title: Protein-truncating variants in moderate-risk breast cancer susceptibility genes: a meta-analysis of high-risk case-control screening studies.
abstract: Several "moderate-risk breast cancer susceptibility genes" have been conclusively identified. Pathogenic mutations in these genes are thought to cause a two to fivefold increased risk of breast cancer. In light of the current development and use of multigene panel testing, the authors wanted to systematically obtain robust estimates of the cancer risk associated with loss-of-function mutations within these genes. An electronic search was conducted to identify studies that sequenced the full coding regions of ATM, CHEK2, BRIP1, PALB2, NBS1, and RAD50 in a general and gene-targeted approach. Inclusion was restricted to studies that sequenced the germline DNA in both high-risk cases and geographically matched controls. A meta-analysis was then performed on protein-truncating variants (PTVs) identified in the studies for an association with breast cancer risk. A total of 10,209 publications were identified, of which 64 studies comprising a total of 25,418 cases and 52,322 controls in the 6 interrogated genes were eligible under our selection criteria. The pooled odds ratios for PTVs in the susceptibility genes were at least >2.6. Additionally, mutations in these genes have shown geographic and ethnic variation. This comprehensive study emphasizes the fact that caution should be taken when identifying certain genes as moderate susceptibility with the lack of sufficient data, especially with regard to the NBS1, RAD50, and BRIP1 genes. Further data from case-control sequencing studies, and especially family studies, are warranted.
authors.affiliation: School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland; Smurfit Institute of Genetics, Trinity College Dublin, College Green, Dublin, Ireland. Electronic address: faloraifi@rcsi.ie.
authors.forename: Fatima
authors.initials: F
authors.lastname: Aloraifi
authors.affiliation: St. Vincent's University Hospital, Elm Park, Dublin, Ireland.
authors.forename: Damian
authors.initials: D
authors.lastname: McCartan
authors.affiliation: National Centre for Medical Genetics, Our Lady's Hospital, Crumlin, Dublin, Ireland.
authors.forename: Trudi
authors.initials: T
authors.lastname: McDevitt
authors.affiliation: School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland; National Centre for Medical Genetics, Our Lady's Hospital, Crumlin, Dublin, Ireland.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Green
authors.affiliation: Smurfit Institute of Genetics, Trinity College Dublin, College Green, Dublin, Ireland. Electronic address: andrew.green@olchc.ie.
authors.forename: Adrian
authors.initials: A
authors.lastname: Bracken
authors.affiliation: School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland; St. Vincent's University Hospital, Elm Park, Dublin, Ireland.
authors.forename: James
authors.initials: J
authors.lastname: Geraghty
mesh_terms: D017766:Acid Anhydride Hydrolases; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D064447:Checkpoint Kinase 2 / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020365:RNA Helicases / Q000235:genetics; D012307:Risk Factors
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; C000618935:BRIP1 protein, human; D020365:RNA Helicases; D045643:DNA Repair Enzymes
keywords: ATM; BRIP1; CHEK2; PALB2; hereditary breast cancer