博碩士論文 107826007 詳細資訊




以作者查詢圖書館館藏 以作者查詢臺灣博碩士 以作者查詢全國書目 勘誤回報 、線上人數:11 、訪客IP:34.234.207.100
姓名 李怡璇(Yi-Xuan Li)  查詢紙本館藏   畢業系所 系統生物與生物資訊研究所
論文名稱 TP53突變對具有EGFR突變的非小細胞肺癌患者帶來的影響
(Role of TP53 Mutations in EGFR-Mutated Patients Treated with Tyrosine Kinase Inhibitors)
相關論文
★ 整合深度學習方法預測年齡以及衰老基因之研究★ 運用深度學習方法預測癌症種類及存活死亡與治癒復發
★ 機械循環拉伸對肺癌細胞功能的影響之研究★ 整合多種基因組型態資料預測肺腺癌患者存活之研究
★ 以系統生物學策略探討臍帶血來源之造血幹細胞分子調控網路★ 以系統生物學方法探討肺腺癌抗藥性成因
★ 在大腸桿菌與酵母菌蛋白質體晶片中量化其蛋白質的濃度
檔案 [Endnote RIS 格式]    [Bibtex 格式]    [相關文章]   [文章引用]   [完整記錄]   [館藏目錄]   至系統瀏覽論文 ( 永不開放)
摘要(中) 肺癌是全世界常見的致死性癌症。肺癌主要分為小細胞肺癌和非小細胞肺癌。已知諸如吉非替尼,阿法替尼和奧西替尼等靶向表皮生長因子受體(EGFR)的酪氨酸激酶抑製劑(TKI)在具有EGFR突變的NSCLC患者中具有顯著療效。不幸的是,大多數患者會在八到十二個月內出現獲得性耐藥。對EGFR-TKIs的耐藥性一直是肺癌治療中的緊迫問題。此外,p53抑癌基因也是肺癌中經常突變的基因。這項研究旨在調查p53對TKI治療的作用。
這項研究分析了可從癌症基因組圖譜(TCGA)數據庫獲得的NSCLC數據,以及來自台中榮民總醫院的66種NSCLC臨床數據。該研究使用t檢驗,卡方檢驗和Kaplan-Meier生存曲線來分析和討論數據之間的生存差異。 Kaplan-Meier生存曲線分析表明,外顯子2、4和6中TP53突變亞組的預後顯著不同。
摘要(英) Lung cancer is a common and lethal cancer worldwide. Lung cancer is mainly divided into small cell lung cancer and non-small cell lung cancer. The epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitors (TKIs) like gefitinib, afatinib, and osimertinib are known to have significant efficacy at NSCLC patients with EGFR mutation. Unfortunately, most patients develop acquired resistance within eight to twelve months. Resistance to EGFR-TKIs has been an urgent issue in the treatment of lung cancer.In addition, the p53 tumor suppressor gene is also a frequently mutated genes in lung cancer. This study is aimed to investigate the effect of p53 on treatment of TKI.
This study analyzes the NSCLC data available from The Cancer Genome Atlas (TCGA) database and 66 NSCLC clinical data from the Taichung Veterans General Hospital. The study used t-test, chi-square test and Kaplan-Meier survival curve to analyze and discuss the difference in survival between data. Furthermore, Kaplan-Meier survival curve analysis showed that the prognosis of the subgroup of TP53 mutations in exon 2、4 and 6 was significantly different.
關鍵字(中) ★ 非小細胞肺癌
★ 肺癌
★ 酪氨酸激酶抑製劑
關鍵字(英) ★ TP53
★ EGFR
★ Tyrosine Kinase Inhibitors
★ EGFR-TKI
★ afatinib
★ T790M
論文目次 中文摘要 i
Abstract ii
致謝 iii
目錄 iv
圖目錄 v
表目錄 vi
一、緒論 - 1 -
1-1 非小細胞肺癌 - 1 -
1-2 非小細胞肺癌肺癌病因 - 2 -
1-3 酪氨酸激酶抑製劑 - 3 -
1-3 T790M突變 - 5 -
1-4 TP53突變 - 6 -
1-5研究動機與目的 - 8 -
二、研究材料與方法 - 9 -
2-1研究材料 - 9 -
2-1-1肺癌患者資料- 9 -
2-1-2癌症基因體圖譜(The Cancer Genome Atlas, TCGA)- 9 -
2-2研究方法 - 10 -
2-2-1分析環境與套件 - 10 -
2-2-2 TP53突變篩選和分類 - 10 -
2-2-3統計分析 - 11 -
三、結果 - 12 -
3-1患者特徵 - 12 -
3-2 TP53突變與患者特徵之間的關係 - 16 -
3-3 TCGA上肺腺癌患者與TP53突變之間的關係 - 18 -
3-4 TP53突變位點和對TKI的反應 - 23 -
3-5 TP53突變類型和對TKI的反應 - 30 -
3-6 TP53多點突變和對TKI的反應 - 32 -
四、討論 - 33 -
五、結論 - 35 -
六、參考文獻 - 36 -
七、附錄表 - 40 -
參考文獻 1. Ferlay, J., et al., Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International Journal of Cancer, 2019. 144(8): p. 1941-1953.
2. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2019. CA: A Cancer Journal for Clinicians, 2019. 69(1): p. 7-34.
3. Travis, W.D., et al., The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. Journal of thoracic oncology, 2015. 10(9): p. 1243-1260.
4. Kocher, F., et al., Longitudinal analysis of 2293 NSCLC patients: a comprehensive study from the TYROL registry. Lung Cancer, 2015. 87(2): p. 193-200.
5. Torre, L.A., R.L. Siegel, and A. Jemal, Lung Cancer Statistics. Adv Exp Med Biol, 2016. 893: p. 1-19.
6. Wakelee, H.A., et al., Lung cancer incidence in never smokers. J Clin Oncol, 2007. 25(5): p. 472-8.
7. Yano, T., et al., Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival. Cancer, 2008. 113(5): p. 1012-8.
8. Toh, C.K., et al., Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J Clin Oncol, 2006. 24(15): p. 2245-51.
9. Paez, J.G., et al., EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science, 2004. 304(5676): p. 1497-500.
10. Shi, Y., et al., A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol, 2014. 9(2): p. 154-62.
11. Passaro, A., et al., Activity of EGFR TKIs in Caucasian Patients With NSCLC Harboring Potentially Sensitive Uncommon EGFR Mutations. Clin Lung Cancer, 2019. 20(2): p. e186-e194.
12. Rusch, V., et al., Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer research, 1993. 53(10): p. 2379-2385.
13. Fukuoka, M., et al., Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol, 2003. 21(12): p. 2237-46.
14. Wu, Y.L., et al., Afatinib versus gemcitabine/cisplatin for first-line treatment of Chinese patients with advanced non-small-cell lung cancer harboring EGFR mutations: subgroup analysis of the LUX-Lung 6 trial. Onco Targets Ther, 2018. 11: p. 8575-8587.
15. Wu, Y.L., et al., Erlotinib versus gemcitabine/cisplatin in Chinese patients with EGFR mutation-positive advanced non-small-cell lung cancer: Crossover extension and post-hoc analysis of the ENSURE study. Lung Cancer, 2019. 130: p. 18-24.
16. Wieduwilt, M.J. and M.M. Moasser, The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci, 2008. 65(10): p. 1566-84.
17. Solca, F., et al., Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther, 2012. 343(2): p. 342-50.
18. Mok, T.S., et al., Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. J Clin Oncol, 2018. 36(22): p. 2244-2250.
19. Wu, Y.L., et al., Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol, 2017. 18(11): p. 1454-1466.
20. Karachaliou, N., et al., EGFR first- and second-generation TKIs—there is still place for them in EGFR -mutant NSCLC patients. 2018, 2018: p. S23-S47.
21. Lau, S.C., et al., Outcome Differences Between First- and Second-generation EGFR Inhibitors in Advanced <em>EGFR</em> Mutated NSCLC in a Large Population-based Cohort. Clinical Lung Cancer, 2019. 20(5): p. e576-e583.
22. Cross, D.A., et al., AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov, 2014. 4(9): p. 1046-61.
23. Soria, J.-C., et al., Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. 2017. 378(2): p. 113-125.
24. Takeda, M. and K. Nakagawa, First- and Second-Generation EGFR-TKIs Are All Replaced to Osimertinib in Chemo-Naive EGFR Mutation-Positive Non-Small Cell Lung Cancer? Int J Mol Sci, 2019. 20(1).
25. Gu, J., et al., TP53 mutation is associated with a poor clinical outcome for non-small cell lung cancer: Evidence from a meta-analysis. Mol Clin Oncol, 2016. 5(6): p. 705-713.
26. Qin, K., et al., Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis. BMC Cancer, 2020. 20(1): p. 328.
27. Toyooka, S., T. Tsuda, and A.F. Gazdar, The TP53 gene, tobacco exposure, and lung cancer. Hum Mutat, 2003. 21(3): p. 229-39.
28. Vogelstein, B., D. Lane, and A.J. Levine, Surfing the p53 network. Nature, 2000. 408(6810): p. 307-10.
29. Kastenhuber, E.R. and S.W. Lowe, Putting p53 in Context. Cell, 2017. 170(6): p. 1062-1078.
30. Kato, S., et al., Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci U S A, 2003. 100(14): p. 8424-9.
31. Lehmann, B.D. and J.A. Pietenpol, Targeting mutant p53 in human tumors. J Clin Oncol, 2012. 30(29): p. 3648-50.
32. Raj, N. and L.D. Attardi, The Transactivation Domains of the p53 Protein. Cold Spring Harb Perspect Med, 2017. 7(1).
33. Fischer, N.W., et al., p53 oligomerization status modulates cell fate decisions between growth, arrest and apoptosis. Cell Cycle, 2016. 15(23): p. 3210-3219.
34. Malkin, D., Li-fraumeni syndrome. Genes Cancer, 2011. 2(4): p. 475-84.
35. Lomax, M.E., et al., Characterization of p53 oligomerization domain mutations isolated from Li-Fraumeni and Li-Fraumeni like family members. Oncogene, 1998. 17(5): p. 643-9.
36. McKinney, K., et al., p53 linear diffusion along DNA requires its C terminus. Mol Cell, 2004. 16(3): p. 413-24.
37. Göhler, T., et al., Specific interaction of p53 with target binding sites is determined by DNA conformation and is regulated by the C-terminal domain. J Biol Chem, 2002. 277(43): p. 41192-203.
38. Huang, Y.H., et al., The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma. Cancer Res Treat, 2018. 50(4): p. 1294-1303.
39. Ross Ihaka, R.G., The R Project for Statistical Computing.
40. Poeta, M.L., et al., TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med, 2007. 357(25): p. 2552-61.
41. Molina-Vila, M.A., et al., Nondisruptive p53 mutations are associated with shorter survival in patients with advanced non-small cell lung cancer. Clin Cancer Res, 2014. 20(17): p. 4647-59.
42. Liu, Y., et al., Mutations in exon 8 of TP53 are associated with shorter survival in patients with advanced lung cancer. Oncol Lett, 2019. 18(3): p. 3159-3169.
43. Hou, H., et al., Concurrent TP53 mutations predict poor outcomes of EGFR-TKI treatments in Chinese patients with advanced NSCLC. Cancer Manag Res, 2019. 11: p. 5665-5675.
44. Sorrell, A.D., et al., Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome : current status of clinical applications and future directions. Mol Diagn Ther, 2013. 17(1): p. 31-47.
45. Phang, B.H., et al., Amino-terminal p53 mutations lead to expression of apoptosis proficient p47 and prognosticate better survival, but predispose to tumorigenesis. Proc Natl Acad Sci U S A, 2015. 112(46): p. E6349-58.
46. Canale, M., et al., Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors. Clin Cancer Res, 2017. 23(9): p. 2195-2202.
47. Labbé, C., et al., Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Lung Cancer, 2017. 111: p. 23-29.
指導教授 許藝瓊(Yi-Chiung Hsu) 審核日期 2020-8-24
推文 facebook   plurk   twitter   funp   google   live   udn   HD   myshare   reddit   netvibes   friend   youpush   delicious   baidu   
網路書籤 Google bookmarks   del.icio.us   hemidemi   myshare   

若有論文相關問題,請聯絡國立中央大學圖書館推廣服務組 TEL:(03)422-7151轉57407,或E-mail聯絡  - 隱私權政策聲明