請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64743完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊泮池(Pan-Chyr Yang) | |
| dc.contributor.author | Ting-Yung Huang | en |
| dc.contributor.author | 黃婷沅 | zh_TW |
| dc.date.accessioned | 2021-06-16T22:58:22Z | - |
| dc.date.available | 2012-09-18 | |
| dc.date.copyright | 2012-09-18 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-08-08 | |
| dc.identifier.citation | 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E et al. (2011) Global cancer statistics. CA Cancer J Clin. 61 (2): 69-90.
2. Mirsadraee S, Oswal D, Alizadeh Y, Caulo A, van Beek EJ. (2012) The 7th lung cancer TNM classification and staging system: Review of the changes and implications. World J Radiol. 4 (4): 128-134. 3. Tyagi P, Mirakhur B (2009) MAGRIT: The largest-ever phase III lung cancer trial aims to establish a novel tumor-specific approach to therapy. Clin Lung Cancer. 10 (5): 371-4. 4. Janku F, Stewart DJ, Kurzrock R. (2010) Targeted therapy in non-small-cell lung cancer--is it becoming a reality? Nat Rev Clin Oncol. 7 (7): 401-14. 5. Tsai TH, Su KY, Wu SG, Chang YL, Luo SC et al. (2012) RNA is favourable for analysing EGFR mutations in malignant pleural effusion of lung cancer. Eur Respir J. 39 (3): 677-84. 6. Becker A, Crombag L, Heideman DA, Thunnissen FB, van Wijk AW. (2011) Retreatment with erlotinib: Regain of TKI sensitivity following a drug holiday for patients with NSCLC who initially responded to EGFR-TKI treatment. Eur J Cancer.47 (17): 2603-6. 7. Nguyen KS, Kobayashi S, Costa DB. (2009) Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin Lung Cancer. 10 (4): 281-9. 8. Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A et al. (2008) First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol. 26 (15): 2442-9. 9. Costa DB, Halmos B, Kumar A, Schumer ST, Huberman MS et al. (2007) BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med. 4 (10): 1669-79 10. Lazzari C, Spreafico A, Bachi A, Roder H, Floriani I et al. (2012) Changes in plasma mass-spectral profile in course of treatment of non-small cell lung cancer patients with epidermal growth factor receptor tyrosine kinase inhibitors. J Thorac Oncol. 7 (1): 40-8. 11. Su KY, Chen HY, Li KC, Kuo ML, Yang JC et al. (2012) Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol. 30 (4): 433-40. 12. Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. (2011) Effectiveness of tyrosine kinase inhibitors on 'uncommon' epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res. 17 (11): 3812-21. 13. Oh JE, An CH, Yoo NJ, Lee SH. (2011) Detection of low-level EGFR T790M mutation in lung cancer tissues. APMIS.119 (7): 403-11. 14. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O et al. (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med, 352 (8): p. 786-92. 15. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R et al. (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med.2 (3): p. e73. 16. Yang SY, Yang TY, Li YJ, Chen KC, Liao KM (2012) EGFR exon 19 in-frame deletion and polymorphisms of DNA repair genes in never-smoking female lung adenocarcinoma patients. Int J Cancer. doi: 10.1002/ijc.27630. 17. Gromet MA, Epstein WL, Blois MS. (1978) The regressing thin malignant melanoma: a distinctive lesion with metastatic potential. Cancer. 42 (5): 2282-92. 18. De Pas T, Giovannini M, Rescigno M, Catania C, Toffalorio F et al. (2012) Vaccines in non-small cell lung cancer: Rationale, combination strategies and update on clinical trials. Crit Rev Oncol Hematol. Available online 24 February. 