The association and risk prediction of the ubiquitination pathway genetic variants and lung cancer incidence: A nested case-control study

BACKGROUND: Dysregulation of the ubiquitin-proteasome system (UPS) promotes tumorigenesis, but population-level evidence linking UPS variants to lung cancer risk is limited. METHODS: We conducted a two-stage genetic association study. In the discovery stage, using a nested case-control design, 70,801 SNPs from 750 UPS-related genes were analyzed in 612 lung cancer cases and 901 controls from the Shanghai Suburban Adult Cohort Biobank. Significant loci were validated in an independent case-control cohort consisting of 2718 individuals. We further evaluated the predictive performance of validated SNPs and performed functional analyses, including eQTL, enhancer-promoter interaction, and TCGA analyses. RESULTS: We identified 2,527 SNPs associated with lung cancer risk in the discovery cohort, six of which were validated. Incorporating these variants significantly improved risk prediction beyond traditional risk models in both cohorts (AUCdiscovery: 0.64 vs. 0.53; AUCvalidation: 0.72 vs. 0.57; all P<0.001). The MGRN1 rs11640681 A>G variant was associated with increased risk of lung cancer [ORdiscovery(95% CI) = 1.26(1.04-1.53), P = 0.017; ORvalidation(95% CI) = 1.32(1.07-1.64), P = 0.011]. Functional analyses suggest the G allele may downregulate MGRN1 expression by enhancer-promoter interaction. Higher MGRN1 expression was present in normal lung compared to NSCLC tissues, and was associated with longer NSCLC patients' survival. CONCLUSIONS: Our findings suggest UPS genetic variants contribute to NSCLC risk, with the G allele of rs11640681 potentially increasing risk by downregulating MGRN1, a potential tumor suppressor. IMPACT: These findings enhance the understanding of NSCLC etiology and highlight potential biomarkers for risk stratification in a population setting.