title: An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers.
abstract: Recent studies indicate that a subclass of APOBEC cytidine deaminases, which convert cytosine to uracil during RNA editing and retrovirus or retrotransposon restriction, may induce mutation clusters in human tumors. We show here that throughout cancer genomes APOBEC-mediated mutagenesis is pervasive and correlates with APOBEC mRNA levels. Mutation clusters in whole-genome and exome data sets conformed to the stringent criteria indicative of an APOBEC mutation pattern. Applying these criteria to 954,247 mutations in 2,680 exomes from 14 cancer types, mostly from The Cancer Genome Atlas (TCGA), 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. Within breast cancer, the HER2-enriched subtype was clearly enriched for tumors with the APOBEC mutation pattern, suggesting that this type of mutagenesis is functionally linked with cancer development. The APOBEC mutation pattern also extended to cancer-associated genes, implying that ubiquitous APOBEC-mediated mutagenesis is carcinogenic.
authors.affiliation: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Durham, North Carolina, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Roberts
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.forename: Leszek J
authors.initials: LJ
authors.lastname: Klimczak
authors.forename: Sara A
authors.initials: SA
authors.lastname: Grimm
authors.forename: David
authors.initials: D
authors.lastname: Fargo
authors.forename: Petar
authors.initials: P
authors.lastname: Stojanov
authors.forename: Adam
authors.initials: A
authors.lastname: Kiezun
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Kryukov
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.forename: Gordon
authors.initials: G
authors.lastname: Saksena
authors.forename: Shawn
authors.initials: S
authors.lastname: Harris
authors.forename: Ruchir R
authors.initials: RR
authors.lastname: Shah
authors.forename: Michael A
authors.initials: MA
authors.lastname: Resnick
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Gordenin
mesh_terms: D000071479:APOBEC-1 Deaminase; D001943:Breast Neoplasms; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003564:Cytidine Deaminase / Q000235:genetics*; D059472:Exome; D005260:Female; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D008297:Male; D016296:Mutagenesis; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics
chemical_list: D000071479:APOBEC-1 Deaminase; D003564:Cytidine Deaminase; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C000605089:APOBEC1 protein, human