Sook Kyung Do

PD-L1 polymorphism can predict clinical outcomes of non-small cell lung cancer patients treated with first-line paclitaxel-cisplatin chemotherapy

This study was conducted to investigate whether polymorphisms of genes involved in immune checkpoints can predict the clinical outcomes of patients with advanced stage non-small cell lung cancer (NSCLC) after 1st line paclitaxel-cisplatin chemotherapy. A total of 379 NSCLC patients were enrolled. Twelve single nucleotide polymorphisms (SNPs) of PD-1, PD-L1, and CTLA-4 genes were selected and genotyped. The associations of SNPs with chemotherapy response and overall survival (OS) were analyzed. Among the 12 SNPs investigated, PD-L1 rs2297136T > C and rs4143815C > G were significantly associated with clinical outcomes after chemotherapy. The rs2297136T > C was significantly associated with both better chemotherapy response and better OS, and the rs4143815C > G had a significantly better response to chemotherapy. Consistent with the individual genotype analyses, rs2297136C-rs4143815G haplotype (ht4) carrying variant alleles at both loci was significantly associated with better chemotherapy response and OS compared with combined other haplotypes. Patients with at least one ht4 had significantly better chemotherapy response and OS compared to those without ht4. PD-L1 rs2297136T > C and rs4143815C > G polymorphisms may be useful for the prediction of clinical outcome of 1st line paclitaxel-cisplatin chemotherapy in NSCLC. Further studies are needed to confirm our findings and to understand the role of PD-L1 in the chemotherapy outcome of NSCLC patients.

TERT Polymorphism rs2853669 Influences on Lung Cancer Risk in the Korean Population.

Short telomeres are known as one of the risk factors for human cancers. The present study was conducted to evaluate the association between 6 polymorphisms, which were related with short telomere length in the Korean population, and lung cancer risk using 1,100 cases and 1,096 controls. Among the 6 polymorphisms, TERT rs2853669 was significantly associated with increased lung cancer risk under a recessive model (odds ratio [OR]=1.38, 95% confidence interval [CI]=1.05-1.81, P=0.02). The effect of rs2853669 on lung cancer risk was significant in younger individuals (OR=1.73, 95% CI=1.18-2.54, P=0.005) and adenocarcinoma (OR=1.50, 95% CI=1.07-2.07, P=0.02). Our results suggest that a common functional promoter polymorphism, TERT rs2853669, may influence both telomere length and lung cancer risk in the Korean population. Graphical Abstract

Functional polymorphisms in PD-L1 gene are associated with the prognosis of patients with early stage non-small cell lung cancer.

INTRODUCTION This study was conducted to investigate whether polymorphisms of genes involved in immune checkpoints can predict the prognosis of patients with early stage non-small cell lung cancer (NSCLC) after surgical resection. MATERIALS AND METHODS Twelve single nucleotide polymorphisms (SNPs) of PD-1, PD-L1, and CTLA-4 genes were selected and genotyped. A total of 354 patients with early stage NSCLC who underwent curative surgical resection were enrolled. The association of the SNPs with overall survival (OS) was analyzed. RESULTS Among the 12 SNPs investigated, PD-L1 rs4143815C>G, rs822336G>C, and rs822337T>A were significantly associated with worse survival outcomes in multivariate analyses. When the three SNPs were combined, OS decreased in a dose-dependent manner as the number of bad genotypes increased (Ptrend=0.0003). In the luciferase assay, rs4143815 G allele exhibited a decreased transcription activity compared with C allele (P=0.001), and the rs822336C-rs822337A haplotype had a decreased promoter activity compared with the rs822336G-rs822337T haplotype (P=0.004). Patients with higher expression of PD-L1 mRNA had a better survival compared with lower expression (P=0.03). CONCLUSIONS PD-L1 polymorphisms may be useful for the prediction of prognosis in patients with surgically resected NSCLC. Further studies are needed to confirm our findings and to understand the role of PD-L1 in the antitumor immunity and prognosis in NSCLC.

