Novel Methylation Biomarker for Non-invasive Diagnostics in Lung Cancer

오태정,( Chang Hun Lee2 ),( Min Ki Lee ),( Yeul Hong Kim ),( Sang Yull Lee ),( Hyo Sung Jeon ),( Shin Yup Lee ),( Seung Soo Yoo ),( Jae Yong Park ),( Sung Whan An ) 대한결핵 및 호흡기학회 2012 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.114 No.-

To identify aberrantly hypermethylated DNA in lung cancer cells we established a genome-wide analysis for hypermethylation sites, namely Methyl DNA Isolation and Amplification (MeDIA) coupled-CpG microarray analysis. In the comprehensive methyaltion profiling analysis between human lung cancer, A549 cells and normal NHBE cells, we observed that several clusters of genes show a significant level of aberrancy in CpG island methylation pattern in cancer cells compared to normal cells. We further identified PCDHGA12 gene as a new marker of non-invasive diagnostics for lung cancer based on followings. 1) Transcription of PCDHGA12 gene is reactivated after treatment of A549 cells with demethylating agent. 2) Bisulfide clonal-sequencing reveals that CpG island of PCDHGA12 shows a distinctive differential methylation between two cell lines. 3) Pyrosequencing-based quantitative methylation assay for such region in tumor and non-tumorous tissues from lung cancer patients shows aberrant hypermethylation in 37 (92%) of the 40 tumor tissues. In clinical validation by pyrosequencingin induced-sputum of lung cancer patients (n=87) and healthy controls (n=51), we observed aberrant hypermethylation incident at significantly elevated level in samples derived from lung cancer patients. According to the optimal threshold calculated by ROC curve analysis, sensitivity and specificity of PCDHGA12 was 86.2% and 82.4%, respectively. PCDHGA12 methylation status could be a potential methylation biomarker alone or combined with others for the screen and the detection of relapse of lung cancer.

Polymorphisms in cancer-related pathway genes and lung cancer

Lee, Shin Yup,Kang, Hyo-Gyoung,Choi, Jin Eun,Jung, Deuk Kju,Lee, Won Kee,Lee, Hyun Chul,Lee, So Yeon,Yoo, Seung Soo,Lee, Jaehee,Seok, Yangki,Lee, Eung Bae,Cha, Seung Ick,Cho, Sukki,Kim, Chang Ho,Lee, European Respiratory Society 2016 The European respiratory journal Vol.48 No.4

<P>We evaluated the associations between potentially functional variants in a comprehensive list of cancer-related genes and lung cancer in a Korean population.</P><P>A total of 1969 potentially functional single nucleotide polymorphisms (SNPs) of 1151 genes involved in carcinogenesis were evaluated using an Affymetrix custom-made GeneChip in 610 nonsmall cell lung cancer patients and 610 healthy controls. A replication study was conducted in an independent set of 490 cases and 486 controls. 68 SNPs were significantly associated with lung cancer in the discovery set and tested for replication.</P><P>Among the 68 SNPs, three SNPs (corepressor interacting with RBPJ 1 (<I>CIR1</I>) rs13009079T>C, ribonucleotide reductase M1 (<I>RRM1</I>) rs1465952T>C and solute carrier family 38, member 4 (<I>SLC38A4</I>) rs2429467C>T) consistantly showed significant associations with lung cancer in the replication study. In combined analysis, adjusted odds ratio for <I>CIR1</I> rs13009079T>C, <I>RRM1</I> rs1465952T>C and <I>SLC38A4</I> rs2429467C>T were 0.69, 0.71 and 0.73, respectively (p=4×10<SUP>−5</SUP>, 0.01 and 0.001, respectively) under the dominant model. The relative mRNA expression level of <I>CIR1</I> was significantly associated with rs13009079T>C genotypes in normal lung tissues (ptrend=0.03).</P><P>These results suggest that the three SNPs, particularly <I>CIR1</I> rs13009079T>C, may play a role in the pathogenesis of lung cancer.</P>

Factors Affecting First-Line Triple Therapy of Helicobacter pylori Including CYP2C19 Genotype and Antibiotic Resistance

Lee, Ju Yup,Kim, Nayoung,Kim, Min Soo,Choi, Yoon Jin,Lee, Jung Won,Yoon, Hyuk,Shin, Cheol Min,Park, Young Soo,Lee, Dong Ho,Jung, Hyun Chae Springer-Verlag 2014 Digestive diseases and sciences Vol.59 No.6

Adjuvant Chemotherapy of Completely Resected Stage 1 Non-Small Cell Lung Cancer

( Shin Yup Lee ) 대한결핵 및 호흡기학회 2021 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.129 No.-

In mid 2000s, key clinical trials reported the benefit of adjuvant chemotherapy in NSCLC. Platinum-based chemotherapy after curative resection has demonstrated to provide an absolute 5-year survival gain of 5% compared to surgery alone. Low-dose CT screening has increased the number of lung cancers detected at early stages which are potentially curable by surgical resection. Unlike advanced NSCLC, however, little progress has been made over the past decades in the treatment of early-stage patients for whom cure is most realizable. In recent years, most clinical trials in early-stage NSCLC focus on targeted agents and immune-checkpoint inhibitors which are effective therapies currently in use for metastatic disease. Adjuvant chemotherapy is generally recommended for patients with resected stage II-IIIA disease, but not recommended for patients with stage IA because of no proven benefit. Controversy exists for stage IB although guidelines suggest that adjuvant chemotherapy be considered for a subgroup of patients with high-risk features. Available evidence for stage IB that patients with larger (≥ 4cm) tumor may benefit from adjuvant chemotherapy came from a randomized trial with a relatively small sample size (CALGB 9633) and from subgroup analysis of other trials, which were underpowered to detect the small differences expected in survival. However, tumors ≥ 4cm were upstaged to stage IIA in the 8th edition of TNM staging system. Other high-risk factors in stage IB include vascular invasion, visceral pleural invasion, poor differentiation among others, mostly from retrospective studies. For adenocarcinoma, high-grade subtype (micropapillary and solid) emerged as a high-risk factor for the decision of adjuvant chemotherapy. While TNM staging remains the most important predictor of benefit from adjuvant therapy, clinical outcomes vary widely even among patients with the same stage. Evidence indicates that even stage I NSCLC comprised of heterogeneous diseases, which may lead to heterogenous prognosis. Therefore, predictive biomarkers are of vital importance to help identify patients who may benefit from adjuvant therapy, especially in stage I where the role of adjuvant chemotherapy is not apparent. Molecular biomarkers or signatures have been extensively investigated, but most were not validated. The most recent frontiers in this field have leveraged leading-edge technologies such as NGS and machinelearning, looking forward to the development of risk-stratification or prognosis-prediction models that integrate genomic and clinicopathologic factors. To ensure the cure of patients with the earliest stage NSCLC, future studies are required to investigate which subgroup of patients in stage I NSCLC should be selected for adjuvant therapy using state-of-the-art agents in welldesigned clinical trials powered with a large number of stage I patients.

Clinical Utility of CT-Based Bronchial Aspirate TB-PCR for the Rapid Diagnosis of Pleural Tuberculosis

Lee, Jaehee,Lee, So Yeon,Choi, Keum Ju,Lim, Jae Kwang,Yoo, Seung Soo,Lee, Shin Yup,Cha, Seung Ick,Park, Jae Yong,Kim, Chang Ho The Korean Academy of Tuberculosis and Respiratory 2013 Tuberculosis and Respiratory Diseases Vol.75 No.4

Background: Thoracoscopic pleural biopsy is often required for rapid and confirmative diagnosis in patients with suspected pleural tuberculosis (PL-TB). However, this method is more invasive and costly than its alternatives. Therefore, we evaluated the clinical utility of the chest computed tomography (CT)-based bronchial aspirate (BA) TB-polymerase chain reaction (PCR) test in such patients. Methods: Bronchoscopic evaluation was performed in 54 patients with presumptive PL-TB through diagnostic thoracentesis but without a positive result of sputum acid-fast bacilli (AFB) smear, pleural fluid AFB smear, or pleural fluid TB-PCR test. Diagnostic yields of BA were evaluated according to the characteristics of parenchymal lesions on chest CT. Results: Chest radiograph and CT revealed parenchymal lesions in 25 (46%) and 40 (74%) of 54 patients, respectively. In cases with an absence of parenchymal lesions on chest CT, the bronchoscopic approach had no diagnostic benefit. BA TB-PCR test was positive in 21 out of 22 (95%) patients with early-positive results. Among BA results from 20 (37%) patients with patchy consolidative CT findings, eight (40%) were AFB smear-positive, 18 (90%) were TB-PCR-positive, and 19 (95%) were culture-positive. Conclusion: The BA TB-PCR test seems to be a satisfactory diagnostic modality in patients with suspected PL-TB and patchy consolidative CT findings. For rapid and confirmative diagnosis in these patients, the bronchoscopic approach with TB-PCR may be preferable to the thoracoscopy.

MicroRNA-23a: A Novel Serum Based Diagnostic Biomarker for Lung Adenocarcinoma

Lee, Yu-Mi,Cho, Hyun-Jung,Lee, Soo-Young,Yun, Seong-Cheol,Kim, Ji-Hye,Lee, Shin-Yup,Kwon, Sun-Jung,Choi, Eu-Gene,Na, Moon-Jun,Kang, Jae-Ku,Son, Ji-Woong The Korean Academy of Tuberculosis and Respiratory 2011 Tuberculosis and Respiratory Diseases Vol.71 No.1

Background: MicroRNAs (miRNAs) have demonstrated their potential as biomarkers for lung cancer diagnosis. In recent years, miRNAs have been found in body fluids such as serum, plasma, urine and saliva. Circulating miRNAs are highly stable and resistant to RNase activity along with, extreme pH and temperatures in serum and plasma. In this study, we investigated serum miRNA profiles that can be used as a diagnostic biomarker of non-small cell lung cancer (NSCLC). Methods: We compared the expression profile of miRNAs in the plasma of patients diagnosed with lung cancer using an miRNA microarray. The data from this assay were validated by quantitative real-time PCR (qRT-PCR). Results: Six miRNAs were overexpressed and three miRNAs were underexpressed in both tissue and serum from squamous cell carcinoma (SCC) patients. Sixteen miRNAs were overexpressed and twenty two miRNAs were underexpressed in both tissue and serum from adenocarcinoma (AC) patients. Of the four miRNAs chosen for qRT-PCR analysis, the expression of miR-23a was consistent with microarray results from AC patients. Receiver operating characteristic (ROC) curve analyses were done and revealed that the level of serum miR-23a was a potential marker for discriminating AC patients from chronic obstructive pulmonary disease (COPD) patients. Conclusion: Although a small number of patients were examined, the results from our study suggest that serum miR-23a can be used in the diagnosis of AC.

Detection of Deep Vein Thrombosis by Follow-up Indirect Computed Tomography Venography after Pulmonary Embolism

Lee, Hye Jin,Cha, Seung-Ick,Shin, Kyung-Min,Lim, Jae-Kwang,Yoo, Seung-Soo,Lee, Shin-Yup,Lee, Jaehee,Kim, Chang-Ho,Park, Jae-Yong The Korean Academy of Tuberculosis and Respiratory 2018 Tuberculosis and Respiratory Diseases Vol.81 No.1

Background: Information regarding the incidence and risk factors for deep vein thrombosis (DVT) detected by follow-up computed tomographic (CT) venography after pulmonary embolism (PE) is sparse. The aim of the present study was to identify the predictors of DVT in follow-up CT images, and to elucidate their clinical significance. Methods: Patients with PE were classified into the following three cohorts based on the time of indirect CT venography follow-up: within 1 month, 1 to 3 months, and 3 to 9 months after the initial CT scan. Each cohort was subdivided into patients with or without DVT detected by follow-up CT. Clinical variables were compared between the two groups. Results: Follow-up CT revealed DVT in 61% of patients with PE within 1 month, in 15% of patients with PE at 1 to 3 months, and in 9% of patients with PE at 3 to 9 months after the initial CT scan. Right ventricular (RV) dilation on the initial CT (odds ratio [OR], 8.30; 95% confidence interval [CI], 1.89-36.40; p=0.005) and proximal DVT at the initial presentation (OR, 6.93; 95% CI, 1.90-25.20; p=0.003) were found to independently predict DVT in follow-up CT images within 1 month, proximal DVT at the initial presentation was found to independently predict DVT in follow-up CT images at 1 to 3 months (OR, 6.69; 95% CI, 1.53-29.23; p=0.012), and central PE was found to independently predict DVT in follow-up CT images at 3 to 9 months (OR, 4.25; 95% CI, 1.22-4.83; p=0.023) after the initial CT scan. Furthermore, the detection of DVT by follow-up CT independently predicted the recurrence of venous thromboembolism (VTE) (OR, 4.67; 95% CI, 2.24-9.74; p<0.001). Conclusion: Three months after PE, DVT was not detected by follow-up CT in most patients with PE. RV dilation on the initial CT, central PE, and proximal DVT at the initial presentation were found to predict DVT on follow-up CT, which might predict VTE recurrence.

Suppression of Egr-1 transcription through targeting of the serum response factor by oncogenic H-Ras

Shin, Soon Young,Bahk, Young Yil,Ko, Jesang,Chung, Il-Yup,Lee, Young Seek,Downward, Julian,Eibel, Hermann,Sharma, Prem M,Olefsky, Jerrold M,Kim, Young-Ho,Lee, Bonghee,Lee, Young Han Wiley (John WileySons) 2006 The EMBO journal Vol.25 No.5

<P>The transcription factor Egr-1 functions as a key regulator in cellular growth, differentiation, and apoptosis. The loss of Egr-1 expression is closely associated with tumor development, although the molecular mechanism behind the suppression of Egr-1 is largely unknown. In this report, we show that growth factor-induced transcriptional activation of Egr-1 gene is downregulated by chronic expression of oncogenic H-Ras in NIH3T3 fibroblasts. Our results demonstrate that phosphoinositide 3-kinase (PI3K) signaling is necessary for oncogenic H-Ras-mediated reduction of Egr-1 gene expression. Aberrant activation of PI3K signaling by oncogenic Ras decreased the level of serum response factor (SRF) protein through the acceleration of proteolysis, which resulted in decreased SRF binding to the serum response element (SRE) sites within the Egr-1 promoter, leading to the suppression of Egr-1 transcription. Inhibition of PI3K signaling restored the downregulation of SRF and Egr-1 expression caused by oncogenic Ras. Our findings suggest a novel signaling mechanism by which prolonged activation of oncogenic H-Ras can trigger the loss of tumor suppressor Egr-1 through the PI3K pathway in NIH3T3 fibroblast model cell lines.</P>

Comparison of clinical manifestations and treatment outcome according to age groups in adult patients with miliary tuberculosis

Lee, Jaehee,Lim, Jae Kwang,Kim, Eun Jin,Lee, Deok Heon,Kim, Yu Kyung,Yoo, Seung Soo,Lee, Shin Yup,Cha, Seung Ick,Park, Jae Yong,Kim, Chang Ho AME Publishing Company 2018 Journal of thoracic disease Vol.10 No.5

<P>Conclusions: The present study suggests that treatment completion, the cause of death, and risk factors for TB-related deaths may be different according to age groups in adult patients with miliary TB.</P>

Clinical relevance of syncope in patients with pulmonary embolism

Lee, Yong-Hoon,Cha, Seung-Ick,Shin, Kyung-Min,Lim, Jae-Kwang,Yoo, Seung-Soo,Lee, Shin-Yup,Lee, Jaehee,Kim, Chang-Ho,Park, Jae-Yong,Lee, Won Kee Elsevier 2018 Thrombosis research Vol.164 No.-

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Syncope is an unusual clinical manifestation of pulmonary embolism (PE), and the clinical significance of syncope in PE patients remains controversial. We investigated the incidence of syncope, examined the clinical factors associated with syncope, and assessed the association between syncope and the short-term outcomes of PE.</P> <P><B>Methods</B></P> <P>We retrospectively classified patients presenting with PE into 2 groups: patients with syncope and those without syncope. We compared the clinical and computed tomography parameters between the groups.</P> <P><B>Results</B></P> <P>Among 1084 patients diagnosed with PE, 45 (4.2%) presented with syncope. Four patients which presented with cardiac arrest were excluded from the study. The syncope group showed significantly higher blood biomarker levels and higher rates of central PE and right ventricular dilation than the control group. Unprovoked PE (odds ratio [OR] 8.046, 95% confidence interval [CI] 3.073–21.069, p < 0.001), female sex (OR 3.419, 95% CI 1.348–8.675, p = 0.010), central PE (OR 2.854, 95% CI 1.298–6.278, p = 0.009), and troponin I level (OR 2.812, 95% CI 1.765–4.480, p < 0.001) were observed to be independent factors associated with syncope in PE patients. However, multivariate analysis showed that the presence of syncope was not a significant predictor of adverse outcomes and recurrent venous thromboembolism in PE patients.</P> <P><B>Conclusions</B></P> <P>Although syncope is associated with a more severe form of PE, it does not influence the short-term prognosis of PE. Central PE, blood troponin I level, unprovoked PE, and female sex were observed to be clinical factors related with syncope in patients with PE.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The clinical implications of syncope in patients with pulmonary embolism are suggested. </LI> <LI> Syncope was associated with a more severe form of pulmonary embolism. </LI> <LI> Syncope did not influence the short-term prognosis of pulmonary embolism. </LI> <LI> Central emboli and blood troponin I level were independent factors of syncope. </LI> <LI> Unprovoked pulmonary embolism and female sex were also associated with syncope. </LI> </UL> </P>