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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張逸良(Yih-Leong Chang) | |
dc.contributor.advisor | 張逸良(Yih-Leong Chang | ntuhylc@gmail.com | ), | |
dc.contributor.author | Cher-wei Liang | en |
dc.contributor.author | 梁哲維 | zh_TW |
dc.date.accessioned | 2023-03-19T22:09:17Z | - |
dc.date.copyright | 2022-06-14 | |
dc.date.issued | 2022 | |
dc.date.submitted | 2022-05-13 | |
dc.identifier.citation | 1. Abraham SC, Krasinskas AM, Hofstetter WL, Swisher SG, Wu T-T: “Seedling” mesenchymal tumors (gastrointestinal stromal tumors and leiomyomas) are common incidental tumors of the esophagogastric junction. The American journal of surgical pathology 2007, 31:1629-35. 2. Agaimy A, Wünsch PH, Hofstaedter F, Blaszyk H, Rümmele P, Gaumann A, Dietmaier W, Hartmann A: Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. The American journal of surgical pathology 2007, 31:113-20. 3. Kawanowa K, Sakuma Y, Sakurai S, Hishima T, Iwasaki Y, Saito K, Hosoya Y, Nakajima T, Funata N: High incidence of microscopic gastrointestinal stromal tumors in the stomach. Human pathology 2006, 37:1527-35. 4. Demetri GD, Von Mehren M, Antonescu CR, DeMatteo RP, Ganjoo KN, Maki RG, Pisters PW, Raut CP, Riedel RF, Schuetze S: NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. Journal of the National Comprehensive Cancer Network 2010, 8:S-1-S-41. 5. Rossi S, Gasparotto D, Toffolatti L, Pastrello C, Gallina G, Marzotto A, Sartor C, Barbareschi M, Cantaloni C, Messerini L: Molecular and clinicopathologic characterization of gastrointestinal stromal tumors (GISTs) of small size. The American journal of surgical pathology 2010, 34:1480-91. 6. Yang J, Du X, Lazar AJ, Pollock R, Hunt K, Chen K, Hao X, Trent J, Zhang W: Genetic aberrations of gastrointestinal stromal tumors. Cancer: Interdisciplinary International Journal of the American Cancer Society 2008, 113:1532-43. 7. Corless CL, Heinrich MC: Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol Mech Dis 2008, 3:557-86. 8. Agaimy A, Wünsch PH, Dirnhofer S, Bihl MP, Terracciano LM, Tornillo L: Microscopic gastrointestinal stromal tumors in esophageal and intestinal surgical resection specimens: a clinicopathologic, immunohistochemical, and molecular study of 19 lesions. The American journal of surgical pathology 2008, 32:867-73. 9. Corless CL, McGreevey L, Haley A, Town A, Heinrich MC: KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. The American journal of pathology 2002, 160:1567-72. 10. Joensuu H, Vehtari A, Riihimäki J, Nishida T, Steigen SE, Brabec P, Plank L, Nilsson B, Cirilli C, Braconi C: Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. The lancet oncology 2012, 13:265-74. 11. Liang C, Rossi S, Dei Tos A, Foo W, Fletcher J: MicroGIST genomic aberrations highlight early mechanisms in GIST pathogenesis. LABORATORY INVESTIGATION: NATURE PUBLISHING GROUP 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA, 2010. pp. 23A-A. 12. Schaefer I-M, Wang Y, Liang C-w, Bahri N, Quattrone A, Doyle L, Mariño-Enríquez A, Lauria A, Zhu M, Debiec-Rychter M: MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. Nature communications 2017, 8:1-6. 