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Genomic copy number alterations in Korean bile duct cancer in comparison with normal healthy Korean : 한국인 담도암 환자의 유전체 복제 수 변이의 특성

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dc.contributor.advisor김선회-
dc.contributor.author강미주-
dc.date.accessioned2017-07-14T01:21:16Z-
dc.date.available2017-07-14T01:21:16Z-
dc.date.issued2013-02-
dc.identifier.other000000008357-
dc.identifier.urihttps://hdl.handle.net/10371/121865-
dc.description학위논문 (박사)-- 서울대학교 대학원 : 의학과 외과학 전공, 2013. 2. 김선회.-
dc.description.abstractBackground: The cytogenetic pathogenesis of bile duct cancer is poorly understood. This study investigated changes in gene copy number in Korean bile duct cancers and compared them with that of normal healthy Koreans. Furthermore, we explored the correlation of copy number variation with the disease free survival of bile duct cancer patients.
Methods: Array comparative genomic hybridization was performed on 24 Korean bile duct cancer specimens and 10 normal healthy Koreans. The results were validated by the disease free survival of bile duct cancer patients.
Results: A total of 984 copy number variations (CNVs) in 306 CNV regions (CNVRs) were distributed throughout all 22 chromosomes in Korean bile duct cancer patients. Korean bile duct cancer patients had a mean of 21.8 gains and 19.2 losses and the average number of CNVR was 35.9 per patient. Frequent sites of gains were located at 22q11.22, 2p11.2-p.11.1, 14q32.33 and 17q12. Frequent site of losses were located at 19q12-q13.43. When comparing 10 normal healthy Korean controls with the 24 Korean bile duct cancer patients, a total of 7,825 CNVs and 2,081 CNVRs were identified. Twenty significant CNVRs showed significant differences between the normal healthy Koreans and the Korean bile duct cancer patients. Significant gains of copy number were observed in 2p11.2, 5p15.33, 22q11.21, 22q11.22, 22q11.23, 22q12.2, 22q12.3, 22q13.1, 22q13.31 and 22q13.33. Significant losses of copy number were observed in 8q11.21, 10q26.3, 11p15.4, 18q21.31 and 18q23. Copy number gains in 5p15.33 and 22q13.33 were correlated with early systemic recurrence in the Korean bile duct cancer patients.
Conclusion: This study defined regions of the genome associated with changes in DNA copy number in Korean bile duct cancer. Copy number gain in 22q11-q13 was the most frequent in Korean bile duct cancer and was correlated to poor disease free survival. The findings have implications for identifying therapeutic targets, screening, and prognostication.		-
dc.description.tableofcontents1. Introduction 1
1.1 Prognosis and prognostic factors of bile duct cancer……………………1
1.2 Copy number variation and disease susceptibility……………………….2
1.3 Copy number variation and cancer………………………………………4
1.4 Previous studies of copy number variation in bile duct cancer………….5
1.5 Array CGH technology as a tool for detection of copy number variation…………………………………………………………………6
1.6 Purpose of this study……………………………………………………6
2. Materials and Methods ……………………………………………… 7
2.1 Patients………………………………………………………………….7
2.1.1 Korean biliary tract cancer………………………………………7
2.1.2 Normal healthy Korean controls………………………………...8
2.2 Tissue collection and DNA extraction…………………………………8
2.2.1 Tissue collection………………………………………………...8
2.2.2 DNA extraction………………………………………………….8
2.3 Array CGH experiment………………………………………………10
2.3.1 Array CGH chip……………………………………………….10
2.3.2 DNA labeling for array CGH………………………………….11
2.3.3 Array hybridization, imaging and data analysis……………….12
2.4 Basic analysis of array CGH…………………………………………13
2.4.1 Data analysis for Korean bile duct cancer samples……………13
2.4.2 Analysis between normal healthy Korean controls and Korean bile duct cancer patients…………………………………..................14
2.4.3 Gene symbol matching for each CNV………………………….15
2.4.4 Hierarchical clustering………………………………………….15
2.5 Selection of significant clones and genes……………………………..15
2.5.1 Permutation test…………………………………………………15
2.5.2 χ 2-test……………………………………………………………16
2.5.3 Kaplan-Meier test……………………………………………….17
2.5.4 Data mining……………………………………………………..17
2.5.5 Selection of candidate genes……………………………………18
2.6 Expression analysis of selected genes…………………………………18
2.6.1 Immunohistochemistry…………………………………………18
3. Results…………………………………………….………………….20
3.1 Clinicopathological characteristics of the study subjects…………….20
3.2 Personal frequency, size of CNV of 24 Korean bile duct cancer patients…………………………………………………………………21
3.2.1 Frequency and size of CNV of each individual…………………21
3.2.2 Summary of mutations in Korean bile duct cancer……………..21
3.3 Selection of candidate genes for prediction of recurrence in Korean bile duct cancer……………………………………………………………..22
3.3.1 Mean comparison for log 2 ratio of bile duct cancer patients…..22
3.3.2 Hierarchical clustering………………………………………..….23
3.4 Selection of candidate genes for prediction of bile duct cancer in comparison with normal healthy Korean controls…………………..….23
3.4.1 Comparison of Korean bile duct cancer patients with normal healthy Korean controls……………………………………...…..23
3.4.2 Permutation test and χ 2-test………………………………...……24
3.4.3 Hierarchical clustering……………………………………...……24
3.4.4 Functional gene annotation, pathway map……………………….24
3.4.5 Disease-free survival analysis……………………………………25
3.5 Expression analysis with immunohistochemical stainin……………….26
3.5.1 Selected gene expression analysis……………………………….26
4. Discussion 27
5. References 36
6. 요약(국문초록) 40		-
dc.formatapplication/pdf-
dc.format.extent2953554 bytes-
dc.format.mediumapplication/pdf-
dc.language.isoen-
dc.publisher서울대학교 대학원-
dc.subjectCopy number variation-
dc.subjectbile duct cancer-
dc.subjectDiagnosis-
dc.subjectBiomarker-
dc.subjectPrognosis-
dc.subjectSurvival analysis-
dc.subject.ddc610-
dc.titleGenomic copy number alterations in Korean bile duct cancer in comparison with normal healthy Korean-
dc.title.alternative한국인 담도암 환자의 유전체 복제 수 변이의 특성-
dc.typeThesis-
dc.contributor.AlternativeAuthorMEE JOO KANG-
dc.description.degreeDoctor-
dc.citation.pages68-
dc.contributor.affiliation의과대학 의학과-
dc.date.awarded2013-02-
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