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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>
Polymorphisms in the Caspase Genes and the Risk of Lung Cancer
Lee, Shin Yup,Choi, Yi Young,Choi, Jin Eun,Kim, Min Jung,Kim, Jong-Sik,Jung, Deuk Kju,Kang, Hyo-Gyoung,Jeon, Hyo-Sung,Lee, Won Kee,Jin, Guang,Cha, Seung Ick,Kim, Chang Ho,Jung, Tae Hoon,Park, Jae Yong Elsevier 2010 JOURNAL OF THORACIC ONCOLOGY Vol.5 No.8
<P>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.</P>
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.
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.
Lee, Jae Yeon,Yoo, Seung Soo,Kang, Hyo-Gyoung,Jin, Guang,Bae, Eun Young,Choi, Yi Young,Choi, Jin Eun,Jeon, Hyo-Sung,Lee, Jaehee,Lee, Shin Yup,Cha, Seung-Ick,Kim, Chang Ho,Park, Jae Yong The Korean Academy of Medical Sciences 2012 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.27 No.12
<P>A genome-wide association study has identified the 15q25 region as being associated with the risk of chronic obstructive pulmonary disease (COPD) in Caucasians. This study intended as a confirmatory assessment of this association in a Korean population. The rs6495309C > T polymorphism in the promoter of nicotinic acetylcholine receptor alpha subunit 3 (<I>CHRNA3</I>) gene was investigated in a case-control study that consisted of 406 patients with COPD and 394 healthy control subjects. The rs6495309 CT or TT genotype was associated with a significantly decreased risk of COPD when compared to the rs6495309 CC genotype (adjusted odds ratio = 0.69, 95% confidence interval = 0.50-0.95, <I>P</I> = 0.023). The effect of the rs6495309C > T on the risk of COPD was more evident in moderate to very severe COPD than in mild COPD under a dominant model for the variant T allele (<I>P</I> = 0.024 for homogeneity). The <I>CHRNA3</I> rs6495309C > T polymorphism on chromosome 15q25 is associated with the risk of COPD in a Korean population.</P>
( Shin Yup Lee ),( Jin Eun Choi ),( Hyo Sung Jeon ),( Mi Jung Hong ),( Yi Young Choi ),( Won Kee Lee ),( Seung Soo Yoo ),( Jae Hee Lee ),( Eung Bae Lee ),( Seung Ick Cha ),( Chang Ho Kim ),( Young Tae 대한결핵 및 호흡기학회 2014 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.118 No.0
Background: MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA-mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small cell lung cancer (NSCLC). Methods: Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenom’s MassARRAY platform were investigated in 357 patients. A replication study was performed on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription- PCR were conducted to examine functional relevance of potentially functional poly-miRTSs. Results: Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In combined analysis, patients with the rs3660 GC+CC genotype had a significantly better overall survival (OS) compared with those with GG genotype (adjusted hazard ratio [aHR] for OS, 0.65; 95% confidence interval [CI] 0.50-0.85; P= 0.001). An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues. Conclusions: The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome.