. note their analysis “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.” The researchers added that the APOBEC mutation pattern they observed “also extended to cancer-associated genes, implying that ubiquitous APOBEC-mediated mutagenesis is carcinogenic.”

    Steven Roberts, Ph.D., a postdoc in the Gordenin lab, explained in a statement that because APOBECs are regulated by the immune system, APOBEC mutagenesis may involve a significant environmental component. “We hope that determining the environmental link to these mutations will lead to viable cancer prevention strategies,” he said.

    “Evidence for APOBEC3B mutagenesis in multiple human cancers” and “An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers” appeared online in Nature Genetics July 14.

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