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

Abstract

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 (BRCA1, BRCA2, PALB2, and RAD51D) and damage-response (TP53) concerning unexposed patients. We performed multiplex PCR-based assays and next-generation sequencing (NGS) of all coding regions and flanking splicing sites of BRCA1, BRCA2, PALB2, TP53, and RAD51D 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 < 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 BRCA1 (p = 0.0138), BRCA2 (p = 0.0366), and/or PALB2 (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.

Brief research report pesticide occupational exposure leads to significant inflammatory changes in normal mammary breast tissue

“…It, in our case, may indicate that the breast tissue from pesticide-exposed women is mobilizing its antioxidant defenses against the continuous pesticideinduced oxidative/nitrosative environment. The changes in the production of oxidative/nitrosative stress mediators found here in normal breast tissue deserve attention because it is directly associated with the development and progression of breast cancer (34,35) and the occurrence of worse prognostic outcomes (7,8,36).…”

“…Pesticide exposure increases the risk of developing breast cancer, as evidenced by increased oxidative stress biomarkers, causing direct DNA damage and high mutational load ( 8 , 31 , 32 ). Therefore, pesticides support a tumor-enabling environment.…”

“…Extensive documentation on the damage caused by pesticides to the health of occupationally exposed BC women has been reported. Immune response compromise (7), DNA repair impairment (8) deregulation of estrogen-mediated responses (9) have been described, as well as the high-risk for BC development in rural exposed women (10)(11)(12)(13) Human contamination by occasional exposure to pesticides through contaminated water and environment also correlates with the occurrence of breast cancer cases worldwide, further aggravating this scenario (14)(15)(16)(17)(18).…”

Deleterious and ethnic-related BRCA1/2 mutations in tissue and blood of Egyptian colorectal cancer patients and its correlation with human papillomavirus

“…Another shared BRCA1 PV (c.3329delA) displays a fourfold elevation in CRC risk. The prevalence of this variant in breast and ovarian cancers among African Americans [ 37 ], Brazilians [ 38 ], and the Chinese population [ 39 ] has been well-documented, suggesting its broader implications.…”

Occupational exposure to pesticides deregulates systemic cortisol levels in women with breast cancer and correlates with poor prognosis features

“…Although the main risk factors related to BC are age, family history, and reproductive and hormonal factors, environmental exposures play a significant role in BC ( 2 , 3 ). The negative impact of pesticide exposure has been extensively associated with BC risk ( 4 - 6 ) and is linked to significant immune deregulation ( 7 , 8 ) and DNA repair impairment ( 9 ).…”