title: Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors.
abstract: High rates of APOBEC-signature mutations are found in many tumors, but factors affecting this mutation pattern are not well understood. Here we explored the contribution of two common germline variants in the APOBEC3 region. SNP rs1014971 was associated with bladder cancer risk, increased APOBEC3B expression, and enrichment with APOBEC-signature mutations in bladder tumors. In contrast, a 30-kb deletion that eliminates APOBEC3B and creates an APOBEC3A-APOBEC3B chimera was not important in bladder cancer, whereas it was associated with breast cancer risk and enrichment with APOBEC-signature mutations in breast tumors. In vitro, APOBEC3B expression was predominantly induced by treatment with a DNA-damaging drug in bladder cancer cell lines, and APOBEC3A expression was induced as part of the antiviral interferon-stimulated response in breast cancer cell lines. These findings suggest a tissue-specific role of environmental oncogenic triggers, particularly in individuals with germline APOBEC3 risk variants.
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Candace D
authors.initials: CD
authors.lastname: Middlebrooks
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: A Rouf
authors.initials: AR
authors.lastname: Banday
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Konichi
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Krizia-Ivana
authors.initials: KI
authors.lastname: Udquim
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Olusegun O
authors.initials: OO
authors.lastname: Onabajo
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Paquin
authors.affiliation: Usher Institute of Population Health Sciences and Informatics, Medical School, University of Edinburgh, Edinburgh, UK.
authors.forename: Jonine D
authors.initials: JD
authors.lastname: Figueroa
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Stella
authors.initials: S
authors.lastname: Koutros
authors.affiliation: Center for Integrative Medical Science, Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Urology, School of Medicine, Kochi University, Kochi, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Shuin
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Freedman
authors.affiliation: Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain.|Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.|Epidemiología y Salud Pública (CIBERESP), Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain.
authors.forename: Manolis
authors.identifier: 0000-0002-9605-0461
authors.initials: M
authors.lastname: Kogevinas
authors.affiliation: Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Malats
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Debra T
authors.initials: DT
authors.lastname: Silverman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ludmila
authors.identifier: 0000-0002-9622-2091
authors.initials: L
authors.lastname: Prokunina-Olsson
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D003564:Cytidine Deaminase / Q000235:genetics*; D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; D004777:Environment; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D016296:Mutagenesis; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms; D011506:Proteins / Q000235:genetics*; D018570:Risk Assessment; D016019:Survival Analysis; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; D015778:Minor Histocompatibility Antigens; D020033:Protein Isoforms; D011506:Proteins; C121399:APOBEC3A protein, human; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase