Unveiling the Metal Mutation Nexus: Exploring the Genomic Impacts of Heavy Metal Exposure in Lung Adenocarcinoma and Colorectal Cancer

Abstract

Mutations that activate oncogenes and deactivate tumor suppressor genes are widely recognized as significant contributors to cancer development. We investigate the relationships between heavy metal exposure and the frequencies and types of gene mutations in patients with lung adenocarcinoma (LC) 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 (ICP-MS), and next-generation sequencing (NGS) of 1123 cancer-related genes was performed on the tumor tissues. Using Bayesian kernel machine regression (BKMR), we found associations between the integrated concentrations of the heavy metals and the number of gene mutations, especially insertions/deletions (indels). Pb, As, and Cd are the most significant contributor to the increased mutation rates. We extracted previously established mutational signatures and found that they exhibited significant correlations with metal exposure. Moreover, we observed substantial shifts in the mutational landscape when comparing groups with high and low metal exposures. Several frequently mutated genes displayed positive correlations with metal exposures, while 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.

Note:
Funding declaration: This work was supported by: (1) National Natural Science Foundation of China (grant number 92259101, 31771466); (2) Cancer Genome Atlas of China (CGAC) project (YCZYPT(2018)06) from the National Human Genetic Resources Sharing Service Platform 551 (2005DKA21300); (3) Strategic Priority Research Program of the Chinese Academy of 552 Sciences, China (grant number XDB38040100).

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: This study was approved by the ethics committee of China Human Genetic Resources Management Office, Ministry of Science and Technology of the People’s Republic of China, and the reference number for approval was 22021SLCJ1864.

Keywords: heavy metal elements, single nucleotide variations, insertions/deletions, cancer-related genes