title: Mutational analysis of telomere genes in BRCA1/2-negative breast cancer families with very short telomeres.
abstract: A majority of the familial breast cancer cases are not explained by mutations in the best-known high susceptibility genes BRCA1 and BRCA2. Since there is a link between DNA repair and telomere maintenance mechanisms, we have investigated for the first time the role of telomere genes in breast cancer predisposition. By a combination of DHPLC and direct sequencing, we screened for sequence variation in 14 telomere-related genes which included telomerase and shelterin complexes in index cases from 50 BRCA1/2-negative families previously characterized to have very short telomere length in peripheral blood leukocytes. Clear pathogenic changes were not detected in any of the genes analyzed. Most of the changes were non-coding variants and only nine corresponded to coding variants located in TPP1, TINF2, NHP2, TNKS, and RAD54B genes; although only two corresponded to coding missense changes leading to aminoacid changes in genes NHP2 and RAD54B. However, functional prediction analysis and control population studies of both variants ruled out its possible pathogenic role. Our results discard a major contribution of telomere-specific genes in hereditary breast cancer.
authors: Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors: Kira
authors: K
authors: Yanowsky
authors: Alicia
authors: A
authors: Barroso
authors: Ana
authors: A
authors: Osorio
authors: Miguel
authors: M
authors: Urioste
authors: Javier
authors: J
authors: Benitez
authors: Beatriz
authors: B
authors: Martinez-Delgado
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D059506:Telomere Shortening; D000091346:Tripeptidyl-Peptidase 1