RESUMEN
This study addresses the prevalence of ATM mutations and the association with breast cancer in Austrian families selected for a history of breast or ovarian cancer or both [hereditary breast and ovarian cancer (HBOC)]. In 270 HBOC families previously screened for BRCA1 and BRCA2 mutations, 137 different sequence alterations of ATM were identified. Seven of these were mutations presumed to cause ataxia telangiectasia based on their effect on the ATM protein, including five that caused a protein truncation and two missense mutations in the catalytic kinase domain of the highly conserved COOH terminus of the protein. The seven mutations were found in 10 families (3.7%). In addition, one missense variant, L1420F, was observed in 13 HBOC families (4.8%) but was not observed in any of the 122 healthy volunteers with no history of breast cancer. In addition, the variant segregated with breast cancer in some of the families, suggesting that it may be pathogenic for breast cancer. Sixty-two additional variants of potential significance were observed in 65 HBOC families, but not in healthy controls. These variants included 24 sequence alterations with possible effects on splicing or protein-protein interactions. This study indicates that there is a significant prevalence of ATM mutations in breast and ovarian cancer families and adds to a growing body of evidence that ATM mutations confer increased susceptibility to breast cancer.
Asunto(s)
Neoplasias de la Mama/genética , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Ováricas/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Anciano , Sustitución de Aminoácidos , Proteínas de la Ataxia Telangiectasia Mutada , Austria/epidemiología , Proteína BRCA2/genética , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama Masculina/epidemiología , Neoplasias de la Mama Masculina/genética , Proteínas de Ciclo Celular , Codón sin Sentido , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Proteínas de Unión al ADN , Femenino , Genes BRCA1 , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Neoplasias Primarias Múltiples/epidemiología , Neoplasias Primarias Múltiples/genética , Síndromes Neoplásicos Hereditarios/epidemiología , Neoplasias Ováricas/epidemiología , Proteínas Serina-Treonina Quinasas/fisiología , Empalme del ARN/genética , Proteínas Supresoras de TumorRESUMEN
Denaturing high performance liquid chromatography (DHPLC) in combination with dye-terminator sequencing was used to survey 516 random genomic sequence tagged sites (STSs) for biallelic polymorphisms in 24 representatives of the major ethnic groups residing in the United States. Of the 301 polymorphic STSs (58.3%), 172 contained a single simple sequence polymorphism (SSP), while 78, 35, and 16 contained 2, 3, and 4-6 SSPs, respectively. Of the 541 SSPs identified, 342 (63%), 152 (28%), and 47 (9%) were transitions, transversions, and insertions or deletions, respectively. Only 21% of the STSs contained SSPs with a minor-allele frequency >20%. The nucleotide diversity estimate for random genomic sequences theta = 8.23 x 10(-4) was on average 50% higher than that for intragenic non-coding regions of the human genome ( theta = 5.52 x 10(-4). The discrepancy in Tajima's D statistic between 22 autosomal genes (D=-1.304+/-0.622, mean+/-SD) and random STSs (D=-0.27) suggests that, in the absence of significant mutation rate heterogeneity, the more negative values for genes are a consequence of directional selection rather than population growth.