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.

골 신연술을 시행받은 가토의 경골 성장골단판에서 골성장 지표와 길이 성장률과의 관계

이순혁,한승엽,변영수 고려대학교 의과대학 1997 고려대 의대 잡지 Vol.34 No.1

The rate of longitudinal bone growth in the physeal plate is modulated by the size of pool of proliferative chondrocyte, the rate of cell division of proliferative chondrocyte. the height of terminal hypertrophic chondrocyte and matrix production in the transverse septa. The parameters such as growth plate thickness and the rate of cell division by proliferating chondrocytes have been indentified as useful indices of longitudinal bone growth rate. Recently the height and volume of hypertrophics have been reported to be one of the decisive factors in modulating the longitudinal growth rate. Fracture. osteotomy or limb lengthening have been known to affect the longitudinal growth rate and, it can be assumed. they could change the relationship betweengrowth rate andparameters. The purposes of this study were to clarify the relationship betweenparameters and longitudinal bone growth in osteotomized and lengthened limbs and t o compare the relationship between the different groups which showed changed growth rate affected by the amount of lengthening. Sixteen eight weeks old New Zealand white rabbitswere allocated into four groups; Group Ⅰ was osteotomized and stabilized by external fixater but without lengthening, Group Ⅱ was lengthened 20% of total tibia1 length at a rate of 0.8mm/day with external fixater. Group Ⅲ was lengthened 30% at a rate of 0.8mm/day and Group Ⅳ was lengthened 40% t o 50% a t a rate of 3. Pmm/day. Left tibia was used for that procedure and right tibia was left as a control. In the proximal & distalphyses of both tibia, following measure ments were performed. The longitudinal growth rates were determined by tetracychine labeling and indirect light fluoroscence microscopy. The physeal thickness was histomorphologically measured and the proliferative rate of chondrocytes in physeal plate was assessed by immunohistochemical staining using anti-bromcdeoxyuridine monoclonal antibody. The results obtained were as follows ; 1) The physeal thickness and the number of proliferating chondrocytes had linearcorrelation with longitudinal growth rate in the physis of the lengthened or osteotomized tibia of rabbits. ) The relationship of the physeal thickness and the number of proliferating chondro cytes with longitudinal growth rate had highercorrelation coefficiency and different slope of regression in the proximalphysis of lengthened or osteotomized tibia of rabbits compared to that in the distal physis of lengthenedorosteotomizedtibia ofrabbits. 3) The relative contribution of the physeal thickness orthe number of proliferating chondrocytes tothe longitudinal growth rates varied following the varied amount or rate oflengtheninginthe physis of lengthened orosteotomizedtibia of rabbits. As a conclusion, physeal thickness and the number of proliferating chondrocytes are considered to be significant parameters of longitudinal growth ratein the osteotomized orlengthened limb, but they may contribute to longitudinal growth rate differently according to the location, ageand local condition of the physis.

수부의 외상성 중수지 관절 탈구의 치료

이승구,송석환,이주엽,문창윤,오재찬 대한골절학회 2003 대한골절학회지 Vol.16 No.2

목적 : 수부의 중수지 관절 탈구의 관혈적 정복이 필요했던 예에서는 정복을 방해하는 구조물에 대해 분석하고 도수 정복이 가능했던 예에서는 성별 및 탈구 형태에 따른 특성에 대해 알아보고자 하였다. 대상 및 방법 : 총 27예의 수부 중수지 관절 탁구 환자 (무지 11예, 이지 14예, 소지 2예)를 대상으로 연구하였다. 탈구된 중수지 관절의 정복을 방해하는 해부학적 구조는 수술시에 확인을 하였으며, 도수 정복이 가능하였던 예들에서도 연령과 손상된 구조물, 그리고 최종적인 임상 결과를 평균 7개월간 추시 관찰하였다. 결과 : 무지 중수지 관절의 탈구 11예 중 파열된 전방 관절낭, 수장판과 단무지 굴건의 파열을 동반한 복합 탈구가 8예 있어 관혈 정복을 시행하였으며, 2예에서만 도수 정복이 가능하였다. 관절염이 있던 1예는 관절 유합술을 시행하였다. 다른 수지의 중수지 관절의 탈구는 Kaplan의 개념에 따라 탈구를 수술 정복하였고 파열된 수장판을 복원하였으며, 1예에서 수술시 표재 중수 횡인대만의 절개와 이완으로 정복할 수 있었다. 소지 중수지 관절 탈구의 2예에서 파열된 요측 측부인대가 수술시 관찰되었고 이를 복원하여 수지의 불안정성을 예방하였다. 이들의 최종 결과는 특별한 운동 제한이나 불안정성 없이 좋은 결과를 보였다. 결론 : 적절한 국소 마취하에 도수 정복을 1~2회 시행할 수 있지만 단순 정복이 가능한 탈구가 부적절한 견인으로 정복이 불가능한 복합 탈구로 진행할 수 있다. 그리고 복합 탈구는 대부분 관혈적 정복이 필요하기 때문에, 정복 방해 구조물에 대한 충분한 이해와 적절한 조치가 필요하다. Purpose : To analyse the obstacles to prevent the reduction for dislocation of the metacarpophalangeal (MP) joints of the hand and evaluate the relationship between the sex and dislocation type in closed reduction case. Materials and Methods : Total 27 cases of MP joint dislocation of the hand (11 cases of thumb, and 14 index and 2 little finger) were reviewed retrospectively. The anatomical structures to prevent the reduction were confirmed at operation and the cases which were reduced immediately were also analysed for their ages and differences of damaged structures, and finally their complications or outcome were reviewed for average 7 months after reduction. Results : In 11 cases of thumb MP joint dislocations, the complex dorsal dislocations in which the protruded metacarpal neck was caught by buttonhole of torn anterior joint capsule, volar plate and FPB were reduced by open method in 8 cases, and closed reduction was done in 2 cases but one old case required arthrodesis. In other finger MP joint dislocations, the Kaplan's concept to prevent the reduction was confirmed. But reduction of torn volar plate and incision of transverse metacarpal ligament were sufficient to reduce the dislocation with gentle longitudinal traction during the operation. In two cases of little finger MP joint dislocation, the ruptured radial collateral ligaments were noted after open reduction and it must the repaired to prevent the finger instability later. Their overall end results were good without any significant restriction of MP joints motions and finger instabilities. Conclusion : One or two times of closed reduction with proper local anesthesia could be tried, but simple reducible dislocation can be converted to complex irreducible ones by the inappropriate traction method, and so proper reduction technique by closed or even in open way is important with the knowledge of anatomical obstacles to prevent the reduction of the metacarpophalangeal joints.

외측 도달법에 의한 원위 상완골 간부 골절의 수술적 치료

이승구,이주엽,서유준,이준호,안농겸 대한골절학회 2004 대한골절학회지 Vol.17 No.2

미세 펄스 전압을 이용한 마이크로 전해가공에 관한 연구

조창래,백승엽,이은상 한국공작기계학회 2003 한국공작기계학회 추계학술대회논문집 Vol.2003 No.-

Electrochemical micromachining which is not normally considered as a precision process is presented in this paper. The application of voltage pulses between a tool electrode and a workpiece in an electrochemical environment allows the three-dimensional machining of conducting materials with micrometer precision. In this paper tool-electrodes(5μm in diameter, l㎜ in length) are developed by electrochemical micromaching and micro holes are manufactured using this tool-electrodes we developed already. Micro holes are achieved the accuracy below 50μm in diameter using ultrashort voltage pulses(0.1-5μs).

초임계 탄산가스에 의한 난휘발성 유기물질의 평형추출

배효광,박재효,이승엽,이철희 嶺南大學校 工業技術硏究所 1987 연구보고 Vol.15 No.2

A flow system was used to measure the equilibrium solubilities of Benzoic acid(308, 318, 328 K), Phenol(303, 309 K) and Menthol(303, 313, 323 K) in supercritical Carbon dioxide at various temperatures and a ranged of pressures. The observed data were correlated with a thermodynamic model based on the Peng and Robinson equation of state. The critical properties and acentric factor for Menthol that could not be available in literature were predicted by the method proposed in this work as well as Lydersen's method.

간흡충 감염증의 진단에서 피내반응 검사의 유용성 검토

최재철,오승환,정해진,신정환,박기형,이은엽,장철훈 대한임상미샐물학회 2003 Annals of clinical microbiology Vol.6 No.2

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>

Genetic variants in the WNT signaling pathway are not associated with survival outcome of non-small cell lung cancer in a Korean population

( Seung Soo Yoo ),( Mi Jeong Hong ),( Jin Eun Choi ),( Won Kee Lee ),( Hyewon Seo ),( Yong Dae Lee ),( So Yeon Lee ),( Shin Yup Lee ),( Jaehee Lee ),( Seung Ick Cha ),( Chang Ho Kim ),( Jae Yong Park 대한결핵 및 호흡기학회 2015 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.120 No.-

Recently, genetic variants in the WNT signaling pathway have been reported to affect the survival outcome of Caucasian patients with early stage non-small cell lung cancer (NSCLC). We therefore attempted to determine whether these same WNT signaling pathway gene variants had similar impacts on the survival outcome of NSCLC patients in a Korean population. A total of 761 patients with stages I-IIIA NSCLC were enrolled in this study. Eight variants of WNT pathway genes were genotyped and their association with overall survival and disease-free survival were analyzed. None of the eight variants were significantly associated with overall survival or disease-free survival. There were no differences in survival outcome after stratifying the subjects according to age, gender, smoking status, and histological type. These results suggest that genetic variants in the WNT signaling pathway may not affect the survival outcome of NSCLC in a Korean population.

Thematic Poster : TP-57 ; Association of Polymorphisms in the MicroRNA Target Sites and Survival of Patients in Early-Stage Non-Small-Cell Lung Cancer

( 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.