Replication of the results of genome-wide and candidate gene association studies on telomere length in a Korean population

Background/Aims: A number of genome-wide and candidate gene association studies have identified polymorphisms associated with telomere length in Caucasian populations. This study was conducted to determine the impacts of 17 polymorphisms identified in Caucasians on telomere length in a Korean population. Methods: Ninety-four healthy individuals were enrolled in this study. Relative telomere length of chromosomes from peripheral blood samples was measured using quantitative polymerase chain reaction. Results: Two polymorphisms, rs10936599 of MYNN and rs412658 of ZNF676, were found to be associated w ith telomere length (under dominant model, p = 0.04; under recessive model, p = 0.001). Three polymorphisms, rs2853669, rs7705526, and rs2736108, at the TERT locus were also associated with telomere length (under recessive model, p = 0.01, p = 0.02, and p = 0.01, respectively). The genotypes of the five polymorphisms associated with short telomere length were considered bad genotypes; telomere length was significantly decreased with increasing number of bad genotypes (p= 1.7 × 10–5). Conclusions: We have identified polymorphisms associated with telomere length in a Korean population.

Unmethylation of the CHRNB4 gene is an unfavorable prognostic factor in non-small cell lung cancer

OBJECTIVES Lung cancer is the leading cause of cancer-related deaths and is currently a major health problem owing to difficulties in diagnosis at the early stage of the disease. Changes in DNA methylation status have now been identified as a critical component in the initiation of lung cancer, and the detection of DNA methylation is expected to be an important method for the early diagnosis of lung cancer. Nicotine, the principal tobacco alkaloid, directly contributes to lung carcinogenesis through the activation of nicotinic acetylcholine receptors (nAchRs). MATERIALS AND METHODS To investigate the role of the CHRNB4 gene, which encodes the nAchR β4 subunit that is ubiquitously expressed on lung epithelial cells, we analyzed its methylation status in 266 patients with non-small cell lung cancer (NSCLC) by using methylation-specific polymerase chain reaction and compared it with clinicopathological parameters. RESULTS AND CONCLUSION The frequency of CHRNB4 unmethylation was 13.5% and 8.3% in malignant and nonmalignant tissues, respectively. CHRNB4 demethylation was associated with upregulation of its mRNA expression and was more frequent in squamous cell carcinoma and pathological stages II-IIIA disease than in adenocarcinoma and pathological stage I disease, respectively (P=0.003 and P=0.01, respectively). Univariate and multivariate analyses showed that CHRNB4 unmethylation was significantly associated with unfavorable overall survival in the entire patient group as well as in men and ever-smokers. These results suggest that epigenetic regulation of CHRNB4 may affect tumor progression and survival in patients with NSCLC. Further investigation into the molecular basis of the role of CHRNB4 in the progression of NSCLC is warranted.

Genetic polymorphisms in glycolytic pathway are associated with the prognosis of patients with early stage non-small cell lung cancer.

This study was conducted to investigate whether polymorphisms of genes involved in glycolysis are associated with the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. Forty-four single nucleotide polymorphisms (SNPs) of 17 genes in glycolytic pathway were investigated in a total of 782 patients with NSCLC who underwent curative surgical resection. The association of the SNPs with overall survival (OS) and disease free survival (DFS) were analyzed. Among the 44 SNPs investigated, four SNPs (ENO1 rs2274971A > G, PFKM rs11168417C > T, PFKP rs1132173C > T, PDK2 rs3785921G > A) were significantly associated with survival outcomes in multivariate analyses. When stratified by tumor histology, three SNPs (ENO1 rs2274971A > G, PFKM rs11168417C > T, and PDK2 rs3785921G > A) were significantly associated with OS and/or DFS only in squamous cell carcinoma, whereas PFKP rs1132173C > T exhibited a significant association with survival outcomes only in adenocarcinoma. When the four SNPs were combined, OS and DFS decreased as the number of bad genotypes increased (Ptrend = 8 × 10−4 and 3 × 10−5, respectively). Promoter assays showed that ENO1 rs2274971G allele had significantly higher promoter activity compared to the rs2274971A allele. The four SNPs, especially ENO1 rs2274971A > G, may be useful for the prediction of prognosis in patients with surgically resected NSCLC.

