CASP8 D302H polymorphism delays the age of onset of breast cancer in BRCA1 and BRCA2 carriers

• Published in: Breast cancer research and treatment Vol. 119; no. 1; pp. 87 - 93
• Main Authors: Palanca Suela, Sarai, Esteban Cardeñosa, Eva, Barragán González, Eva, de Juan Jiménez, Inmaculada, Chirivella González, Isabel, Segura Huerta, Ángel, Guillén Ponce, Carmen, Martínez de Dueñas, Eduardo, Montalar Salcedo, Joaquín, Castel Sánchez, Victoria, Bolufer Gilabert, Pascual
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 2010; Springer US; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Age; Age of Onset; Aged; Aged, 80 and over; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Cancer; Cancer research; Cancer therapies; Caspase 8 - genetics; DNA Mutational Analysis; Female; Gene mutations; Genes; Genes, BRCA1; Genes, BRCA2; Genetic aspects; Genetic Predisposition to Disease; Genotype; Gynecology. Andrology. Obstetrics; Health aspects; Heterozygote; Humans; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Mutation; Oncology; Ovarian Neoplasms - genetics; Polymorphism; Polymorphism, Genetic; Preclinical Study; Risk; Tumor proteins; Tumors; Valencia Spain; Spain; Breast cancer; D302H polymorphism; mutation carriers; /; Breast disease; Genetic variability; CASP8 D302H polymorphism; Genotype; BRCA1/BRCA2 mutation carriers; Malignant tumor; Mammary gland diseases; Age of onset; BRCA2 gene; Genetics; Mutation; BRCA1 gene; Cancer; Tumor suppressor gene; Polymorphism
• ISSN: 0167-6806; 1573-7217; 1573-7217
• DOI: 10.1007/s10549-009-0316-2

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.