19. Boon T, Coulie P, Marchand M, Weynants P, Wolfel T et al. (1994) Genes coding for tumor rejection antigens: perspectives for specific immunotherapy. Important Adv Oncol. 53-69. 20. Marchand M, van Baren N, Weynants P, Brichard V, Dreno B (1999) Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1. Int J Cancer. 80 (2): 219-30. 21. Parmigiani RB, Bettoni F, Vibranovski MD, Lopes MH, Martins WK et al. (2006) Characterization of a cancer/testis (CT) antigen gene family capable of eliciting humoral response in cancer patients. Proc Natl Acad Sci U S A.103 (48): 18066-71. 22. Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ. (2005) Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer. 5 (8): 615-25 23. Tabor H, Tabor CW, Cohn MS. (1983) Mass screening for mutants in the polyamine biosynthetic pathway in Saccharomyces cerevisiae. Methods Enzymol. 94: 104-8. 24. Traversari C, van der Bruggen P, Van den Eynde B, Hainaut P, Lemoine C et al. (1992) Transfection and expression of a gene coding for a human melanoma antigen recognized by autologous cytolytic T lymphocytes. Immunogenetics Immunogenetics. 35 (3): 145-52. 25. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E et al. (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 254 (5038): 1643-7. 26. Chen YT, Scanlan MJ, Sahin U, Tureci O, Gure AO et al. (1997) A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc Natl Acad Sci U S A.94 (5): 1914-8. 27. Gaugler B, Van den Eynde B, van der Bruggen P, Romero P, Gaforio JJ et al. (1994) Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J Exp Med. 179 (3): 921-30. 28. Gure AO, Chua R, Williamson B, Gonen M, Ferrera CA et al. (2005) Cancer-Testis Genes Are Coordinately Expressed and Are Markers of Poor Outcome in Non-Small Cell Lung Cancer. Clin Cancer Res. 11 (22): 8055-62. 29. Van den Eynde BJ, van der Bruggen P. (1997) T cell defined tumor antigens. Curr Opin Immunol. 9 (5): 684-93. 30. Karimi S, Mohammadi F, Porabdollah M, Mohajerani SA, Khodadad K et al. (2012) Characterization of melanoma-associated antigen-a genes family differential expression in non-small-cell lung cancers. Clin Lung Cancer. 13 (3): 214-9. 31. De Plaen E, Arden K, Traversari C, Gaforio JJ, Szikora JP et al. (1994) Structure, chromosomal localization, and expression of 12 genes of the MAGE family. Immunogenetics.40 (5): 360-9. 32. Sang M, Lian Y, Zhou X, Shan B. (2011) MAGE-A family: attractive targets for cancer immunotherapy. Vaccine. 29 (47): 8496-500. 33. Gure AO, Chua R, Williamson B, Gonen M, Ferrera CA et al. (2005) Cancer-testis genes are coordinately expressed and are markers of poor outcome in non-small cell lung cancer. Clin Cancer Res. 11 (22): 8055-62. 34. Weynants P, Lethe B, Brasseur F, Marchand M, Boon T. (1994) Expression of mage genes by non-small-cell lung carcinomas. Int J Cancer. 56 (6): 826-9. 35. Marchand M, Weynants P, Rankin E, Arienti F, Belli F et al. (1995) Tumor regression responses in melanoma patients treated with a peptide encoded by gene MAGE-3. Int J Cancer. 63 (6): 883-5. 36. Brichard VG, Lejeune D. (2007) GSK's antigen-specific cancer immunotherapy programme: pilot results leading to Phase III clinical development. Vaccine. 25 Suppl 2: B61-71. 37. Schnurr M, Chen Q, Shin A, Chen W, Toy T.(2005) Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery. Blood. 105 (6): 2465-72. 38. Atanackovic D, Altorki NK, Stockert E, Williamson B, Jungbluth AA.et al. (2004) Vaccine-induced CD4+ T cell responses to MAGE-3 protein in lung cancer patients. J Immunol. 