AUTHOR=Scandolara Thalita Basso , Valle Sara Ferreira , Esteves Cristiane , Scherer Nicole de Miranda , de Armas Elvismary Molina , Furtado Carolina , Gomes Renan , Boroni Mariana , Jaques Hellen dos Santos , Alves Fernanda Mara , Rech Daniel , Panis Carolina , Bonvicino Cibele Rodrigues 

TITLE=Somatic DNA Damage Response and Homologous Repair Gene Alterations and Its Association With Tumor Variant Burden in Breast Cancer Patients With Occupational Exposure to Pesticides

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.904813

DOI=10.3389/fonc.2022.904813

ISSN=2234-943X

ABSTRACT=<p>Homologous recombination is a crucial pathway that is specialized in repairing double-strand breaks; thus, alterations in genes of this pathway may lead to loss of genomic stability and cell growth suppression. Pesticide exposure potentially increases cancer risk through several mechanisms, such as the genotoxicity caused by chronic exposure, leading to gene alteration. To analyze this hypothesis, we investigated if breast cancer patients exposed to pesticides present a different mutational pattern in genes related to homologous recombination (<italic>BRCA1</italic>, <italic>BRCA2</italic>, <italic>PALB2</italic>, and <italic>RAD51D</italic>) and damage-response (<italic>TP53</italic>) concerning unexposed patients. We performed multiplex PCR-based assays and next-generation sequencing (NGS) of all coding regions and flanking splicing sites of <italic>BRCA1</italic>, <italic>BRCA2</italic>, <italic>PALB2</italic>, <italic>TP53</italic>, and <italic>RAD51D</italic> in 158 unpaired tumor samples from breast cancer patients on MiSeq (Illumina) platform. We found that exposed patients had tumors with more pathogenic and likely pathogenic variants than unexposed patients (p = 0.017). In general, tumors that harbored a pathogenic or likely pathogenic variant had a higher mutational burden (p &lt; 0.001). We also observed that breast cancer patients exposed to pesticides had a higher mutational burden when diagnosed before 50 years old (p = 0.00978) and/or when carrying <italic>BRCA1</italic> (p = 0.0138), <italic>BRCA2</italic> (p = 0.0366), and/or <italic>PALB2</italic> (p = 0.00058) variants, a result not found in the unexposed group. Our results show that pesticide exposure impacts the tumor mutational landscape and could be associated with the carcinogenesis process, therapy response, and disease progression. Further studies should increase the observation period in exposed patients to better evaluate the impact of these findings.</p>