Glucose Transporter 1 Gene Variants Predict the Prognosis of Patients with Early-Stage Non-small Cell Lung Cancer

BackgroundThis study was conducted to investigate whether polymorphisms of glucose transporter 1 (GLUT1) gene are associated with the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection.MethodsFive single nucleotide polymorphisms (SNPs) in GLUT1 were investigated in a total of 354 patients with NSCLC who underwent curative surgery. The association of the SNPs with patients’ survival was analyzed.ResultsAmong the five SNPs investigated, two SNPs (GLUT1 rs3820589T > A and rs4658G > C) were significantly associated with OS in multivariate analyses. GLUT1 rs3820589T > A was associated with significantly better OS (adjusted hazard ratio [aHR] = 0.57, 95% confidence interval [CI] = 0.34–0.94, P = 0.03, under dominant model), and rs4658G > C was associated with significantly worse OS (aHR = 1.91, 95% CI = 1.09–3.33, P = 0.02, under recessive model). In the stratified analysis by tumor histology, the effect of these SNPs on OS was only significant in squamous cell carcinoma but not in adenocarcinoma. When the two SNPs were combined, OS decreased as the number of bad genotypes increased (Ptrend = 4 × 10−3).ConclusionsThis study suggests that genetic variation in GLUT1 may be useful in predicting survival of patients with early stage NSCLC.

Effects of polymorphisms identified in genome-wide association studies of never-smoking females on the prognosis of non-small cell lung cancer

A number of genome-wide association studies have reported several variants that influence the risk of lung cancer in never-smoking females. We evaluated the impact of these variants on survival outcome in never-smoking females with non-small cell lung cancer (NSCLC). In total, 510 never-smoking females with NSCLC who underwent curative surgery were enrolled. Eleven variants associated with lung cancer susceptibility in never-smoking females were genotyped and their associations with survival outcome were analyzed. Among these 11 variants, TP63 rs7631358 and CSF1R rs10079250 affected survival outcomes. TP63 rs7631358 G > A was associated with a relatively worse overall survival (under a dominant model; hazard ratio = 2.31, 95% confidence interval = 1.18-4.52, P = 0.01). CSF1R rs10079250 A > G was associated with a relatively better disease-free survival (under a codominant model; hazard ratio = 0.70, 95% confidence interval = 0.53-0.93, P = 0.01). These results suggest that TP63 rs7631358 G > A and CSF1R rs10079250 A > G may affect the prognosis of NSCLC in never-smoking females, as well as the risk of lung cancer.

Intronic variant of EGFR is associated with GBAS expression and survival outcome of early-stage non-small cell lung cancer: Polymorphism located in intron of EGFR

Genome‐wide association studies have indicated that most of the currently identified disease and trait‐associated single nucleotide polymorphisms (SNPs) are intronic or intergenic. RegulomeDB is a recently developed database that provides functional annotations for regulatory features of SNPs located in non‐coding regions. We evaluated the potential regulatory SNPs in the EGFR gene region using RegulomeDB and their associations with prognosis after surgery in non‐small cell lung cancer (NSCLC) patients.

A functional intronic variant of SLC5A10 affects DRG2 expression and survival outcomes of early-stage non-small cell lung cancer

RegulomeDB is a new tool that can predict the regulatory function of genetic variants. We applied RegulomeDB in selecting putative functional variants and evaluated the relationship between these variants and survival outcomes of surgically resected non‐small‐cell lung cancer. Among the 244 variants studied, 14 were associated with overall survival (P < 0.05) in the discovery cohort and one variant (rs2257609 C>T) was replicated in the validation cohort. In the combined analysis, rs2257609 C>T was significantly associated with worse overall and disease‐free survival under a dominant model (P = 2 × 10−5 and P = 0.001, respectively). rs2257609 is located in the SLC5A10 intron, but RegulomeDB predicted that this variant affected DRG2, not SLC5A10 expression. The expression level of SLC5A10 was not different with the rs2257609 genotype. However, DRG2 expression was different according to the rs2257609 genotype (Ptrend = 0.03) and was significantly higher in tumor than in non‐malignant lung tissues (P = 1 × 10−5). Luciferase assay also showed higher promoter activity of DRG2 in samples with the rs2257609 T allele (P < 0.0001). rs2257609 C>T affected DRG2 expression and, thus, influenced the prognosis of early‐stage non‐small‐cell lung cancer. This study was approved by the Institutional Review Broad of Kyungpook National University of Hospital (Approval No. KNUMC 2014‐04‐210‐003).