Purpose: This study was conducted to investigate the associations between single nucleotide polymorphisms (SNPs) in 19q13.3 and survival of early-stage non-small cell lung cancer (NSCLC) patients, and to define the causative functional SNP of the association. Methods: 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=565). Luciferase assay and real-time PCR was performed 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 1 study. The rs967591A allele had significantly higher promoter activity of CD3EAP compared with the rs967591G allele (P=0.002), but the SNP did not have an effect on the promoter activity of PPP1R13L. The rs967591G＞A was associated with the level of CD3EAP mRNA expression in lung tissues (P=0.01). The rs967591G＞A exhibited consistent associations in a stage 2 study. In combined analysis, the rs967591 AA genotype exhibited a worse overall survival (adjusted hazard ratio=1.69, 95% confidence interval=1.29-2.20, P=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.
Background/Aims Genome wide and candidate gene association studies have identified polymorphisms associated with the risk of lung cancer in never-smokers. This study was conducted to evaluate the association between 11 polymorphisms identified in female never smokers and the lung cancer risk in male smokers. Methods This study included 714 lung cancer patients and 626 healthy controls. The polymorphisms were genotyped using SEQUENOM MassARRAY iPLEX assay or Taq-Man assay. Results Two polymorphisms were associated with the risk of lung cancer in male smokers, as in female never smokers. Male smokers carrying the rs4975616 variant allele had a significantly decreased risk of lung cancer (in a codominant model: odds ratio, 0.77; 95% confidence interval, 0.61 to 0.96; p = 0.02). The rs9387478 polymorphism also reduced lung cancer risk in male smokers (in a codominant model: odds ratio, 0.85; 95% confidence interval, 0.73 to 0.997; p = 0.046). In a stratified analysis, the association between these polymorphisms and the risk of lung cancer was predominant in lighter smokers and for cases of adenocarcinoma. Conclusions These results suggest that a subset of polymorphisms known to be associated with the risk of lung cancer in female never smokers is also associated with the risk of lung cancer in male smokers.
Abstract Neurogenic differentiation factor 1 (NEUROD1) is frequently overexpressed in small-cell lung cancer (SCLC). NEUROD1 plays an important role in promoting malignant behavior and survival. In this study, we evaluated the association between putative functional polymorphisms in 45 NEUROD1 target genes and chemotherapy response and survival outcomes in 261 patients with SCLC. Among the 100 single nucleotide polymorphisms (SNPs) studied, two were significantly associated with both chemotherapy response and overall survival (OS) of patients with SCLC. The SNP rs3806915C>A in semaphorin 6A ( SEMA6A) gene was significantly associated with better chemotherapy response and OS ( P = 0.04 and P = 0.04, respectively). The SNPrs11265375C>T in nescient helix-loop helix 1 ( NHLH1) gene was also associated with better chemotherapy response and OS ( P = 0.04 and P = 0.02, respectively). Luciferase assay showed a significantly higher promoter activity of SEMA6A with the rs3806915 A allele than C allele in H446 lung cancer cells ( P = 4 × 10-6). The promoter activity of NHLH1 showed a significantly higher with the rs11265375 T allele than C allele ( P = 0.001). These results suggest that SEMA6A rs3806915C>A and NHLH1 rs11265375C>T polymorphisms affect the promoter activity and expression of the genes, which may affect the survival outcome of patients with SCLC.
The present study was performed to investigate the association of single nucleotide polymorphisms (SNPs) located in the miRNA target sites with the clinical outcomes of first line paclitaxel-cisplatin chemotherapy in advanced NSCLC. Eighty SNPs in miRNA binding sites of cancer related genes selected from 18,500 miRNA:target bindings in crosslinking, ligation, and sequencing of hybrids (CLASH) data were investigated in 379 advanced NSCLC patients using a sequenom mass spectrometry-based genotype assay. qRT-PCR and luciferase assay were conducted to examine functional relevance of potentially functional SNPs in miRNA binding sites. Of the 80 SNPs analyzed, 16 SNPs were significantly associated with the clinical outcomes after chemotherapy. Among these, ANAPC1 rs3814026C>T, ETS2 rs461155A>G, SORBS1 rs7081076C>A and POLR2A rs2071504C>T could predict both chemotherapy response and survival. Notably, ETS2 rs461155A>G was significantly associated with decreased ETS2 mRNA expression in both tumor and paired normal lung tissues (Ptrend = 4 × 10-7, and 3 × 10-4, respectively). Consistently, a decreased expression of the reporter gene for the G allele of rs461155 compared with the A allele was observed by luciferase assay. These findings suggest that the four SNPs, especially ETS2 rs461155A>G, could be used as biomarkers predicting the clinical outcomes of NSCLC patients treated with first-line paclitaxel-cisplatin chemotherapy.
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