# Integrated genetic and epigenetic analysis identifies that rs939408 affects non-smoking lung adenocarcinoma risk by modulating the DNA methylation of LRRC2

## TL;DR

This study finds that a genetic variant (rs939408) affects lung cancer risk by changing DNA methylation of the LRRC2 gene, which in turn influences tumor growth and metastasis.

## Contribution

The study identifies rs939408 as a meQTL that modulates LRRC2 methylation and expression, linking it to non-smoking lung adenocarcinoma risk.

## Key findings

- The rs939408 A allele is associated with decreased methylation of cg09596674 in LRRC2, which correlates with lower LUAD risk.
- Lower LRRC2 expression is linked to metastasis and poor survival-related imaging features in LUAD.
- Increased LRRC2 expression inhibits LUAD cell malignancy and tumor growth in mice.

## Abstract

This study aimed to investigate the relationship between methylation quantitative trait loci (meQTL) and lung adenocarcinoma (LUAD) susceptibility. Candidate SNPs linked to differentially methylated CpG sites in LUAD were identified through meQTL datasets. Genome-wide association study (GWAS) data were analyzed to assess the correlation between selected meQTLs and LUAD risk. The effects of target genes on malignant LUAD phenotypes were examined through both in vitro and in vivo experiments. Additionally, machine learning and radiomics models were employed to evaluate the association of target genes on LUAD progression. The variant A allele of rs939408 was associated with decreased methylation levels of cg09596674 in LRRC2 (β < 0, P < 0.001). While cg09596674 was highly methylated, LRRC2 showed lower expression in LUAD tumor tissues. Consistently, a negative correlation was observed between methylation of cg09596674 and LRRC2 expression (r = −0.32, P < 0.001), indicating that lower methylation of cg09596674 modulated by rs939408 may reduce non-smoking LUAD risk (OR = 0.89, P = 0.019). Increased LRRC2 expression inhibited LUAD cell line malignancy and suppressed tumor growth in mice. Furthermore, lower LRRC2 expression was linked to metastasis (P = 0.02) and higher levels of two poorer survival-related imaging features (P = 0.03). The meQTL rs939408 may modulate DNA methylation of LRRC2, thereby influencing its expression and potentially affecting non-smoking LUAD risk. These findings offer valuable insights into the role of meQTLs in LUAD carcinogenesis.