title: Germline mutation in the RAD51B gene confers predisposition to breast cancer.
abstract: BACKGROUND
  Most currently known breast cancer predisposition genes play a role in DNA repair by homologous recombination. Recent studies conducted on RAD51 paralogs, involved in the same DNA repair pathway, have identified rare germline mutations conferring breast and/or ovarian cancer predisposition in the RAD51C, RAD51D and XRCC2 genes. The present study analysed the five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3) to estimate their contribution to breast and ovarian cancer predisposition.
  
  
  METHODS
  The study was conducted on 142 unrelated patients with breast and/or ovarian cancer either with early onset or with a breast/ovarian cancer family history. Patients were referred to a French family cancer clinic and had been previously tested negative for a BRCA1/2 mutation. Coding sequences of the five genes were analysed by EMMA (Enhanced Mismatch Mutation Analysis). Detected variants were characterized by Sanger sequencing analysis.
  
  
  RESULTS
  Three splicing mutations and two likely deleterious missense variants were identified: RAD51B c.452 + 3A > G, RAD51C c.706-2A > G, RAD51C c.1026 + 5_1026 + 7del, RAD51B c.475C > T/p.Arg159Cys and XRCC3 c.448C > T/p.Arg150Cys. No RAD51D and XRCC2 gene mutations were detected. These mutations and variants were detected in families with both breast and ovarian cancers, except for the RAD51B c.475C > T/p.Arg159Cys variant that occurred in a family with 3 breast cancer cases.
  
  
  CONCLUSIONS
  This study identified the first RAD51B mutation in a breast and ovarian cancer family and is the first report of XRCC3 mutation analysis in breast and ovarian cancer. It confirms that RAD51 paralog mutations confer breast and ovarian cancer predisposition and are rare events. In view of the low frequency of RAD51 paralog mutations, international collaboration of family cancer clinics will be required to more accurately estimate their penetrance and establish clinical guidelines in carrier individuals.
authors.affiliation: Institut Curie, Department of Tumour Biology, 26 rue d'Ulm, 75248, Paris, Cedex 05, France. lisa.golmard@curie.net.
authors.forename: Lisa
authors.initials: L
authors.lastname: Golmard
authors.forename: Virginie
authors.initials: V
authors.lastname: Caux-Moncoutier
authors.forename: Grégoire
authors.initials: G
authors.lastname: Davy
authors.forename: Essam
authors.initials: E
authors.lastname: Al Ageeli
authors.forename: Brigitte
authors.initials: B
authors.lastname: Poirot
authors.forename: Carole
authors.initials: C
authors.lastname: Tirapo
authors.forename: Dorothée
authors.initials: D
authors.lastname: Michaux
authors.forename: Catherine
authors.initials: C
authors.lastname: Barbaroux
authors.forename: Catherine Dubois
authors.initials: CD
authors.lastname: d'Enghien
authors.forename: André
authors.initials: A
authors.lastname: Nicolas
authors.forename: Laurent
authors.initials: L
authors.lastname: Castéra
authors.forename: Xavier
authors.initials: X
authors.lastname: Sastre-Garau
authors.forename: Marc-Henri
authors.initials: MH
authors.lastname: Stern
authors.forename: Claude
authors.initials: C
authors.lastname: Houdayer
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D010375:Pedigree; D012326:RNA Splicing
chemical_list: D004268:DNA-Binding Proteins; C413002:RAD51B protein, human; C448305:RAD51C protein, human; C110901:X-ray repair cross complementing protein 3