title: Mutational analysis of FANCL, FANCM and the recently identified FANCI suggests that among the 13 known Fanconi Anemia genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition.
abstract: Fanconi Anemia (FA) is a rare recessive syndrome characterized by cellular hypersensitivity to DNA-cross-linking agents. To date, 13 FA complementation groups have been described and all 13 genes associated to each of these groups have been currently identified. Three of the known FA genes are also high-risk (FANCD1/BRCA2) or moderate-risk (FANCN/PALB2 and FANCJ/BRIP1) breast cancer susceptibility genes, which makes all members of the FA pathway particularly attractive breast cancer candidate genes. Most FA genes have been screened for mutations in breast cancer families negative for BRCA1/2 mutations but the role of FANCL, FANCM and the recently identified FANCI has not been evaluated to date. This fact and novel data sustaining greater functional relevance of the three genes within the FA pathway prompted us to scrutinize all coding sequences and splicing sites of FANCI, FANCL and FANCM in 95 BRCA1/2-negative index cases from Spanish high-risk breast cancer families. We identified 68 sequence variants of which 24 were coding and 44 non-coding. Six exonic and 26 non-coding variants had not been described previously. None of the coding changes caused clearly pathogenic changes and computational analysis of all non-described intronic variants did not revealed major impact in splicing. With the present study, all known FA genes have been evaluated within the context of breast cancer high-risk predisposition. Our results rule out a major role of FANCI, FANCL and FANCM in familial breast cancer susceptibility, suggesting that among the 13 known FA genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition.
authors.affiliation: Group of Human Genetics, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain. mjgarcia@cnio.es
authors.forename: María J
authors.initials: MJ
authors.lastname: García
authors.forename: Victoria
authors.initials: V
authors.lastname: Fernández
authors.forename: Ana
authors.initials: A
authors.lastname: Osorio
authors.forename: Alicia
authors.initials: A
authors.lastname: Barroso
authors.forename: Fernando
authors.initials: F
authors.lastname: Fernández
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
mesh_terms: D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons; D005199:Fanconi Anemia / Q000235:genetics; D052240:Fanconi Anemia Complementation Group L Protein / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D009154:Mutation
chemical_list: D024682:BRCA2 Protein; C519921:FANCI protein, human; D051856:Fanconi Anemia Complementation Group Proteins; C499908:FANCL protein, human; D052240:Fanconi Anemia Complementation Group L Protein; C518295:FANCM protein, human; D004265:DNA Helicases