Somatic DNA Damage Response and Homologous Repair Gene Alterations and Its Association With Tumor Variant Burden in...

Area of Science:

• Genomics
• Environmental Health
• Oncology

Background:

• Homologous recombination (HR) pathway genes are critical for repairing DNA double-strand breaks, maintaining genomic stability.
• Alterations in HR genes can lead to genomic instability and suppressed cell growth, contributing to cancer development.
• Pesticide exposure is a potential risk factor for cancer, possibly through genotoxic mechanisms causing gene alterations.

Purpose of the Study:

• To investigate if breast cancer patients with pesticide exposure exhibit distinct mutational patterns in key homologous recombination (BRCA1, BRCA2, PALB2, RAD51D) and DNA damage-response (TP53) genes compared to unexposed patients.
• To analyze the impact of pesticide exposure on the tumor mutational landscape in breast cancer.

Main Methods:

• Multiplex PCR-based assays and next-generation sequencing (NGS) were employed.
• All coding regions and flanking splicing sites of BRCA1, BRCA2, PALB2, TP53, and RAD51D were analyzed.
• 158 unpaired tumor samples from breast cancer patients were sequenced using the Illumina MiSeq platform.

Main Results:

• Pesticide-exposed breast cancer patients showed significantly more pathogenic/likely pathogenic variants than unexposed patients (p = 0.017).
• Tumors with pathogenic/likely pathogenic variants generally exhibited a higher mutational burden (p < 0.001).
• Exposed patients diagnosed before age 50 and/or carrying BRCA1, BRCA2, or PALB2 variants had a higher mutational burden compared to unexposed individuals.

Conclusions:

• Pesticide exposure significantly impacts the tumor mutational landscape in breast cancer patients.
• These findings suggest a potential association between pesticide exposure, carcinogenesis, therapy response, and disease progression.
• Further long-term studies are warranted to fully elucidate the impact of pesticide exposure on breast cancer outcomes.