title: Breast cancer-associated Abraxas mutation disrupts nuclear localization and DNA damage response functions.
abstract: Breast cancer is the most common cancer in women in developed countries and has a well-established genetic component. Germline mutations in a network of genes encoding BRCA1, BRCA2, and their interacting partners confer hereditary susceptibility to breast cancer. Abraxas directly interacts with the BRCA1 BRCT (BRCA1 carboxyl-terminal) repeats and contributes to BRCA1-dependent DNA damage responses, making Abraxas a candidate for yet unexplained disease susceptibility. Here, we have screened 125 Northern Finnish breast cancer families for coding region and splice-site Abraxas mutations and genotyped three tagging single-nucleotide polymorphisms within the gene from 991 unselected breast cancer cases and 868 female controls for common cancer-associated variants. A novel heterozygous alteration, c.1082G>A (Arg361Gln), that results in abrogated nuclear localization and DNA response activities was identified in three breast cancer families and in one additional familial case from an unselected breast cancer cohort, but not in healthy controls (P = 0.002). On the basis of its exclusive occurrence in familial cancers, disease cosegregation, evolutionary conservation, and disruption of critical BRCA1 functions, the recurrent Abraxas c.1082G>A mutation connects to cancer predisposition. These findings contribute to the concept of a BRCA-centered tumor suppressor network and provide the identity of Abraxas as a new breast cancer susceptibility gene.
authors.affiliation: Laboratory of Cancer Genetics, Department of Clinical Genetics, Institute of Clinical Medicine and Biocenter Oulu, University of Oulu, Oulu University Hospital, Aapistie 5A, FI-90220 Oulu, Finland.
authors.forename: Szilvia
authors.initials: S
authors.lastname: Solyom
authors.forename: Bernadette
authors.initials: B
authors.lastname: Aressy
authors.forename: Katri
authors.initials: K
authors.lastname: Pylkäs
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Patterson-Fortin
authors.forename: Jaana M
authors.initials: JM
authors.lastname: Hartikainen
authors.forename: Anne
authors.initials: A
authors.lastname: Kallioniemi
authors.forename: Saila
authors.initials: S
authors.lastname: Kauppila
authors.forename: Jenni
authors.initials: J
authors.lastname: Nikkilä
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
authors.forename: Roger A
authors.initials: RA
authors.lastname: Greenberg
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D005260:Female; D005387:Finland; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D021381:Protein Transport
chemical_list: C520310:ABRAXAS1 protein, human; D002352:Carrier Proteins