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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
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Abstract
Homologous recombination is a crucial pathway that is specialized in repairing doublestrand
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 damageresponse
(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.
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