13. Astolfi A, Nannini M, Pantaleo MA, Di Battista M, Heinrich MC, Santini D, Catena F, Corless CL, Maleddu A, Saponara M: A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number. Laboratory investigation 2010, 90:1285-94. 14. Belinsky MG, Skorobogatko YV, Rink L, Pei J, Cai KQ, Vanderveer LA, Riddell D, Merkel E, Tarn C, Eisenberg BL: High density DNA array analysis reveals distinct genomic profiles in a subset of gastrointestinal stromal tumors. Genes, Chromosomes and Cancer 2009, 48:886-96. 15. Ässämäki R, Sarlomo‐Rikala M, Lopez‐Guerrero JA, Lasota J, Andersson LC, Llombart‐Bosch A, Miettinen M, Knuutila S: Array comparative genomic hybridization analysis of chromosomal imbalances and their target genes in gastrointestinal stromal tumors. Genes, Chromosomes and Cancer 2007, 46:564-76. 16. Gunawan B, Bergmann F, Höer J, Langer C, Schumpelick V, Becker H, Füzesi L: Biological and clinical significance of cytogenetic abnormalities in low-risk and high-risk gastrointestinal stromal tumors. Human pathology 2002, 33:316-21. 17. Sabah M, Cummins R, Leader M, Kay E: Altered expression of cell cycle regulatory proteins in gastrointestinal stromal tumors: markers with potential prognostic implications. Human pathology 2006, 37:648-55. 18. Wang Y, Marino-Enriquez A, Bennett RR, Zhu M, Shen Y, Eilers G, Lee J-C, Henze J, Fletcher BS, Gu Z: Dystrophin is a tumor suppressor in human cancers with myogenic programs. Nature genetics 2014, 46:601-6. 19. Serrano C, Wang Y, Mariño-Enríquez A, Lee J-C, Ravegnini G, Morgan JA, Bertagnolli MM, Beadling C, Demetri GD, Corless CL: KRAS and KIT gatekeeper mutations confer polyclonal primary imatinib resistance in GI stromal tumors: relevance of concomitant phosphatidylinositol 3-kinase/AKT dysregulation. Journal of clinical oncology 2015, 33:e93. 20. Parkkila S, Lasota J, Fletcher JA, Ou W-b, Kivelä AJ, Nuorva K, Parkkila A-K, Ollikainen J, Sly WS, Waheed A: Carbonic anhydrase II. A novel biomarker for gastrointestinal stromal tumors. Modern Pathology 2010, 23:743-50. 21. Gill AJ, Chou A, Vilain R, Clarkson A, Lui M, Jin R, Tobias V, Samra J, Goldstein D, Smith C: Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types. The American journal of surgical pathology 2010, 34:636-44. 22. Van Beers E, Joosse S, Ligtenberg M, Fles R, Hogervorst F, Verhoef S, Nederlof P: A multiplex PCR predictor for aCGH success of FFPE samples. British journal of cancer 2006, 94:333-7. 23. Michalik S, Williams C: Qualitative multiplex PCR assay for assessing DNA quality from FFPE tissues and other sources of damaged DNA. Life Sci 2008, 23. 24. Nasri S, Anjomshoaa A, Song S, Guilford P, McNoe L, Black M, Phillips V, Reeve A, Humar B: Oligonucleotide array outperforms SNP array on formalin-fixed paraffin-embedded clinical samples. Cancer genetics and cytogenetics 2010, 198:1-6. 25. Liegl B, Kepten I, Le C, Zhu M, Demetri G, Heinrich M, Fletcher C, Corless C, Fletcher J: Heterogeneity of kinase inhibitor resistance mechanisms in GIST. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland 2008, 216:64-74. 