RESUMEN
In Ashkenazi (East European) Jews, three predominant mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) account for the majority of germline mutations in high-risk breast and/or ovarian cancer families. Among non-Ashkenazi Jews, the 185delAG, Tyr978Ter, and a handful of "private" mutations have been reported anecdotally within both genes. In this study we attempted to determine the spectrum of BRCA1 and BRCA2 mutations in high-risk Jewish individuals, non-carriers of any of the predominant Jewish mutations. We employed multiplex PCR and denaturing gradient gel electrophoresis (DGGE) analysis for BRCA2, and combined denaturing high performance liquid chromatography (DHPLC) and protein truncation test (PTT) for BRCA1, complemented by DNA sequencing. We screened 47 high-risk Jewish individuals, 26 Ashkenazis, and 21 non-Ashkenazis. Overall, 13 sequence alterations in BRCA1 and eight in BRCA2 were detected: nine neutral polymorphisms and 12 missense mutations, including five novel ones. The novel missense mutations did not co-segregate with disease in BRCA1 and were detected at rates of 6.25% to 52.5% in the general population for BRCA2. Our findings suggest that except for the predominant mutations in BRCA1 and BRCA2 in Jewish individuals, there are only a handful of pathogenic mutations within these genes. It may imply novel genes may underlie inherited susceptibility to breast/ovarian cancer in Jewish individuals.
Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1/genética , Proteínas de Neoplasias/genética , Neoplasias Ováricas/genética , Factores de Transcripción/genética , Adulto , Anciano , Proteína BRCA2 , Neoplasias de la Mama Masculina/genética , Análisis Mutacional de ADN/métodos , ADN de Neoplasias/análisis , Femenino , Humanos , Judíos/genética , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Polimorfismo Genético/genéticaRESUMEN
Male breast cancer is a rare disorder, and little is known about the molecular mechanisms associated with the tumorigenic process. We genotyped 31 Jewish Israeli males with breast cancer for the predominant Jewish BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT) germline mutations: 11 individuals from high-risk families and 20 patients unselected for family history of cancer. Two patients of the high-risk group (18.2%) displayed germline mutations: one harbored the 185delAG BRCA1 mutation, and the other the 6174delT mutation in BRCA2. None of the unselected patients displayed any mutation. In 2 patients, complete mutation analysis of the BRCA2 gene did not reveal any disease-associated mutations. We conclude that the predominant Jewish germline mutations in BRCA1/BRCA2 contribute to male breast cancer in Israel, primarily in Ashkenazi individuals with a family history of cancer.
Asunto(s)
Neoplasias de la Mama Masculina/genética , Genes BRCA1 , Judíos , Proteínas de Neoplasias/genética , Factores de Transcripción/genética , Adulto , Proteína BRCA2 , Análisis Mutacional de ADN , Genotipo , Mutación de Línea Germinal , Humanos , Israel , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
To gain insight into the molecular mechanisms underlying the inherited predisposition to breast cancer in non-Ashkenazi Jews, we genotyped 54 Jewish Moroccan women with breast cancer, unselected for family history of cancer, for the predominant Jewish mutations in BRCA1, BRCA2, and ATM. One patient (2%) was found to have the 185de1AG BRCA1 mutation, none was a carrier of the 6174delT BRCA2 mutation, and 2/54 (4%) were heterozygous for the ATM mutation. These rates were not significantly different from the rates in the general non-Ashkenazi population. These preliminary data may indicate that the predominant Jewish mutations in BRCA1, BRCA2, and ATM genes contribute little, if any, to breast cancer predisposition and risk among Moroccan Jews.