P2.03-27 Polymorphisms in Folate Metabolism Related Genes Affect the Survival Outcomes of Early-Stage Non-Small Cell Lung Cancer

Abstract

Cellular folate status influences the DNA stability and integrity, and many epidemiologic, animal and human studies suggest that folate status modulates carcinogenesis. This study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) in genes involved in folate metabolism and survival outcomes of surgically resected non-small cell lung cancer (NSCLC). We genotyped 182 potentially functional SNPs in folate metabolism pathway in a discovery study involving 354 NSCLC patients who underwent curative surgery. A replication study was performed in an independent cohort of 428 patients. In the discovery set, 38 SNPs were significantly associated with survival outcomes in multivariate analyses. Among these, two SNPs (ALPL rs2242421G>A, MTHFD1L rs9397033A>T) were replicated in the replication set. In combined analysis, ALPL rs2242421G>A was significantly associated with better overall survival under a codominant model (adjusted hazard ratio [aHR] = 0.72, 95% confidence interval [CI] = 0.59-0.88, P = 0.002). MTHFD1L rs9397033A>T was significantly associated with worse disease-free survival under a recessive model (aHR = 1.45, 95% CI = 1.13–1.87, P = 0.004). In a luciferase assay, the rs2242421A allele showed significantly higher luciferase activity than the rs2242421G allele (P = 0.02) in H1299 cell lines. Consistently, the level of ALPL mRNA expression in tumor tissues increased as the number of A allele increased (P trend = 0.05). Our results suggest that the 2 SNPs, especially ALPL rs2242421G>A could be used as a biomarker for predicting the clinical outcomes of patients with early stage NSCLC.