STUDY ON THE GENETIC PREDISPOSITION TO BREAST CANCER AND THE DNA DAMAGE RESPONSE AT TELOMERES AND IN CELLULAR SENESCENCE

Abstract

Germ line mutations in the coding sequence of some genes, mainly BRCA1 and BRCA2, confer a high risk of developing breast cancer. However, about 70% of tumors cases are not associated with any known mutation. By screening by sequencing peripheral blood of patients and healthy controls, we identified some previously unknown germline mutations in the 3 'UTR non-coding region of the BRCA1 gene. These mutations can modify gene expression, and can therefore be useful to predict, with greater accuracy, familiar breast cancer predisposition. Subsequently, to understand the mechanisms of aging in non-proliferating cells we studied the persistent DNA damage response (DDR) signal in senescent cells, both in cell cultures and in animal tissues, and we found that these signals mainly localize to telomeres, independently from their length. The accumulation of damage at the telomeric DNA, due to the inhibition of the repair mechanisms, causes cellular and individual aging, but it is also an important anti-tumor mechanism, as it prevents the uncontrolled cell growth during the early stages of neoplastic transformation.