Evaluation of BRCA1 silencing by epigenetic and genetic mechanisms in metastatic triple-negative breast cancer and its association with ancestry and prognosis

• Grant number: 19/22749-0
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): March 01, 2020
• Effective date (End): September 30, 2020
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Dirce Maria Carraro
• Grantee: Julia Salles Oliveira
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil

Abstract

Breast cancer (BC) is the most common malignant neoplasm in women. Triple-negative (TN)breast cancer subtype is characterized by the absence of expression of estrogen receptor (ER), progesterone (PR) and human epidermal growth factor receptor 2 (HER2). This subtype represents less than 15% of all cases of BC with a higher incidence in young women of African descent (in American women) and is associated with a worse prognosis and is likely to progress to metastasis.In women with BRCA1 mutation who develop BC, there is a high prevalence of the TN subtype. BRCA1 is envolved with repair of DNA double-strand break by homologous recombination (HR) mechanism. Silencing or loss of function of BRCA1/2 and other genes of this pathway leads to double-stranded repair deficiency, favoring the tumorigenesis and genetic instability of BC associated with this deficiency. Studies show that BRCA1 silencing in TN tumors occurs by distinct mechanisms, one genetic of germinal origin and another epigenetic of somatic origin that have associations with European and African ancestry, respectively. A previous study by the group showed that, among young women (<40yo), 26% had germline mutation in BRCA1/2 and 29% of their tumors had BRCA1 promoter hypermethylation, totaling 55% of cases had BRCA1 deficiency, either by genetic or epigenetic gene silencing mechanisms. The data from this study demonstrate that BRCA1 deficiency is enriched in young women and is associated with better survival in this group of patients. The percentages of the causal mechanisms, epigenetic mutation or silencing associated with HR deficiency (HRD) in TN tumors of Brazilian women present intermediate values to those identified in populations with predominant European or African ancestry, suggesting that the typical European and African ancestry mixture Brazilian population can play an important role. Recent studies have shown that HRD tumors are more sensitive to platinum-based therapies as well as PARP inhibitors and that the mechanism leading to HRD appears to play an important role in this sensitivity. Thus, since the population of Brazil is considered tri-hybrid (Amerindian, European and African) with different percentages of the three ancestries given the great miscegenation, it is necessary to characterize if there is preferably any predominant mechanism associated with silencing this pathway in patients with predominantly African or European ancestry.Thus, this study proposes to evaluate BRCA1 silencing mechanisms in patients with TN metastatic tumors and the association with genetic ancestry and clinical and anatomopathological variables. (AU)