EVALUATION OF THE MUTATIONAL REPERTOIRE OF HEREDITARY AND SPORADIC TRIPLE NEGATIVE BREAST CANCER (TNBC) IN THE CONTEXT OF HOMOLOGOUS RECOMBINATION DEFICIENCY

• Grant number: 24/06408-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2025
• End date: August 31, 2028
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Dirce Maria Carraro
• Grantee: Leticia Santos Pimentel
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil

Abstract

Triple-negative breast cancer (TNBC) accounts for 15%-20% of breast cancer cases, is particularly aggressive, and occurs more frequently in young women and women of African ancestry, with highly variable clinical outcomes. This subtype is characterized by the absence of expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor type 2 (HER2), which limits treatment options and makes the therapeutic approach more challenging for many patients.Approximately 30% of women diagnosed with TNBC carry loss-of-function (LOF) pathogenic germline variants (GPVs) in genes involved in the repair of DNA double-strand breaks by homologous recombination (HRR), such as BRCA1, which plays a central role in this process. Women with GPVs in the BRCA1 and BRCA2 genes have an increased risk of developing breast tumors, especially the triple-negative subtype, as well as ovarian cancer. Tumors associated with loss of function in the BRCA1/2 genes often have a deficiency in homologous recombination repair (HRD), making them more sensitive to treatments that cause DNA damage, such as platinum salts and PARP inhibitors, approved therapies for patients with metastatic TNBC.In addition to loss of function (germinal or somatic) in the BRCA1/2 genes, epigenetic silencing of BRCA1 and RAD51C can also lead to HRD. Studies conducted in American women show that the HRD phenotype in TNBC of white women is associated with genetic variants in BRCA1/2, while in black women, epigenetic silencing of BRCA1/RAD51C is the predominant mechanism. This suggests that African and European ancestries may influence the HRD phenotype in triple-negative tumors.Preliminary data from the group indicate that women with hereditary TNBC have better survival compared to those with sporadic TNBC. Furthermore, women with BRCA2-associated hereditary TNBC present a pattern of metastasis with a higher incidence in the central nervous system and bones, differing from the pattern observed in BRCA1-associated hereditary and sporadic tumors. This illustrates the heterogeneity of this group of tumors and suggests different pathways of tumorigenesis.Understanding these distinct pathways of emergence and progression of TNBC, both hereditary and sporadic, is essential to understand the heterogeneity of this aggressive tumor and contribute to the development of more personalized and effective treatments. The objective of this study is to characterize the tumorigenic processes of the different groups of TNBC in the context of HRD. At least 80 triple-negative tumor samples will be included for whole exome sequencing (WES). Based on the WES data, the mutational repertoire and signatures, in addition to molecular ancestry, will be evaluated. Functional immunofluorescence-based assays and analysis of epigenetic silencing of BRCA1 and RAD51C in the tumor by bisulfite-NGS will be performed to investigate the homologous recombination deficiency (HRD) or proficiency (HRP) phenotype. The data obtained will be evaluated together with clinical information from the patients, aiming to significantly contribute to the understanding of the genetic and clinical heterogeneity of this aggressive breast cancer. (AU)