Eungbae Lee

Polymorphisms in the CASPASE Genes and Survival in Patients With Early-Stage Non–Small-Cell Lung Cancer

PURPOSE This study was conducted to determine the impact of potentially functional polymorphisms in the CASPASE (CASP) genes on the survival of early-stage non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS Four hundred eleven consecutive patients with surgically resected NSCLC were enrolled. Nine potentially functional polymorphisms in the CASP3, CASP7, CASP8, CASP9, and CASP10 genes were investigated. The genotype and haplotype associations with overall survival (OS) and disease-free survival (DFS) were analyzed. RESULTS Patients with the rs2227310 GG genotype had a significantly decreased OS and DFS compared with patients with the CC + CG genotype (adjusted hazard ratio [aHR] for OS, 1.67; 95% CI, 1.19 to 2.35; P = .003; aHR for DFS, 1.62; 95% CI, 1.19 to 2.22; P = .002). The rs4645981C>T genotype also had a significant effect on OS and DFS (under a recessive model; aHR for OS, 2.00; 95% CI, 1.04 to 3.85; P = .04; aHR for DFS, 2.76; 95% CI, 1.58 to 4.80; P = .0003). When the rs2227310 and rs4645981 genotypes were combined, patients with one or two bad genotypes had worse OS and DFS compared with those who had zero bad genotypes (aHR for OS, 1.75; 95% CI, 1.25 to 2.45; P = .001; aHR for DFS, 1.66; 95% CI, 1.23 to 2.26; P = .001). CONCLUSION The CASP7 rs2227310 and CASP9 rs4645981 polymorphisms may affect survival in early-stage NSCLC. The analysis of these polymorphisms can help identify patients at high risk for a poor disease outcome.

Polymorphisms in the FAS and FASL Genes and Survival of Early Stage Non–small Cell Lung Cancer

Purpose: This study was conducted to investigate the impact of functional polymorphisms in the FAS and FASL genes on the survival of early stage non–small cell lung cancer (NSCLC) patients. Experimental Design: Three hundred and thirty-eight consecutive patients with surgically resected NSCLC were enrolled. The FAS -1377G>A (rs2234767) and -670A>G (rs1800682) and FASL -844C>T (rs763110) polymorphisms were investigated. Immunohistochemistry was used to assess FAS protein expression in tumors. The genotype and haplotype associations with survival were analyzed using Cox proportional hazards model, Kaplan-Meier method, and the log-rank test. Results: Patients with the GG and combined AG + GG genotypes of the FAS -670A>G locus had a significantly decreased survival when compared with patients with the AA genotype [adjusted hazard ratio = 1.71, 95% confidence interval (95% CI) = 1.06-2.77, and P = 0.03; and adjusted hazard ratio = 1.48, 95% CI = 1.01-2.20, and P = 0.047, respectively]. In addition, the FAS -1377G/-670G and -1377A/-670G haplotypes exhibited a significantly lower survival compared with the -1377G/-670A haplotype (adjusted hazard ratio = 1.87, 95% CI = 1.20-2.91, and P = 0.006; and adjusted hazard ratio = 1.31, 95% CI = 1.05-1.65, P = 0.02, respectively). Strongly positive FAS immunostaining was significantly less frequent in patients with the FAS -670 AG + GG genotype than in patients with the -670 AA genotype (4.5% versus 10.8%; P = 0.04). Conclusion: The FAS -670A>G polymorphism may affect survival in early-stage NSCLC. The analysis of the FAS -670A>G polymorphism can help identify patients at high risk for a poor disease outcome.

Telomere length of tumor tissues and survival in patients with early stage non‐small cell lung cancer

Telomere shortening leads to genomic instability that drives oncogenesis through the activation of telomerase and the generation of other mutations necessary for tumor progression. This study was conducted to determine the impact of telomere shortening on the survival of patients with early stage non‐small cell lung cancer (NSCLC). Relative telomere length in tumor tissues was measured by quantitative polymerase chain reaction in 164 patients with surgically resected NSCLC. The association between telomere length and overall survival (OS) and disease‐free survival (DFS) was analyzed. When the patients were categorized into quartiles based on telomere length, those patients with the 1st quartile (shortest) of telomere length had a significantly worse OS and DFS compared to patients with the 2nd to the 4th quartiles of telomere length (adjusted hazard ratio for OS = 2.67, 95% confidence interval = 1.50–4.75, P = 0.001; and adjusted hazard ratio for DFS = 1.92, 95% confidence interval = 1.17–3.14, P = 0.01). An association between telomere length and survival outcome was more pronounced in squamous cell carcinomas than adenocarcinomas (P‐value of test for homogeneity for OS and DFS = 0.05 and 0.02, respectively). Telomere length of tumor tissues is an independent prognostic factor in patients with surgically resected early stage NSCLC.

Quiescin Sulfhydryl Oxidase 1 (QSOX1) Secreted by Lung Cancer Cells Promotes Cancer Metastasis

As lung cancer shows the highest mortality in cancer-related death, serum biomarkers are demanded for lung cancer diagnosis and its treatment. To discover lung cancer protein biomarkers, secreted proteins from primary cultured lung cancer and adjacent normal tissues from patients were subjected to LC/MS–MS proteomic analysis. Quiescin sulfhydryl oxidase (QSOX1) was selected as a biomarker candidate from the enriched proteins in the secretion of lung cancer cells. QSOX1 levels were higher in 82% (51 of 62 tissues) of lung cancer tissues compared to adjacent normal tissues. Importantly, QSOX1 serum levels were significantly higher in cancer patients (p < 0.05, Area Under curve (AUC) = 0.89) when measured by multiple reaction monitoring (MRM). Higher levels of QSOX1 were also uniquely detected in lung cancer tissues, among several other solid cancers, by immunohistochemistry. QSOX1-knock-downed Lewis lung cancer (LLC) cells were less viable from oxidative stress and reduced migration and invasion. In addition, LLC mouse models with QSOX1 knock-down also proved that QSOX1 functions in promoting cancer metastasis. In conclusion, QSOX1 might be a lung cancer tissue-derived biomarker and be involved in the promotion of lung cancers, and thus can be a therapeutic target for lung cancers.

P1-187: Aberrant DNA methylation profiles of non-small cell lung cancers in a korean population

We performed this study to investigate the aberrant methylation profile of the cancer-related genes in Korean non-small cell lung cancer (NSCLC) that previously exhibited high frequencies of methylation in Western populations. The aberrant promoter methylation of eight genes (GSTP1, p16, FHIT, APC, RASSF1A, hMLH1, hMSH2, AGT) was determined by MSP in 99 surgically resected NSCLCs and their corresponding nonmalignant lung tissues. Methylation in the tumor samples was detected at 15% for GSTP1, 22% for p16, 34% for FHIT1, 48% for APC, 40% for RASSF1A, 18% for hMLH1, 8% for hMSH2 and 21% for AGT, whereas it occurred at lower frequencies in the corresponding nonmalignant lung tissues, particularly in the p16 (1%) and RASSF1A (1%) genes. These results suggest that the methylation profiles of NSCLCs in a Korean population are similar to those in Western populations.