Lipid Metabolism Pathway Genes and Lung Cancer: ACADSB rs12220683G>C Is Associated with Better Survival Outcome in Patients with Non-Small Cell Lung Cancer

Introduction: Altered lipid metabolism has been reported to be associated with prognosis in multiple cancers. This study aimed to investigate the association of polymorphisms in lipid metabolism pathway genes with survival outcomes in patients with surgically resected non-small cell lung cancer (NSCLC). Methods: In total, 744 patients with surgically resected NSCLC (380 in the discovery cohort and 364 in the validation cohort) were included in this study. The association between 176 polymorphisms of lipid metabolism pathway genes and the clinical outcomes of NSCLC patients was analyzed. Results: Among the polymorphisms investigated, ACADSB rs10902859GA was associated with significantly better overall survival (OS) in the discovery, validation, and combined cohorts. ACADSB rs10902859GA was located in the repressed region and had strong linkage disequilibrium (D′ = 1.00 and r2 = 0.94), with rs12220683GC located in the H3K4me3 peak region, which indicates the presence of active promoters. ACADSB rs12220683GC was also associated with better OS in the discovery, validation, and combined cohorts (in a dominant model; adjusted hazard ratio [aHR] = 0.53, 95% confidence interval [CI] = 0.30-0.94, p = 0.03; aHR = 0.37, 95% CI = 0.15-0.89, p = 0.03; and aHR = 0.47, 95% CI = 0.29-0.75, p = 0.002, respectively). In vitro luciferase assay demonstrated that the promoter activity of ACADSB was significantly increased in the rs12220683 variant C allele compared with that in the wild G allele (p = 3 × 10-5). Conclusion: These results suggest that ACADSB rs12220683GC increases promoter activity and that increased ACADSB expression may result in better OS in patients with surgically resected NSCLC.