title: A haplotype containing the p53 polymorphisms Ins16bp and Arg72Pro modifies cancer risk in BRCA2 mutation carriers.
abstract: Germline mutations in the BRCA1 and BRCA2 genes confer a high lifetime risk of developing breast and other cancers; however, remarkable differences exist regarding disease manifestation in mutation carriers. It has been suggested that other genetic and/or environmental factors modify not only the appearance but also the age of onset and type of tumor in BRCA1/2-associated cases. The aim of the present study was to investigate the role of two p53 polymorphisms (c.97-147ins16bp and c.215c>g, p.Arg72Pro) as potential modifiers. For this purpose we investigated the possible association between the two polymorphisms and disease status in 447 BRCA1/2 mutation carriers belonging to 170 Spanish breast and/or ovarian cancer families. Genotype and haplotype analyses revealed that the presence of a specific haplotype carrying the allele without the 16-bp insertion and the variant allele for the Arg72Pro (No Ins-72Pro haplotype) was associated with an earlier age of onset in BRCA2 mutation carriers. We found an increased risk of developing a first primary tumor (breast or ovarian) before 35 years of age for individuals who carried at least one No Ins-72Pro haplotype (OR: 2.69; 95% CI: 1.15-6.29; P=0.022). We confirmed these data by a functional study in which we compared different p53 genotypes in relation to their apoptotic response after cell treatment with a cytotoxic drug (AraC). Our results revealed a decrease in p53 apoptotic rate associated with the No Ins-72Pro haplotype.
authors.affiliation: Department of Human Genetics, Spanish National Cancer Center, Madrid, Spain. aosorio@cnio.es
authors.forename: A
authors.initials: A
authors.lastname: Osorio
authors.forename: B
authors.initials: B
authors.lastname: Martínez-Delgado
authors.forename: M
authors.initials: M
authors.lastname: Pollán
authors.forename: M
authors.initials: M
authors.lastname: Cuadros
authors.forename: M
authors.initials: M
authors.lastname: Urioste
authors.forename: C
authors.initials: C
authors.lastname: Torrenteras
authors.forename: L
authors.initials: L
authors.lastname: Melchor
authors.forename: O
authors.initials: O
authors.lastname: Díez
authors.forename: M
authors.initials: M
authors.lastname: De La Hoya
authors.forename: E
authors.initials: E
authors.lastname: Velasco
authors.forename: R
authors.initials: R
authors.lastname: González-Sarmiento
authors.forename: T
authors.initials: T
authors.lastname: Caldés
authors.forename: C
authors.initials: C
authors.lastname: Alonso
authors.forename: J
authors.initials: J
authors.lastname: Benítez
mesh_terms: D000328:Adult; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D024522:Genes, BRCA2; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D012306:Risk