title: Detection of novel germline mutations for breast cancer in non-BRCA1/2 families.
abstract: The identification of the breast cancer susceptibility genes BRCA1 and BRCA2 enhanced clinicians' ability to select high-risk individuals for aggressive surveillance and prevention, and led to the development of targeted therapies. However, BRCA1/2 mutations account for only 25% of familial breast cancer cases. To systematically identify rare, probably pathogenic variants in familial cases of breast cancer without BRCA1/2 mutations, we developed a list of 312 genes, and performed targeted DNA enrichment coupled to multiplex next-generation sequencing on 104 'BRCAx' patients and 101 geographically matched controls in Ireland. As expected, this strategy allowed us to identify mutations in several well-known high-susceptibility and moderate-susceptibility genes, including ATM (~ 5%), RAD50 (~ 3%), CHEK2 (~ 2%), TP53 (~ 1%), PALB2 (~ 1%), and MRE11A (~ 1%). However, we also identified novel pathogenic variants in 30 other genes, which, when taken together, potentially explain the etiology of the missing heritability in up to 35% of BRCAx patients. These included novel potential pathogenic mutations in MAP3K1, CASP8, RAD51B, ZNF217, CDKN2B-AS1, and ERBB2, including a splice site mutation, which we predict would generate a constitutively active HER2 protein. Taken together, this work extends our understanding of the genetics of familial breast cancer, and supports the need to implement hereditary multigene panel testing to more appropriately orientate clinical management.
authors.affiliation: Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Fatima
authors.initials: F
authors.lastname: Aloraifi
authors.affiliation: National Centre for Medical Genetics, Our Lady's Hospital, Crumlin, Dublin 12, Ireland.
authors.forename: Trudi
authors.initials: T
authors.lastname: McDevitt
authors.affiliation: Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Rui
authors.initials: R
authors.lastname: Martiniano
authors.affiliation: Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Jonah
authors.initials: J
authors.lastname: McGreevy
authors.affiliation: Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Russell
authors.initials: R
authors.lastname: McLaughlin
authors.affiliation: Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Egan
authors.affiliation: National Centre for Medical Genetics, Our Lady's Hospital, Crumlin, Dublin 12, Ireland.
authors.forename: Nuala
authors.initials: N
authors.lastname: Cody
authors.affiliation: National Centre for Medical Genetics, Our Lady's Hospital, Crumlin, Dublin 12, Ireland.
authors.forename: Marie
authors.initials: M
authors.lastname: Meany
authors.affiliation: TrinSeq, Trinity College Dublin, Ireland.
authors.forename: Elaine
authors.initials: E
authors.lastname: Kenny
authors.affiliation: National Centre for Medical Genetics, Our Lady's Hospital, Crumlin, Dublin 12, Ireland.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Green
authors.affiliation: Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bradley
authors.affiliation: St. Vincent University Hospital, Dublin 4, Ireland.
authors.forename: James G
authors.initials: JG
authors.lastname: Geraghty
authors.affiliation: Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Bracken
mesh_terms: D000328:Adult; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D053181:Caspase 8 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D053181:Caspase 8; D004268:DNA-Binding Proteins; D048728:MAP Kinase Kinase Kinase 1; D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding; D018719:Erb-b2 Receptor Tyrosine Kinases; D015534:Trans-Activators; C492913:BRCA1 protein, human; C551750:BRCA2 protein, human; C561518:CDKN2B antisense RNA, human; C413002:RAD51B protein, human; C113698:ZNF217 protein, human; C508053:ERBB2 protein, human; C482576:MAP3K1 protein, human; C505530:CASP8 protein, human
keywords: BRCA1; BRCA2; familial breast cancer; genetics; next-generation sequencing