title: Analysis of FANCB and FANCN/PALB2 fanconi anemia genes in BRCA1/2-negative Spanish breast cancer families.
abstract: Recent reports have shown that mutations in the FANCJ/BRIP1 and FANCN/PALB2 Fanconi Anemia (FA) genes confer a moderate breast cancer risk. Discussion has been raised on the phenotypic characteristics of the PALB2-associated families and tumors. The role of FANCB in breast cancer susceptibility has not been tested to date. Likewise PALB2 mutation frequency has not been studied in Spanish population. We analyzed the complete coding sequence and splicing sites of FANCB and PALB2 in 95 index cases of BRCA1/2-negative Spanish breast cancer families. We also performed an exhaustive screening of three previously described rare but recurrent PALB2 mutations in 725 additional probands. Pathogenic changes were not detected in FANCB. We found a novel PALB2 truncating mutation c.1056_1057delGA (p.K353IfsX7) in one of the 95 screened patients, accounting for a mutation frequency of 1% in our series. Further comprehensive screening of the novel mutation and of previously reported rare but recurrent PALB2 mutations did not reveal any carrier patient. We report the first example of LOH occurring in a PALB2-associated tumor. Our results rule out a major contribution of FANCB to hereditary breast cancer. Our data are consistent with the notion of individually rare PALB2 mutations, lack of mutational hot-spots in the gene and existence of between-population disease-allele heterogeneity. We show evidence that PALB2 loss of function might also conform to the inactivation model of a classic tumor-suppressor gene and present data that adds to the clinically relevant discussion about the existence of a PALB2-breast cancer phenotype.
authors.affiliation: Group of Human Genetics, Human Cancer Genetics Program, Spanish National Cancer Centre, CNIO, Madrid, Spain.
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: Gemma
authors.initials: G
authors.lastname: Llort
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco
authors.forename: Trinidad
authors.initials: T
authors.lastname: Caldés
authors.forename: Miguel
authors.initials: M
authors.lastname: de la Hoya
authors.forename: Teresa
authors.initials: T
authors.lastname: Ramón Y Cajal
authors.forename: Carmen
authors.initials: C
authors.lastname: Alonso
authors.forename: María-Isabel
authors.initials: MI
authors.lastname: Tejada
authors.forename: Carlos
authors.initials: C
authors.lastname: San Román
authors.forename: Luis
authors.initials: L
authors.lastname: Robles-Díaz
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000235:genetics; D000076164:Fanconi Anemia Complementation Group N Protein; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics; D010375:Pedigree; D013030:Spain; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C515775:FANCB protein, human; D000076164:Fanconi Anemia Complementation Group N Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins