Seung Ick Cha

Replication of results of genome-wide association studies on lung cancer susceptibility loci in a Korean population.

Background and objective:u2003 Genome‐wide association studies (GWAS) have identified the three chromosomal regions, 5p15, 6p21 and 15q25, as being associated with lung cancer risk in European populations. This study was performed to confirm these associations in Korean patients with lung cancer.

Polymorphisms in the caspase genes and the risk of lung cancer.

Introduction: Caspases (CASPs) are important regulators and executioners in apoptosis pathway and play a crucial role in the development and progression of cancer. On the basis of the interactions of CASPs in the apoptotic pathway, we evaluated the association between 11 polymorphisms of CASP3, 6, 7, 8, 9, and 10 genes and the risk of lung cancer. Methods: The genotypes were determined in 720 patients with lung cancer and 720 healthy controls frequency matched for age and gender. Results: In individual polymorphism analysis, the CASP7 rs2227310C>G and CASP9 rs4645981C>T were associated with 1.40-fold and 1.28-fold increased risk of lung cancer under recessive and dominant models for the variant allele of each polymorphism, respectively. In the case of the CASP3 77G>A, subjects with the GG genotype were at a 1.19-fold increased risk of lung cancer compared with those with at least one variant allele. When the three polymorphisms were combined, the risk of lung cancer increased in a dose-dependent manner as the number of risk genotypes increased (ptrend <0.001). Subjects with two and three risk genotypes carried a significantly increased risk of lung cancer compared with those with zero risk genotype (adjusted odds ratio = 1.56, 95% confidence interval = 1.14–2.13, p = 0.005 and adjusted odds ratio = 2.54, 95% confidence interval = 1.28–5.02, p = 0.008, respectively). Conclusions: These results suggest that a combined analysis of these three CASP gene polymorphisms might better predict the risk of lung cancer than analysis of a single polymorphism.

Comprehensive analysis of DNA repair gene polymorphisms and survival in patients with early stage non-small-cell lung cancer.

This study was conducted to analyze a comprehensive panel of single nucleotide polymorphisms (SNP) in DNA repair genes to determine the relationship between polymorphisms and the survival outcome of patients with early stage non‐small‐cell lung cancer (NSCLC). Three hundred and ten consecutive patients with surgically resected NSCLC were enrolled. Forty‐eight SNP in 27 DNA repair genes were genotyped and their associations with overall survival (OS) and disease‐free survival (DFS) were analyzed. Individually, six SNP exhibited significant associations with survival outcome. When the six SNP were combined, OS and DFS decreased as the number of bad genotypes increased (Ptrendu2003<u20030.0001 for both). Patients with three, and four or five bad genotypes had a significantly worse OS and DFS compared with those carrying zero or one bad genotypes (adjusted hazard ratio [aHR] for OSu2003=u20033.53, 95% confidence interval [CI]u2003=u20031.25–9.97, Pu2003=u20030.02, and aHR for DFSu2003=u20033.31, 95% CIu2003=u20031.41–7.76, Pu2003=u20030.006; and aHR for OSu2003=u20035.47, 95% CIu2003=u20031.87–16.00, Pu2003=u20030.002, and aHR for DFSu2003=u20034.42, 95% CIu2003=u20031.82–10.74, Pu2003=u20030.001, respectively). These findings suggest that the six SNP identified can be used as prognostic markers for patients with surgically resected early stage NSCLC. (Cancer Sci 2010; 101: 2436–2442)

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 OSu2009=u20092.67, 95% confidence intervalu2009=u20091.50–4.75, Pu2009=u20090.001; and adjusted hazard ratio for DFSu2009=u20091.92, 95% confidence intervalu2009=u20091.17–3.14, Pu2009=u20090.01). 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 DFSu2009=u20090.05 and 0.02, respectively). Telomere length of tumor tissues is an independent prognostic factor in patients with surgically resected early stage NSCLC.

A Nationwide Survey of Lymphangioleiomyomatosis in Korea: Recent Increase in Newly Diagnosed Patients

In 2007, the Korean Interstitial Lung Disease Society had collected clinical data of patients who have diagnosed as Lymphangioleiomyomatosis (LAM) since 1990 through nationwide survey, which showed that LAM patients had increased sharply after 2004. The present study was performed to show the clinical features of Korean patients with LAM, and to establish the reason for the recent increase in the diagnosis. All 63 patients were women and the mean age at diagnosis was 36 yr. The most common presenting symptom was dyspnea and 8 patients had tuberous sclerosis complex. The survival rate at 5 yr after diagnosis was 84%. Compared with patients diagnosed after 2004 (n=34), the patients diagnosed before 2004 (n=29) complained with dyspnea more (P=0.016) and had lower FEV1% predicted (P=0.003), and DLco% predicted (P=0.042). The higher proportion of patients diagnosed after 2004 showed the normal chest radiography, and they were detected by routine chest CT screening (P=0.016). This study showed that clinical features of Korean patients with LAM were not different from those reported elsewhere. It is concluded that the reason for the increase of newly diagnosed patients is the result of increase in detection of the early stage LAM by the widespread use of chest CT screening.

Clinical Features and Outcomes of Idiopathic Pulmonary Alveolar Proteinosis in Korean Population

Idiopathic pulmonary alveolar proteinosis (PAP) is a rare disorder in which lipoproteinaceous material accumulates within alveoli. There were few reports on Asian populations with idiopathic PAP. We retrospectively reviewed 38 patients with idiopathic PAP in Korea. We assessed clinical features, therapeutic efficacy and outcomes of whole lung lavage in patients with idiopathic PAP. The mean age at diagnosis was 52 yr. Eighty six percent of patients were symptomatic at diagnosis. Dyspnea and cough were the most common symptoms. Crackles were the most common physical examination finding. On pulmonary function test, a mild restrictive ventilatory defect was common, with a predicted mean forced vital capacity (FVC) of 77% and forced expiratory volume in one second (FEV1) of 84.6%. Diffusing capacity was disproportionately reduced at 67.7%. Arterial blood gas analysis revealed hypoxemia with a decreased PaO2 of 69.0 mmHg and an increased D(A-a)O2 of 34.2 mmHg. After whole lung lavage, PaO2, D(A-a)O2 and DLCO were significantly improved, but FVC and total lung capacity (TLC) were not different. This is the first multicenter study to analyze 38 Korean patients with idiopathic PAP. The clinical features and pulmonary parameters of Korean patients with idiopathic PAP are consistent with reports in other published studies. Whole lung lavage appears to be the most effective form of treatment.

Mortality of Community-Acquired Pneumonia in Korea: Assessed with the Pneumonia Severity Index and the CURB-65 Score

The pneumonia severity index (PSI) and CURB-65 are widely used tools for the prediction of community-acquired pneumonia (CAP). This study was conducted to evaluate validation of severity scoring system including the PSI and CURB-65 scores of Korean CAP patients. In the prospective CAP cohort (participated in by 14 hospitals in Korea from January 2009 to September 2011), 883 patients aged over 18 yr were studied. The 30-day mortalities of all patients were calculated with their PSI index classes and CURB scores. The overall mortality rate was 4.5% (40/883). The mortality rates per CURB-65 score were as follows: score 0, 2.3% (6/260); score 1, 4.0% (12/300); score 2, 6.0% (13/216); score 3, 5.7% (5/88); score 4, 23.5% (4/17); and score 5, 0% (0/2). Mortality rate with PSI risk class were as follows: I, 2.3% (4/174); II, 2.7% (5/182); III, 2.3% (5/213); IV, 4.5% (11/245); and V, 21.7% (15/69). The subgroup mortality rate of Korean CAP patients varies based on the severity scores and CURB-65 is more valid for the lower scores, and PSI, for the higher scores. Thus, these variations must be considered when using PSI and CURB-65 for CAP in Korean patients.

SERPINE2 Polymorphisms and Chronic Obstructive Pulmonary Disease

A number of genome-wide linkage analyses have identified the 2q33.3-2q37.2 region as most likely to contain the genes that contribute to the susceptibility to chronic obstructive pulmonary disease (COPD). It was hypothesized that the SERPINE2 gene, which is one of the genes located at the 2q33.3-2q37.2 region, may act as a low-penetrance susceptibility gene for COPD. To test this hypothesis, the association of four SERPINE2 single nucleotide polymorphisms (SNPs; rs16865421A>G, rs7583463A>C, rs729631C>G, and rs6734100C>G) with the risk of COPD was investigated in a case-control study of 311 COPD patients and 386 controls. The SNP rs16865421 was associated with a significantly decreased risk of COPD in a dominant model for the polymorphic allele (adjusted odds ratio [OR]=0.66, 95% confidence interval [CI]=0.45-0.97, P=0.03). In haplotype analysis, the GACC haplotype carrying the polymorphic allele at the rs16865421 was associated with a significantly decreased risk of COPD when compared to the AACC haplotype (adjusted OR=0.58, 95% CI=0.38-0.89, P=0.01), and this effect was evident in younger individuals (adjusted OR=0.30, 95% CI=0.14-0.64, P=0.002). This study suggests that the SERPINE2 gene contributes to the susceptibility to COPD.

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).

Clinical significance of cigarette smoking and dust exposure in pulmonary alveolar proteinosis: a Korean national survey

BackgroundThis study aimed to investigate clinical characteristics of Korean PAP patients and to examine the potential risk factors of PAP.MethodsWe retrospectively reviewed medical records of 78 Korean PAP patients diagnosed between 1993 and 2014. Patients were classified into two groups according to the presence/absence of treatment (lavage). Clinical and laboratory features were compared between the two groups.ResultsOf the total 78 PAP patients, 60% were male and median age at diagnosis was 47.5xa0years. Fifty three percent were ever smokers (median 22 pack-years) and 48% had a history of dust exposure (metal 26.5%, stone or sand 20.6%, chemical or paint 17.7%, farming dust 14.7%, diesel 14.7%, textile 2.9%, and wood 2.9%). A history of cigarette smoking or dust exposure was present in 70.5% of the total PAP patients, with 23% having both of them. Patients who underwent lavage (nu2009=u200938) presented symptoms more frequently (38/38 [100%] vs. 24/40 [60%], Pu2009<u20090.001) and had significantly lower PaO2 and DLCO with higher D(A-a)O2 at the onset of disease than those without lavage (nu2009=u200940) (Pu2009=u20090.006, Pu2009<u20090.001, and Pu2009=u20090.036, respectively). Correspondingly, the distribution of disease severity score (DSS) differed significantly between the two groups (Pu2009=u20090.001). Based on these, when the total patients were categorized according to DSS (low DSS [DSS 1–2] vs. high DSS [DSS 3–5]), smoking status differed significantly between the two groups with the proportion of current smokers significantly higher in the high DSS group (11/22 [50%] vs. 7/39 [17.9%], Pu2009=u20090.008). Furthermore, current smokers had meaningfully higher DSS and serum CEA levels than non-current smokers (Pu2009=u20090.011 and Pu2009=u20090.031), whereas no difference was found between smokers and non-smokers. Regarding type of exposed dust, farming dust was significantly associated with more severe form of PAP (Pu2009=u20090.004).ConclusionA considerable proportion of PAP patients had a history of cigarette smoking and/or dust exposure, suggestive of their possible roles in the development of PAP. Active cigarette smoking at the onset of PAP is associated with the severity of PAP.