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– 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. During my master thesis internship, I participated to a project focused on understanding better the genetic predisposition to familiar breast cancer [Ch. 1]. Germline mutations with higher penetration, which confer a high risk of developing breast cancer, are located in the BRCA1 and BRCA2 coding region. Other mutations in other genes that determine a moderate risk of cancer are also known. However, about 70% of breast cancers are not associated with any known mutations. We performed a screening by sequencing to identify germline mutations in the non-coding region 3’ UTR of the BRCA1 gene, starting from peripheral blood of female breast cancer patients who had no mutations in the coding region of BRCA1 and 2 genes. Healthy donors were used for the control group. As a result of this screening, we have identified new variants not previously described, which were detected only in patients. Mutations in the 3’ UTR regions can cause gene expression alteration by forming new miRNA interaction sites. By in silico studies, we have shown that some of these variants produce new sites for some miRNAs. BRCA1 acts as an oncosuppressor, so a reduction in its expression can cause a greater cancer incidence. To experimentally validate the hypothesis that these novel identified variants could determine an altered expression of the BRCA1 gene, we performed luciferase expression experiments, in which luciferase gene was cloned upstream of the 3’ UTR FRANCESCA ROSSIELLO, et al. 214

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