title: APOBEC-Induced Cancer Mutations Are Uniquely Enriched in Early-Replicating, Gene-Dense, and Active Chromatin Regions.
abstract: An antiviral component of the human innate immune system-the APOBEC cytidine deaminases-was recently identified as a prominent source of mutations in cancers. Here, we investigated the distribution of APOBEC-induced mutations across the genomes of 119 breast and 24 lung cancer samples. While the rate of most mutations is known to be elevated in late-replicating regions that are characterized by reduced chromatin accessibility and low gene density, we observed a marked enrichment of APOBEC mutations in early-replicating regions. This unusual mutagenesis profile may be associated with a higher propensity to form single-strand DNA substrates for APOBEC enzymes in early-replicating regions and should be accounted for in statistical analyses of cancer genome mutation catalogs aimed at understanding the mechanisms of carcinogenesis as well as highlighting genes that are significantly mutated in cancer.
authors.affiliation: Research and Training Center on Bioinformatics, A.A. Kharkevich Institute for Information Transmission Problems, RAS, Moscow 127051, Russia.
authors.forename: Marat D
authors.initials: MD
authors.lastname: Kazanov
authors.affiliation: National Institute of Environmental Health Sciences, Durham, NC 27709, USA; School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Roberts
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Paz
authors.initials: P
authors.lastname: Polak
authors.affiliation: Departments of Genome Sciences and Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: John
authors.initials: J
authors.lastname: Stamatoyannopoulos
authors.affiliation: National Institute of Environmental Health Sciences, Durham, NC 27709, USA.
authors.forename: Leszek J
authors.initials: LJ
authors.lastname: Klimczak
authors.affiliation: National Institute of Environmental Health Sciences, Durham, NC 27709, USA. Electronic address: gordenin@niehs.nih.gov.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Gordenin
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ssunyaev@rics.bwh.harvard.edu.
authors.forename: Shamil R
authors.initials: SR
authors.lastname: Sunyaev
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D003564:Cytidine Deaminase / Q000235:genetics*; D004261:DNA Replication; D022041:Euchromatin / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D061986:MCF-7 Cells; D009154:Mutation; D059645:Mutation Rate
chemical_list: D022041:Euchromatin; D003564:Cytidine Deaminase