genetic anticipation is associated with telomere shortening in hereditary breast cancer遗传与端粒缩短预期遗传性乳腺癌.pdfVIP

Genetic Anticipation Is Associated with Telomere Shortening in Hereditary Breast Cancer Beatriz Martinez-Delgado1,2.*, Kira Yanowsky1,2., Lucia Inglada-Perez2,3, Samuel Domingo1,2, Miguel Urioste1,2, Ana Osorio1,2, Javier Benitez1,2 ´ ´ 1 Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, 2 Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Spanish National Cancer Research Centre, Madrid, Spain, 3 Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain 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