Sex disparities in the association between rare earth elements exposure and genetic mutation frequencies in lung cancer patients

The ubiquitous use of rare earth elements (REEs) in modern living environments raised concern about their impact on human health. With the detrimental and beneficial effects of REEs reported by different studies, the genuine role of REEs in the human body remains a mystery. This study explored the association between REEs and genetic mutations in patients with lung adenocarcinoma (LUAD). A cohort of 53 LUAD patients underwent tumor DNA sequencing (1123 cancer-related genes) and plasma REE (lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), and yttrium (Y)) quantification. We found divergent relationships between plasma REE levels and mutation load between sexes. Specifically, Ce levels and mutation load were positively correlated in males but negatively correlated in females, while La exposure exhibited opposite associations in the two sexes. This observation was validated using the Bayesian Kernel Machine Regression (BKMR) model. Additionally, plasma REE levels was associated with specific mutation types and variant allele frequencies (VAFs) of particular genes in a sex-dependent manner. Mutational signature analysis revealed sex-specific associations of La with indel signatures. These findings highlight the intricate interplay between plasma REE levels and genetic mutations in LUAD, emphasizing the need for a personalized, sex-oriented approach to understand and treat this disease.