Functional evaluation of DNA repair genes to determine their role in the development and treatment of Hereditary breast cancer

• Grant number: 18/25118-8
• Support Opportunities: Regular Research Grants
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Viviane Aline Oliveira Silva
• Grantee: Viviane Aline Oliveira Silva
• Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil
• Associated researchers: Cristiano de Pádua ; Matias Eliseo Melendez ; Renata Barbosa Vahia de Abreu ; Rui Manuel Vieira Reis ; Viviane Aline Oliveira Silva

Abstract

Individuals with hereditary breast cancer (HBC) have an increased cancer risk and may benefit from PARP-targeted therapy with PARP inhibitors (PARPi). Additionally, symptomatic or asymptomatic first-degree relatives have a 50% chance of being carriers of the segregating mutation in the family. Most genes associated with HBC are involved in DNA damage repair. However, about 50% of HBC cases do not have well defined associated genes. Thus, considering (i) the importance of DNA repair pathways in HBC, (ii) the lack of knowledge about the causal factor of about 50% of HBC cases, and (iii) the therapeutic importance of understanding the genetic basis of familial/hereditary tumors, the present study intends to investigate the involvement of DNA repair genes not yet associated with HBC. To this end, we will (A) functionally evaluate the biological effect of non-classical variants identified in high risk HBC families, previously identified in previous studies of our research group, by DNA damage repair, proliferation, invasion, apoptosis and cell cycle assays, and (B) assess if the use of PARPi (alone or in combination with Carboplatin) may promote synthetic lethality in cellular models, mutated at homologous recombination-DNA repair-associated genes. We expect to characterize new variants involved in HBC that may respond to PARPi synthetic lethality therapeutic approach. (AU)