26. Liau J-Y, Lee J-C, Tsai J-H, Yang C-Y, Liu T-L, Ke Z-L, Hsu H-H, Jeng Y-M: Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas. Modern Pathology 2015, 28:1545-54. 27. Nagy PL, Price DH: Formaldehyde‐assisted isolation of regulatory elements. Wiley Interdisciplinary Reviews: Systems Biology and Medicine 2009, 1:400-6. 28. Giresi PG, Kim J, McDaniell RM, Iyer VR, Lieb JD: FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements) isolates active regulatory elements from human chromatin. Genome research 2007, 17:877-85. 29. Simon JM, Giresi PG, Davis IJ, Lieb JD: Using formaldehyde-assisted isolation of regulatory elements (FAIRE) to isolate active regulatory DNA. Nature protocols 2012, 7:256-67. 30. Roy A, Kucukural A, Zhang Y: I-TASSER: a unified platform for automated protein structure and function prediction. Nature protocols 2010, 5:725-38. 31. Henke RT, Kim SE, Maitra A, Paik S, Wellstein A: Expression analysis of mRNA in formalin-fixed, paraffin-embedded archival tissues by mRNA in situ hybridization. Methods 2006, 38:253-62. 32. Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM: Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Proceedings of the National Academy of Sciences 2004, 101:9309-14. 33. Brumbaugh CD, Kim HJ, Giovacchini M, Pourmand N: NanoStriDE: normalization and differential expression analysis of NanoString nCounter data. BMC bioinformatics 2011, 12:1-4. 34. Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R, Hibbard MK, Chen C-J, Xiao S, Tuveson DA: KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer research 2001, 61:8118-21. 35. Lee C-H, Liang C-w, Espinosa I: The utility of discovered on gastrointestinal stromal tumor 1 (DOG1) antibody in surgical pathology—the GIST of it. Advances in anatomic pathology 2010, 17:222-32. 36. Ou W, Zhu M, Demetri GD, Fletcher CD, Fletcher JA: Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors. Oncogene 2008, 27:5624-34. 37. Chi P, Chen Y, Zhang L, Guo X, Wongvipat J, Shamu T, Fletcher JA, Dewell S, Maki RG, Zheng D: ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature 2010, 467:849-53. 38. Gromova P, Ralea S, Lefort A, Libert F, Rubin BP, Erneux C, Vanderwinden JM: Kit K641E oncogene up‐regulates Sprouty homolog 4 and Trophoblast glycoprotein in interstitial cells of Cajal in a murine model of gastrointestinal stromal tumours. Journal of cellular and molecular medicine 2009, 13:1536-48. 39. Steigen SE, Schaeffer DF, West RB, Nielsen TO: Expression of insulin-like growth factor 2 in mesenchymal neoplasms. Modern Pathology 2009, 22:914-21. 40. Arne G, Kristiansson E, Nerman O, Kindblom LG, Ahlman H, Nilsson B, Nilsson O: Expression profiling of GIST: CD133 is associated with KIT exon 11 mutations, gastric location and poor prognosis. International journal of cancer 2011, 129:1149-61. 41. Yamaguchi U, Nakayama R, Honda K, Ichikawa H, Hasegawa T, Shitashige M, Ono M, Shoji A, Sakuma T, Kuwabara H: Distinct gene expression–defined classes of gastrointestinal stromal tumor. Journal of Clinical Oncology 2008, 26:4100-8. 42. West RB, Corless CL, Chen X, Rubin BP, Subramanian S, Montgomery K, Zhu S, Ball CA, Nielsen TO, Patel R: The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. The American journal of pathology 2004, 165:107-13. 