title: Genetic anticipation is associated with telomere shortening in hereditary breast cancer.
abstract: There is increasing evidence suggesting that short telomeres and subsequent genomic instability contribute to malignant transformation. Telomere shortening has been described as a mechanism to explain genetic anticipation in dyskeratosis congenita and Li-Fraumeni syndrome. Since genetic anticipation has been observed in familial breast cancer, we aimed to study telomere length in familial breast cancer patients and hypothesized that genetic defects causing this disease would affect telomere maintenance resulting in shortened telomeres. Here, we first investigated age anticipation in mother-daughter pairs with breast cancer in 623 breast cancer families, classified as BRCA1, BRCA2, and BRCAX. Moreover, we analyzed telomere length in DNA from peripheral blood leukocytes by quantitative PCR in a set of 198 hereditary breast cancer patients, and compared them with 267 control samples and 71 sporadic breast cancer patients. Changes in telomere length in mother-daughter pairs from breast cancer families and controls were also evaluated to address differences through generations. We demonstrated that short telomeres characterize hereditary but not sporadic breast cancer. We have defined a group of BRCAX families with short telomeres, suggesting that telomere maintenance genes might be susceptibility genes for breast cancer. Significantly, we described that progressive telomere shortening is associated with earlier onset of breast cancer in successive generations of affected families. Our results provide evidence that telomere shortening is associated with earlier age of cancer onset in successive generations, suggesting that it might be a mechanism of genetic anticipation in hereditary breast cancer.
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. bmartinez@cnio.es
authors.forename: Beatriz
authors.initials: B
authors.lastname: Martinez-Delgado
authors.forename: Kira
authors.initials: K
authors.lastname: Yanowsky
authors.forename: Lucia
authors.initials: L
authors.lastname: Inglada-Perez
authors.forename: Samuel
authors.initials: S
authors.lastname: Domingo
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.forename: Ana
authors.initials: A
authors.lastname: Osorio
authors.forename: Javier
authors.initials: J
authors.lastname: Benitez
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D020132:Anticipation, Genetic; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D059506:Telomere Shortening / Q000235:genetics*; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein