A Functional Variant at 19q13.3, rs967591G>A, Is Associated with Shorter Survival of Early-Stage Lung Cancer

Abstract

Purpose: This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) in 19q13.3 and survival of patients with early-stage non-small cell lung cancer (NSCLC), and to define the causative functional SNP of the association.Experimental Design: A two-stage study design was used to evaluate five SNPs in relation to survival outcomes in 328 patients and then to validate the results in an independent patient population (n ¼ 483). Luciferase assay and real-time PCR were conducted to examine functional relevance of a potentially functional SNP.Results: Of the five SNPs, three SNPs (rs105165C>T, rs967591G>A, and rs735482A>C) were significantly associated with survival outcomes in a stage I study. The rs967591A allele had significantly higher activity of the CD3EAP promoter compared with the rs967591G allele (P ¼ 0.002), but the SNP did not have an effect on the activity of PPP1R13L promoter. The rs967591G>A was associated with the level of CD3EAP mRNA expression in lung tissues (P ¼ 0.01). The rs967591G>A exhibited consistent associations in a stage II study. In combined analysis, the rs967591 AA genotype exhibited a worse overall survival (adjusted HR ¼ 1.69; 95% confidence interval ¼ 1.29-2.20; P ¼ 0.0001).Conclusion: The rs967591G>A affects CD3EAP expression and thus influences survival in early-stage NSCLC. The analysis of the rs967591G>A polymorphism can help identify patients at high risk of a poor disease outcome. Clin Cancer Res; 19(15); 4185-95. Ó2013 AACR.

3018 Functional intronic ERCC1 polymorphism from RegulomeDB can predict survival in lung cancer after surgery

“…We previously investigated these two SNPs in terms of the clinical outcomes of earlystage NSCLC after surgery and advanced NSCLC after platinum-based chemotherapy in Koreans [13,25,26]. However, neither rs11615T>C nor rs3212986C>A showed significant association with the outcome of NSCLC [13,25,26]. In the present study, we searched RegulomeDB for potential regulatory SNPs in ERCC1, and investigated their association with survival after surgery in NSCLC.…”

“…luc, luciferase. www.impactjournals.com/oncotarget in many types of cancer including NSCLC [6][7][8][9][10][11][12][13][14]. However, most of the studies have focused on only a few SNPs, such as ERCC1 rs11615T>C (N118N) and rs3212986C>A in 3′-UTR, and the results have not been consistent among studies.…”

“…However, most of the studies have focused on only a few SNPs, such as ERCC1 rs11615T>C (N118N) and rs3212986C>A in 3′-UTR, and the results have not been consistent among studies. We previously investigated these two SNPs in terms of the clinical outcomes of earlystage NSCLC after surgery and advanced NSCLC after platinum-based chemotherapy in Koreans [13,25,26]. However, neither rs11615T>C nor rs3212986C>A showed significant association with the outcome of NSCLC [13,25,26].…”

“…The expression of ERCC1 by quantitative real-time polymerase chain reaction or immunohistochemistry has been correlated with the clinical outcomes of non-small cell lung cancer (NSCLC) [3][4][5]. Genetic polymorphism of ERCC1 has also been investigated for the association with the risk and clinical outcome of many types of cancer including NSCLC [6][7][8][9][10][11][12][13][14]. The most widely studied single nucleotide polymorphisms (SNPs) include rs11615T>C (N118N) which is the only SNP tested in the exon region of ERCC1, and rs3212986C>A in 3′-UTR of ERCC1 (Q504K for CD3EAP, antisense to ERCC1).…”

iRegNet3D: three-dimensional integrated regulatory network for the genomic analysis of coding and non-coding disease mutations

“…One of them (T to C; chr19: 45927610, hg19) is located in the promoter of the ERCC1 gene about 1 kb upstream of the start codon, and has been reported to affect transcriptional regulation of ERCC1 [67]. The other (G to A; chr19: 45909934, hg19) is located 21 base pairs upstream of the start codon of the CD3EAP gene, and the mutant allele has increased promoter activity and is associated with increased expression of CD3EAP [68]. The former mutation is within a putative TFAP2C-binding site, whereas the latter is located within a putative NR1I2-binding site.…”