Unveiling the metal mutation nexus: Exploring the genomic impacts of heavy metal exposure in lung adenocarcinoma and colorectal cancer

Mutations that activate oncogenes and deactivate tumor suppressor genes are widely recognized as significant contributors to cancer development. We investigated relationships between heavy metal exposure and the frequencies and types of gene mutations in patients with lung adenocarcinoma (LUAD) and colorectal cancer (CRC). Plasma concentrations of arsenic (As), cadmium (Cd), chromium (Cr), mercury (Hg), and lead (Pb) were measured using inductively coupled plasma mass spectrometry (ICPMS), and next-generation sequencing (NGS) of 1123 cancer-related genes was performed using the tumor tissues. Through Bayesian kernel machine regression (BKMR) analysis, we found associations between the integrated concentrations of the heavy metals and the number of gene mutations, especially insertions/deletions (indels), and Pb, As, and Cd were found to be the most significant contributors to the increased mutation rates. We extracted previously established mutational signatures and observed that they exhibit significant correlations with metal exposure. Moreover, we detected substantial shifts in the mutational landscape when comparing groups with high and low metal exposures. Several frequently mutated genes displayed positive correlations with metal exposure, whereas EGFR indels showed a negative association with Cd exposure. These findings suggest that heavy metal exposure can impact genomic stability in cancer-related genes, underscoring the importance of heavy metal exposure in cancer development.