172 (5): 3289-96. 39. Yang B, O'Herrin SM, Wu J, Reagan-Shaw S, Ma Y et al.(2007) MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. Cancer Res. 67(20): 9954-62. 40. Marcar L, Maclaine NJ, Hupp TR, Meek DW. (2010) Mage-A cancer/testis antigens inhibit p53 function by blocking its interaction with chromatin. Cancer Res. 70 (24): 10362-70. 41. Bernig T, Chanock SJ. (2006) Challenges of SNP genotyping and genetic variation: its future role in diagnosis and treatment of cancer. Expert Rev Mol Diagn. 6 (3): 319-31. 42. Griffin TJ, Smith LM. (2000) Single-nucleotide polymorphism analysis by MALDI-TOF mass spectrometry. Trends Biotechnol.18 (2): 77-84. 43. Sobrino B, Brion M, Carracedo A. (2005) SNPs in forensic genetics: a review on SNP typing methodologies. Forensic Sci Int. 154 (2-3): 181-94. 44. Imai Y, Shichijo S, Yamada A, Katayama T, Yano H et al. (1995) Sequence analysis of the MAGE gene family encoding human tumor-rejection antigens. Gene.160 (2): 287-90. 45. Kloth M, Goering W, Ribarska T, Arsov C, Sorensen KD et al. (2012) The SNP rs6441224 influences transcriptional activity and prognostically relevant hypermethylation of RARRES1 in prostate cancer. Int J Cancer. doi:10. 1002/ijc.27628. 46. Li M, Mo Y, Luo XJ, Xiao X, Shi L et al. (2011) Genetic association and identification of a functional SNP at GSK3beta for schizophrenia susceptibility. Schizophr Res. 133 (1-3): 165-71. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64743 | - |
| dc.description.abstract | 肺癌是全球癌症中致死率最高的一項疾病，依照其病理型態主要可區分為非小細胞肺癌及小細胞肺癌兩大類。目前非小細胞肺癌的治療主要是以手術切除配合化療或是放射治療為主，但是這些療法都會有明顯的副作用。因此開發新的治療策略，對於肺癌研究而言，是現階段許多科學家積極努力的一個重要方向；免疫療法便是最近幾年廣被研究人員所採取的一項具有潛力的治療策略，此種治療是利用病人的免疫系統，使其能夠辨識在癌細胞上特有的抗原進而殺死癌細胞。MAGE-A3 與PRAME是兩個與腫瘤細胞形成相關的抗原，一般在正常細胞中並不會表現。根據研究，大約有35~50%的肺癌病患會在其癌組織檢體中偵測到MAGE-A3的表現，同時這些病患也伴隨著較差的預後情形。根據荷商葛蘭素藥廠所進行的一個大型的三期臨床試驗 (MAGRIT) 顯示，對摘除腫瘤後的病人施以MAGE-A3 antigen specific immunotherapy (ASCI) 有助於避免病患癌症的再次復發。在這個臨床試驗中也同時發現MAGE-A3與PRAME基因的表現量在鱗狀上皮細胞肺癌和肺腺癌細胞中有明顯的不同；此外，在不同人種中這類基因的表現也有極大的差異，歐洲人的表現量是遠高於亞洲人種;是以這兩個基因成為現階對研究癌症免疫療法相當中要的兩個指標。考慮到MAGE-A3 及PRAME 在亞洲人的低表現和亞洲人的表皮生長因子接受器的高比例突變，在本篇研究中我們很有興趣探討這兩個基因的表現量在表皮生長因子接受器活化突變之間是否有所關連。近年來，有許多證據顯示許多單一核苷酸多型態現象(SNP)存在MAGE-A3 和PRAME中。在本篇研究裡，我們利用即時定量PCR的偵測方式分析兩個基因的表現量，同時也運用direct sequence 以及質譜分析的方式檢測檢體中產生SNP的機率；希望藉由我們的實驗釐清是否有特殊的SNP存在於MAGE-A3 及PRAME 這兩個基因，進而影響台灣地區非小細胞肺癌病患組織中此兩基因的表現量。本篇研究中，我們也同時分析SNP的存在是否與病人的EGFR status有關。實驗結果顯示，MAGE-A3與PRAME基因的表現量在台灣地區非小細胞肺癌病患中明顯偏低；有關SNP的分析也發現，有3個特殊的SNP 存在於PRAME基因中，但此情形在MAGE-A3的基因中並未發現；不僅如此，我們更找到一個PRAME的SNP與其基因本身的表現量及病人產生EGFR activating mutation相關有關。藉由我們的研究，希望未來可以找出相關的機制作為病人面臨治療過程選擇上，一個有效的篩選指標。 | zh_TW |
| dc.description.abstract | Lung cancer is the leading cause of cancer related death worldwide, and can be divided into non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Typically doctors will consider removing the cancer cell mass and combine this operation with chemo- or radio- therapy, but there may have many side effects of cancer patients. For this reason, developing a new strategy for lung cancer treatment has become an important topic for cancer research. One of them is to develop the method of immunotherapy. Scientists attempt to allow a patients’ immune system to have the ability to recognize the specific antigen of cancer cells and further to kill them. MAGE-A3 and PRAME are two tumor-associated antigens, both of them specifically expressed in cancer cells but not normal cells. According to the interim preliminary data of MAGRIT phase III trial, scientists at GlaxoSmithKline found that patients can have a better clinical outcome when they receive MAGE-A3 antigen specific immunotherapy (ASCI) after their operations; in addition, they also found that the expression levels of these two genes are significantly different between squamous cell carcinoma and adenocarcinoma, and also slightly different with regards to ethnicities. The expression level in Europeans is higher than in Asians. For these reasons, these two genes have become good candidates for studies related to cancer immunotherapy. Considering the low expression rate of MAGE-A3 and PRAME genes and highly mutation frequency of EGFR status in NSCLC patients in Asia especially Southeast Asia, it would be quite interesting to investigate whether the expression levels of MAGE-A3 are related to the status of EGFR. Recently, evidence has also indicated that several single nucleotide polymorphisms (SNPs) exist in both MAGE-A3 and PRAME genes; furthermore, differences with regards to MAGE-A3 or PRAME polymorphism between racial populations may potentially contribute to its regulation as well as the relevant differential mRNA expression and the relationship between the SNPs and the EGFR activation mutation status have become a very important study topics related to cancer immunotherapy in Asia. In this study, we will analyze expression levels by Real-time Quantitative RT-PCR and potential polymorphisms of MAGE-A3 by direct sequencing and PRAME by DNA Mass in NSCLC patients in Taiwan; In addition, we will also investigate whether their expressions are correlated with the EGFR status of these patients. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T22:58:22Z (GMT). No. of bitstreams: 1 ntu-101-R99444006-1.pdf: 2006781 bytes, checksum: 04594a720e3964245102885c2e96a250 (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 致謝 II
中文摘要 III Abstract V Content VII 1. Introduction 1 1.1 Lung cancer 1 1.1.1 Population 1 1.1.2 Staging 1 1.1.3 Management and prognosis 4 1.1.4 Non-small cell lung cancer 4 1.1.5 Pathogenesis 5 1.2 Cancer Immunotherapy 6 1.3 Cancer/testis (CT) antigens 7 1.3.1 Cancer/germline genes in non-small cell lung cancer 7 1.4 MAGRIT 8 1.4.1 MAGE-A3 8 1.4.2 MAGE-A family 9 1.4.3 MAGE-A3 and immunotherapy 10 1.4.4 MAGE-A3 function 11 1.5 PRAME 11 1.6 Single Nucleotide Polymorphism 11 1.7 The specific aims 12 2. Materials and Methods 13 2.1 Patients and samples 13 2.2 Reverse transcription-PCR 13 2.3 Real-time Quantitative RT-PCR 15 2.4 SNPs detection of MAGE-A3 by direct sequencing 15 2.5 SNPs detection of PRAME by MassARRAY 16 2.6 Statistical Analysis 18 3. Results 19 3.1 The expression of MAGE-A3 in NSCLC patients in Taiwan 19 3.2 The expression of PRAME in NSCLC patients in Taiwan 19 3.3 The mRNA expression levels of MAGE-A3 are low and not associated with the clinical outcome of NSCLC patients in Taiwan 20 3.4 The mRNA expression levels of PRAME are not associated with overall survival in NSCLC patients in Taiwan 20 3.5 The expression levels of MAGE-A3 but not PRAME were correlated with EGFR mutation status of NSCLC patients in Taiwan 22 3.6 Non-significant occurrence of SNP hot spots of MAGE-A3 in NSCLC patients in Taiwan 22 3.7 Three SNP occurrence hot spots, rs2266988, rs61745687 and rs34866162, of PRAME are existed in NSCLC patients in Taiwan 23 3.8 SNP occurrence of rs2266988 are correlated to the EGFR status and the expression levels of PRAME gene of NSCLC patients in Taiwan 24 Chapter 4. Discussion 25 Chapter 5. Conclusion 28 Chapter 6. Figures and Tables 29 Figure 1. Relative expression level of MAGE-A3 in NSCLC patients in Taiwan 29 Figure 2. Relative expression level of PRAME in NSCLC patients in Taiwan 30 Figure 3. Kaplan-Meier survival plots for NSCLC patients grouped by MAGE-A3 mRNA expression levels. 31 Figure 4. Kaplan-Meier survival plots for NSCLC patients grouped by PRAME mRNA expression levels. 32 Figure 5. Correlation between MAGE-A3 expression levels and EGFR status of NSCLC patients in Taiwan. 33 Figure 6. Correlation between PRAME expression levels and EGFR status of NSCLC patients in Taiwan. 34 Figure 7. Frequency of SNP occurrence of MAGE-A3. 35 Figure 8. Frequency of SNP occurrence of PRAME. 36 Table 1. MAGE-A3 Expression by Histopathology - Screened Cohort 37 Table 2. Histological characteristics NSCLC patients that joined to MAGE-A3 and PRAME studies in Taiwan. 37 Table 3. HRs for death among patients with NSCLC, according to multivariable Cox regression analysis 39 Table 4. HRs for death among patients with NSCLC, according to multivariable Cox regression analysis 40 Table 5. Occurrence of 18 SNP detection sites of MAGE-A3 in NSCLC patients in Taiwan 41 Table 6. MAGE-A3 expression and EGFR activating mutation of primary tumor from 198 NSCLC patients in Taiwan. 42 Table 7. MAGE-A3 expression and EGFR activating mutation (direct sequence) of primary tumor from 91 NSCLC patients in Taiwan. 43 Table 8. PRAME expression and EGFR activating mutation of primary tumor from 198 NSCLC patients in Taiwan. 44 Table 9. Occurrence Frequency of 24 SNP detection sites of PRAME in 200 NSCLC patients in Taiwan 45 Table 10. Occurrence of PRAME SNP rs2266988 and EGFR activating mutation of primary tumor from 205 NSCLC patients in Taiwan. 46 Table 11. Occurrence of PRAME SNP rs2266988 and PRAME gene expression levels of primary tumor from 132 NSCLC patients in Taiwan. 47 Table 12. HRs for death (from any cause) among patients with NSCLC, according to multivariable Cox regression analysis 48 Table 13. Sequence of MAGE-A3, PRAME and β-actin real-time quantitative RT-PCR 49 Table 14. Sequence of MAGE-A3 PCR primer 49 Table 15. Sequence of PRAME MassARRAY (PCR primer) 50 Table 16. Sequence of PRAME MassARRAY (Extending probes) 51 7. References 52 8. Appendix 59 | |
| dc.language.iso | en | |
| dc.subject | PRAME | zh_TW |
| dc.subject | 非小細胞肺癌 | zh_TW |
| dc.subject | 表皮生長因子接受器突變 | zh_TW |
| dc.subject | 單核酸多型態現象 | zh_TW |
| dc.subject | MAGE-A3 | zh_TW |
| dc.subject | MAGE-A3 | en |
| dc.subject | PRAME | en |
| dc.subject | SNPs | en |
| dc.subject | EGFR mutation | en |
| dc.subject | NSCLC patients in Taiwan | en |
| dc.title | MAGE-A3 及 PRAME 基因在台灣非小細胞肺癌病人中的表現量及單一核苷酸多型性盛行率與表皮生長因子受體突變相關性探討 | zh_TW |
| dc.title | The prevalence of SNPs and gene expression in MAGE-A3 and PRAME of Taiwan NSCLC patients with or without EGFR mutation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.coadvisor | 張逸良(Yih-Leong Chang) | |
| dc.contributor.oralexamcommittee | 陳惠文(Huei-Wen Chen) | |
| dc.subject.keyword | MAGE-A3,PRAME,表皮生長因子接受器突變,單核酸多型態現象,非小細胞肺癌, | zh_TW |
| dc.subject.keyword | MAGE-A3,PRAME,SNPs,EGFR mutation,NSCLC patients in Taiwan, | en |
| dc.relation.page | 59 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-08-09 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 病理學研究所 | zh_TW |
| 顯示於系所單位： | 病理學科所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-101-1.pdf 未授權公開取用 | 1.96 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。