43. Schroeder BC, Cheng T, Jan YN, Jan LY: Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell 2008, 134:1019-29. 44. Kang HJ, Nam SW, Kim H, Rhee H, Kim N-G, Kim H, Hyung WJ, Noh SH, Kim J-H, Yun C-O: Correlation of KIT and platelet-derived growth factor receptor α mutations with gene activation and expression profiles in gastrointestinal stromal tumors. Oncogene 2005, 24:1066-74. 45. Subramanian S, West RB, Corless CL, Ou W, Rubin BP, Chu K-M, Leung SY, Yuen ST, Zhu S, Hernandez-Boussard T: Gastrointestinal stromal tumors (GISTs) with KIT and PDGFRA mutations have distinct gene expression profiles. Oncogene 2004, 23:7780-90. 46. Zhu M, Ou W, Fletcher C, Cohen P, Demetri G, Fletcher J: KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance. Oncogene 2007, 26:6386-95. 47. Berglund E, Akcakaya P, Berglund D, Karlsson F, Vukojević V, Lee L, Bogdanović D, Lui W-O, Larsson C, Zedenius J: Functional role of the Ca2+-activated Cl− channel DOG1/TMEM16A in gastrointestinal stromal tumor cells. Experimental cell research 2014, 326:315-25. 48. Simon S, Grabellus F, Ferrera L, Galietta L, Schwindenhammer B, Mühlenberg T, Taeger G, Eilers G, Treckmann J, Breitenbuecher F: DOG1 regulates growth and IGFBP5 in gastrointestinal stromal tumors. Cancer research 2013, 73:3661-70. 49. Lasota J, Miettinen M: Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology 2008, 53:245-66. 50. Antonescu CR, Sommer G, Sarran L, Tschernyavsky SJ, Riedel E, Woodruff JM, Robson M, Maki R, Brennan MF, Ladanyi M: Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors. Clinical Cancer Research 2003, 9:3329-37. 51. DeMatteo RP, Gold JS, Saran L, Gönen M, Liau KH, Maki RG, Singer S, Besmer P, Brennan MF, Antonescu CR: Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer: Interdisciplinary International Journal of the American Cancer Society 2008, 112:608-15. 52. Martín J, Poveda A, Llombart-Bosch A, Ramos R, López-Guerrero JA, Garcia del Muro J, Maurel J, Calabuig S, Gutierrez A, González de Sande JL: Deletions affecting codons 557-558 of the c-KIT gene indicate a poor prognosis in patients with completely resected gastrointestinal stromal tumors: a study by the Spanish Group for Sarcoma Research (GEIS). J Clin Oncol 2005, 23:6190-8. 53. Lasota J, Corless CL, Heinrich MC, Debiec-Rychter M, Sciot R, Wardelmann E, Merkelbach-Bruse S, Schildhaus H-U, Steigen SE, Stachura J: Clinicopathologic profile of gastrointestinal stromal tumors (GISTs) with primary KIT exon 13 or exon 17 mutations: a multicenter study on 54 cases. Modern pathology 2008, 21:476-84. 54. Lammie A, Drobnjak M, Gerald W, Saad A, Cote R, Cordon-Cardo C: Expression of c-kit and kit ligand proteins in normal human tissues. Journal of Histochemistry & Cytochemistry 1994, 42:1417-25. 55. Wu JJ, Rothman TP, Gershon MD: Development of the interstitial cell of Cajal: origin, kit dependence and neuronal and nonneuronal sources of kit ligand. Journal of neuroscience research 2000, 59:384-401. 