title: An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers.
abstract: Elucidation of mutagenic processes shaping cancer genomes is a fundamental problem whose solution promises insights into new treatment, diagnostic and prevention strategies. Single-strand DNA-specific APOBEC cytidine deaminase(s) are major source(s) of mutation in several cancer types. Previous indirect evidence implicated APOBEC3B as the more likely major mutator deaminase, whereas the role of APOBEC3A is not established. Using yeast models enabling the controlled generation of long single-strand genomic DNA substrates, we show that the mutation signatures of APOBEC3A and APOBEC3B are statistically distinguishable. We then apply three complementary approaches to identify cancer samples with mutation signatures resembling either APOBEC. Strikingly, APOBEC3A-like samples have over tenfold more APOBEC-signature mutations than APOBEC3B-like samples. We propose that APOBEC3A-mediated mutagenesis is much more frequent because APOBEC3A itself is highly proficient at generating DNA breaks, whose repair can trigger the formation of single-strand hypermutation substrates.
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: Kin
authors.initials: K
authors.lastname: Chan
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.|School of Molecular Biosciences, Washington State University, Pullman, Washington, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Roberts
authors.affiliation: Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: Leszek J
authors.initials: LJ
authors.lastname: Klimczak
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: Joan F
authors.initials: JF
authors.lastname: Sterling
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Saini
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Ewa P
authors.initials: EP
authors.lastname: Malc
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Jaegil
authors.initials: J
authors.lastname: Kim
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.affiliation: Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Fargo
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Piotr A
authors.initials: PA
authors.lastname: Mieczkowski
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Gordenin
mesh_terms: D001483:Base Sequence; D003564:Cytidine Deaminase / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D004252:DNA Mutational Analysis; D006801:Humans; D015778:Minor Histocompatibility Antigens; D016296:Mutagenesis; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D011506:Proteins / Q000235:genetics*
chemical_list: D015778:Minor Histocompatibility Antigens; D011506:Proteins; C121399:APOBEC3A protein, human; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase