Dados do Resumo

Título

Mutational repertoire of hereditary and sporadic triple-negative breast cancer (TNBC) in the context of homologous recombination deficiency (HRD)

Introdução

Triple-negative breast cancer (TNBC) comprises 10-20% of all breast cancer cases and is often aggressive, typically diagnosed at a young age. Hereditary TNBC is strongly associated with loss-of-function mutations in the BRCA1 gene and other homologous recombination repair (HRR) genes, primarily through germline pathogenic variants. Sporadic TNBC frequently exhibits hypermethylation in BRCA1 and RAD51C promoters. Loss-of-function mutations and transcriptional silencing of these genes commonly lead to homologous recombination deficiency (HRD). Tumors with HRD may benefit from therapies targeting DNA damage, such as PARP inhibitors.

Objetivo

The aim of this study is to evaluate the mutational landscape underlying the tumorigenic process in hereditary and sporadic TNBC in the context of HRD by whole exome sequencing (WES) analysis.

Métodos

Whole exome sequencing (WES) was performed on 43 paired samples (leukocyte and tumor tissue) from TNBC patients previously tested for germline mutations in BRCA1/2 and other HRR genes. Somatic promoter methylation of BRCA1 and RAD51C in tumor DNA was assessed by bisulfite sequencing. Based on these findings, patients were categorized into three groups: Hereditary-HRD (n=14), Sporadic Hypermethylated-HRD (n=17), and Sporadic Non-Hypermethylated (n=12). Survival outcomes were analyzed and compared across the groups, and genetic data were correlated with clinical and pathological characteristics. The study was approved by the Research Ethics Committee (protocol number 1746/13) and conducted in accordance with the Declaration of Helsinki.

Resultados

The preliminary results showed that germline mutations identified in a multigene panel were confirmed by leukocyte WES. Tumor-acquired mutations were found in 251 genes, with TP53 being the most frequently mutated gene (70% - 30/43 cases). Somatic variants in HRR genes were detected in 12% (4/33) of cases, including BARD1, ATM, RAD51D, and NBN. Sporadic hypermethylated-HRD tumors had significantly more somatic mutations compared to hereditary-HRD tumors. Tumors diagnosed in patients aged 60 or older had a significantly higher proportion of somatic mutations than those diagnosed at younger ages. Hereditary-HRD tumors were associated with better survival outcomes compared to other groups. These tumors also tended to be diagnosed at younger ages, with fewer positive lymph nodes and distant metastases compared to sporadic hypermethylated-HRD and sporadic non-hypermethylated tumors.

Conclusões

Sporadic tumors (without HRR germline mutations) exhibited a higher mutation burden, worse survival outcomes, and more positive lymph nodes and distant metastases compared to hereditary-HRD tumors. Overall, our preliminary data highlight distinct molecular profiles between hereditary and sporadic TNBC.

Financiador do resumo

CAPES, CNPq, FAPESP and INCITO-INOTE.

Palavras Chave

triple-negative breast cancer; homologous recombination deficiency; mutational repertoire