56. Hollins F, Kaur D, Yang W, Cruse G, Saunders R, Sutcliffe A, Berger P, Ito A, Brightling CE, Bradding P: Human airway smooth muscle promotes human lung mast cell survival, proliferation, and constitutive activation: cooperative roles for CADM1, stem cell factor, and IL-6. The Journal of Immunology 2008, 181:2772-80. 57. Sarlomo-Rikala M, Miettinen M, Knuutila S, Andersson LC: DNA copy number losses in chromosome 14: an early change in gastrointestinal stromal tumors. Cancer research 1996, 56:3230-3 58. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA: Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Human pathology 2002, 33:484-95. 59. Sarlomo-Rikala M, Andersson LC, Knuutila S, Miettinen M: DNA sequence copy number changes in gastrointestinal stromal tumors: tumor progression and prognostic significance. Cancer research 2000, 60:3899-903. 60. Breiner JA, Meis-Kindblom J, Kindblom L-G, McComb E, Liu J, Nelson M, Bridge JA: Loss of 14q and 22q in gastrointestinal stromal tumors (pacemaker cell tumors). Cancer genetics and cytogenetics 2000, 120:111-6. 61. Meza-Zepeda LA, Kresse SH, Barragan-Polania AH, Bjerkehagen B, Ohnstad HO, Namløs HM, Wang J, Kristiansen BE, Myklebost O: Array comparative genomic hybridization reveals distinct DNA copy number differences between gastrointestinal stromal tumors and leiomyosarcomas. Cancer Research 2006, 66:8984-93. 62. Wozniak A, Sciot R, Guillou L, Pauwels P, Wasag B, Stul M, Vermeesch JR, Vandenberghe P, Limon J, Debiec‐Rychter M: Array CGH analysis in primary gastrointestinal stromal tumors: cytogenetic profile correlates with anatomic site and tumor aggressiveness, irrespective of mutational status. Genes, Chromosomes and Cancer 2007, 46:261-76. 63. Silva M, Veiga I, Ribeiro FR, Vieira J, Pinto C, Pinheiro M, Mesquita B, Santos C, Soares M, Dinis J: Chromosome copy number changes carry prognostic information independent of KIT/PDGFRA point mutations in gastrointestinal stromal tumors. BMC medicine 2010, 8:1-8. 64. Nagy PL, Cleary ML, Brown PO, Lieb JD: Genomewide demarcation of RNA polymerase II transcription units revealed by physical fractionation of chromatin. Proceedings of the National Academy of Sciences 2003, 100:6364-9. 65. Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi PG, Fogarty MP, Panhuis TM, Mieczkowski P, Secchi A, Bosco D: A map of open chromatin in human pancreatic islets. Nature genetics 2010, 42:255-9. 66. Antonescu CR, Viale A, Sarran L, Tschernyavsky SJ, Gonen M, Segal NH, Maki RG, Socci ND, DeMatteo RP, Besmer P: Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site. Clinical Cancer Research 2004, 10:3282-90. 67. Nielsen TO, West RB, Linn SC, Alter O, Knowling MA, O'Connell JX, Zhu S, Fero M, Sherlock G, Pollack JR: Molecular characterisation of soft tissue tumours: a gene expression study. The Lancet 2002, 359:1301-7. 68. Janeway KA, Kim SY, Lodish M, Nosé V, Rustin P, Gaal J, Dahia PL, Liegl B, Ball ER, Raygada M: Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proceedings of the National Academy of Sciences 2011, 108:314-8. 69. Agaimy A, Haller F, Gunawan B, Wünsch PH, Füzesi L: Distinct biphasic histomorphological pattern in gastrointestinal stromal tumours (GISTs) with common primary mutations but divergent molecular cytogenetic progression. Histopathology 2009, 54:295-302. 