title: Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer.
abstract: The somatic mutations in a cancer genome are the aggregate outcome of one or more mutational processes operative through the lifetime of the individual with cancer. Each mutational process leaves a characteristic mutational signature determined by the mechanisms of DNA damage and repair that constitute it. A role was recently proposed for the APOBEC family of cytidine deaminases in generating particular genome-wide mutational signatures and a signature of localized hypermutation called kataegis. A germline copy number polymorphism involving APOBEC3A and APOBEC3B, which effectively deletes APOBEC3B, has been associated with modestly increased risk of breast cancer. Here we show that breast cancers in carriers of the deletion show more mutations of the putative APOBEC-dependent genome-wide signatures than cancers in non-carriers. The results suggest that the APOBEC3A-APOBEC3B germline deletion allele confers cancer susceptibility through increased activity of APOBEC-dependent mutational processes, although the mechanism by which this increase in activity occurs remains unknown.
authors.affiliation: 1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. [2] Department of Medical Genetics, Addenbrooke's Hospital National Health Service (NHS) Trust, Cambridge, UK.
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Ludmil B
authors.identifier: 0000000335964515
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Mia
authors.initials: M
authors.lastname: Petljak
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Butler
authors.affiliation: 1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. [2] Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: Niccolo
authors.initials: N
authors.lastname: Bolli
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Davies
authors.affiliation: 1] Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway. [2] Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Stian
authors.initials: S
authors.lastname: Knappskog
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Sancha
authors.initials: S
authors.lastname: Martin
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Manasa
authors.initials: M
authors.lastname: Ramakrishna
authors.affiliation: 1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. [2] Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Adam
authors.initials: A
authors.lastname: Shlien
authors.affiliation: Regional Genetics Laboratories, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Simonic
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Yali
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Tyler-Smith
authors.affiliation: 1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. [2] Department of Haematology, University of Cambridge, Cambridge, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D003564:Cytidine Deaminase / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D015778:Minor Histocompatibility Antigens; D016296:Mutagenesis; D011506:Proteins / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D015778:Minor Histocompatibility Antigens; D011506:Proteins; C121399:APOBEC3A protein, human; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase
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