Genetic Polymorphisms in Activating Transcription Factor 3 Binding Site and the Prognosis of Early-Stage Non-Small Cell Lung Cancer

Abstract

<b><i>Background:</i></b> Activating transcription factor 3 (ATF3) plays a significant role in cancer development and progression. We investigated the association between variants in expression quantitative trait loci (eQTLs) within ATF3 binding regions and the prognosis of non-small cell lung cancer (NSCLC) after surgery. <b><i>Methods:</i></b> A total of 772 patients with NSCLC who underwent curative surgery were enrolled. Using a public database (http://galaxyproject.org), we selected 104 single nucleotide polymorphisms (SNPs) in eQTLs in the ATF3 binding regions. The association of those SNPs with disease-free survival (DFS) was evaluated. <b><i>Results:</i></b> Among those SNPs, <i>HAX1</i> rs11265425T&#x3e;G was associated with significantly worse DFS (aHR = 1.30, 95% CI = 1.00–1.69, <i>p</i> = 0.05), and <i>ME3</i> rs10400291C&#x3e;A was associated with significantly better DFS (aHR = 0.66, 95% CI = 0.46–0.95, <i>p</i> = 0.03). Regarding <i>HAX1</i> rs11265425T&#x3e;G, the significant association remained only in adenocarcinoma, and the association was significant only in squamous cell carcinoma regarding <i>ME3</i> rs10400291C&#x3e;A. ChIP-qPCR assays showed that the two variants reside in active enhancers where H3K27Ac and ATF3 binding occurs. Promoter assays showed that rs11265425 G allele had significantly higher <i>HAX1</i> promoter activity than T allele. <i>HAX1</i> RNA expression was significantly higher in tumor than in normal lung, and higher in rs11265425 TG+GG genotypes than in TT genotype. Conversely, <i>ME3</i> expression was significantly lower in tumor than in normal lung, and higher in rs10400291 AA genotype than in CC+CA genotypes. <b><i>Conclusions:</i></b> In conclusion, this study shows that the functional polymorphisms in ATF3 binding sites, <i>HAX1</i> rs11265425T&#x3e;G and <i>ME3</i> rs10400291C&#x3e;A are associated with the clinical outcomes of patients in surgically resected NSCLC.