70. Huang H-Y, Huang W-W, Lin C-N, Eng H-L, Li S-H, Li C-F, Lu D, Yu S-C, Hsiung C-Y: Immunohistochemical expression of p16INK4A, Ki-67, and Mcm2 proteins in gastrointestinal stromal tumors: prognostic implications and correlations with risk stratification of NIH consensus criteria. Annals of surgical oncology 2006, 13:1633-44. 71. Okamoto Y, Sawaki A, Ito S, Nishida T, Takahashi T, Toyota M, Suzuki H, Shinomura Y, Takeuchi I, Shinjo K: Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour. Gut 2012, 61:392-401. 72. Takeshima H, Wakabayashi M, Hattori N, Yamashita S, Ushijima T: Identification of coexistence of DNA methylation and H3K27me3 specifically in cancer cells as a promising target for epigenetic therapy. Carcinogenesis 2015, 36:192-201. 73. Ghoshal A, Ghosh SS: Expression, purification, and therapeutic implications of recombinant sFRP1. Applied biochemistry and biotechnology 2015, 175:2087-103. 74. Heinrich MC, Patterson J, Beadling C, Wang Y, Debiec-Rychter M, Dewaele B, Corless CL, Duensing A, Raut CP, Rubin B: Genomic aberrations in cell cycle genes predict progression of KIT-mutant gastrointestinal stromal tumors (GISTs). Clinical sarcoma research 2019, 9:1-15. 75. Indio V, Astolfi A, Tarantino G, Urbini M, Patterson J, Nannini M, Saponara M, Gatto L, Santini D, Do Valle IF: Integrated molecular characterization of gastrointestinal stromal tumors (GIST) harboring the rare D842V mutation in PDGFRA gene. International journal of molecular sciences 2018, 19:732. 76. Saponara M, Urbini M, Astolfi A, Indio V, Ercolani G, Del Gaudio M, Santini D, Pirini MG, Fiorentino M, Nannini M: Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRα genotype evaluated by next generation sequencing (NGS). Oncotarget 2015, 6:42243. 77. Ou W-B, Ni N, Zuo R, Zhuang W, Zhu M, Kyriazoglou A, Wu D, Eilers G, Demetri GD, Qiu H: Cyclin D1 is a mediator of gastrointestinal stromal tumor KIT-independence. Oncogene 2019, 38:6615-29. 78. Meng Y, Wang Q-G, Wang J-X, Zhu S-t, Jiao Y, Li P, Zhang S-t: Epigenetic inactivation of the SFRP1 gene in esophageal squamous cell carcinoma. Digestive diseases and sciences 2011, 56:3195-203. 79. Nojima M, Suzuki H, Toyota M, Watanabe Y, Maruyama R, Sasaki S, Sasaki Y, Mita H, Nishikawa N, Yamaguchi K: Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer. Oncogene 2007, 26:4699-713. 80. Kinoshita T, Nomoto S, Kodera Y, Koike M, Fujiwara M, Nakao A: Decreased expression and aberrant hypermethylation of the SFRP genes in human gastric cancer. Hepato-gastroenterology 2011, 58:1051-6. 81. Davaadorj M, Imura S, Saito Y, Morine Y, Ikemoto T, Yamada S, Takasu C, Hiroki T, Yoshikawa M, Shimada M: Loss of SFRP1 expression is associated with poor prognosis in hepatocellular carcinoma. Anticancer research 2016, 36:659-64. 82. Wang Z, Li R, He Y, Huang S: Effects of secreted frizzled-related protein 1 on proliferation, migration, invasion, and apoptosis of colorectal cancer cells. Cancer Cell International 2018, 18:1-10. 