title: CASP8 D302H polymorphism delays the age of onset of breast cancer in BRCA1 and BRCA2 carriers.
abstract: The polymorphic genetic differences among individuals may modify the high risk for breast cancer (BC) and/or ovarian cancer (OC) susceptibility conferred by BRCA1 and BRCA2 mutations. In the present study we investigate the relevance of RAD51 -135C > G, TP53 R72P, NQO1*2 and CASP8 D302H polymorphisms as potential modifiers of BC and/or OC susceptibility conferred by these mutations. The study group encompasses 390 BRCA1/BRCA2 mutation carriers (182 affected with BC and/or OC and 208 unaffected) of 131 unrelated families studied in the Program of Genetic Counselling on Cancer of Valencia Community. The polymorphisms were detected in genomic DNA by ASRA method or real time PCR using fluorescently labeled probes. We found similar incidence of RAD51 -135C > G, TP53 R72P and NQO1*2 polymorphisms among affected and unaffected individuals considering BRCA1/BRCA2 mutations together and separately. However, the CASP8 D302H polymorphism was strongly associated with the absence of BC [OR = 3.41 (95% CI 1.33-8.78, P = 0.01)]. In fact, in the females with CASP8 D302H polymorphism the BC appeared at a median age of 58 in opposition to the 47 years observed for the wild type subjects (P = 0.03). Furthermore, the CASP8 D302H positive females showed a 50% probability of being free of BC by the age of 78 versus the 2% of the CASP8 negative ones. Our results support that the presence of the CASP8 D302H polymorphism diminishes the high risk of BC conferred by BRCA1 and BRCA2 mutations, making possible that some of the carriers could escape from suffering BC along their life span.
authors.affiliation: Molecular Biology Laboratory (Service of Analytical Chemistry), Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Sarai
authors.initials: S
authors.lastname: Palanca Suela
authors.forename: Eva
authors.initials: E
authors.lastname: Esteban Cardeñosa
authors.forename: Eva
authors.initials: E
authors.lastname: Barragán González
authors.forename: Inmaculada
authors.initials: I
authors.lastname: de Juan Jiménez
authors.forename: Isabel
authors.initials: I
authors.lastname: Chirivella González
authors.forename: Angel
authors.initials: A
authors.lastname: Segura Huerta
authors.forename: Carmen
authors.initials: C
authors.lastname: Guillén Ponce
authors.forename: Eduardo
authors.initials: E
authors.lastname: Martínez de Dueñas
authors.forename: Joaquín
authors.initials: J
authors.lastname: Montalar Salcedo
authors.forename: Victoria
authors.initials: V
authors.lastname: Castel Sánchez
authors.forename: Pascual
authors.initials: P
authors.lastname: Bolufer Gilabert
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics*; D053181:Caspase 8 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics; D011110:Polymorphism, Genetic; D012306:Risk
chemical_list: C505530:CASP8 protein, human; D053181:Caspase 8