83. Wang Z, Ye Y, Liu D, Yang X, Wang F: Hypermethylation of multiple Wnt antagonist genes in gastric neoplasia: Is H pylori infection blasting fuse? Medicine 2018, 97. 84. Igarashi S, Suzuki H, Niinuma T, Shimizu H, Nojima M, Iwaki H, Nobuoka T, Nishida T, Miyazaki Y, Takamaru H: A novel correlation between LINE-1 hypomethylation and the malignancy of gastrointestinal stromal tumors. Clinical Cancer Research 2010, 16:5114-23. 85. Liu X, Fu J, Bi H, Ge A, Xia T, Liu Y, Sun H, Li D, Zhao Y: DNA methylation of SFRP1, SFRP2, and WIF1 and prognosis of postoperative colorectal cancer patients. BMC cancer 2019, 19:1-14. 86. Feng Q, Stern JE, Hawes SE, Lu H, Jiang M, Kiviat NB: DNA methylation changes in normal liver tissues and hepatocellular carcinoma with different viral infection. Experimental and molecular pathology 2010, 88:287-92. 87. Fukui T, Kondo M, Ito G, Maeda O, Sato N, Yoshioka H, Yokoi K, Ueda Y, Shimokata K, Sekido Y: Transcriptional silencing of secreted frizzled related protein 1 (SFRP1) by promoter hypermethylation in non-small-cell lung cancer. Oncogene 2005, 24:6323-7. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/84355 | - |
dc.description.abstract | 腸胃道間質腫瘤(gastrointestinal stromal tumor, GIST)是腸胃道最常見的惡性非上皮性軟組織間質腫瘤,年發生率約介於每百萬人口6.5~14.5之間。但小於一公分之微小腸胃道間質腫瘤(microGIST)在一般成年人口的盛行率卻可達20~30%。這些須微觀才能發現之微小腫瘤,似乎是臨床可見腫瘤(大於一公分)之前驅病灶,故其可作為研究這類腫瘤之早期發生、演進及退化的良好模型。大部分的microGISTs,無法進一步生長至臨床可見的腫瘤而退化了。此研究利用回溯性案件搜尋找出了43例的microGISTs,證明了這些微小腫瘤無論在形態上、關鍵基因的突變上、基因的表現型、及蛋白質表現的模式上,均是與臨床可見的案例處在同一個光譜上。他們雖有著一樣促發腫瘤生成的KIT及PDGFRA特定基因的突變,但這也顯示了這些突變本身,並非腫瘤演進侵襲的主因。相同的,在臨床腫瘤演進中所發現的染色體變化,例如14q缺失、22q缺失、15q缺失、及1p缺失,一樣可以在microGISTs中發現,代表這些變化,雖然為腫瘤演進所必須,但單獨這些變化,並不足以使得GIST惡性轉變。經過全基因體複製的技術,也發現在臨床腫瘤內關鍵表現的生物標記,其基因諸如KIT、ANO1、PRKCQ、ETV1、SPRY4及PROM1,在microGISTs內也一樣被活躍的轉譯中。藉由突變功能性測試、免疫螢光染色、及mRNA原位雜交法,發現在microGISTs中發生了比例較高之特定KIT突變型,其產生之異常KIT接受體(KIT receptor)對於KIT配位基(KIT ligand)的敏感度較高,而這些KIT配位基主要是由腸胃道之平滑肌壁細胞所分泌。故當腫瘤成長之大小超過周邊平滑肌可供應配位基的範圍時,其下游的AKT/S6路徑將會被抑制不再活化,進一步導致了腫瘤的退化。 接下來,計畫繼續探討若腫瘤獲得了繼續演進生長的能力,那麼其高惡性度轉變的關鍵步驟為何。研究中發現有少量具有雙相特徵的GISTs (biphasic GISTs),即在同一個腫瘤中具有相鄰的低惡性度區域及高惡性度區域,代表腫瘤剛好在高度惡性轉變期間被手術所擷取。計畫執行期間總共回溯性搜尋了263例GISTs,並從其間找出了19例的雙相腫瘤。研究亦另外涵蓋了82例橫跨各惡性度的一般GISTs做為比對之用。在進行了基因突變、螢光原位雜交(fluorescence in situ hybridization, FISH)、NanoString基因數平台、端粒酶(telomere)、及基因表現量之分析後,進一步使用資料庫分析(in silico)、細胞株、及免疫化學染色來做進一步的確認。在基因表現量的分析上,發現SFRP1之調降為GIST高惡性度轉變的關鍵步驟(p = 0.013)。此現象亦伴隨著EZH2之調升。分析已被釋出的腫瘤資料庫內的案例,發現在不同的系列中,SFRP1之調降是一個可以被普遍驗證的事項。利用免疫組織化學染色做再驗證,發現SFRP1蛋白的表現量,在高惡性度的GISTs中(WHO風險分群3a級或以上),有明顯降低的現象(p < 0.001)。而SFRP1蛋白表現的減弱或喪失,正比於GIST演進之惡性度。利用NanoString基因數平台及FISH進行分析,發現在雙相腫瘤中,染色體9及9p的缺失,是在腫瘤高惡性度轉變中,唯一有被發現反覆出現的事件,而且此缺失現象,亦與SFRP1之調降相關。另在螢光檢查中,可在雙相腫瘤中之低惡性度區發現有染色體9及9p缺失的次族群(subclones)。TP53基因突變、RB1基因缺失、KIT/PDGFRA基因突變、及端粒酶之替代性延展(alternative lengthening),則沒有發現與腫瘤高惡性度轉變有重要的相關。總結上,SFRP1的調降及染色體9/9p之缺失,為GIST高惡性度轉變的關鍵步驟。 | zh_TW |
dc.description.abstract | Gastrointestinal stromal tumor (GIST) is the most common malignant mesenchymal tumor in the gastrointestinal tract with an annual incidence rate ranging from 6.5 to 14.5 per million, and benign microGISTs (less than 1 cm in diameter) are found in 20-30% of the general adult population. These microGISTs seem to be precursor lesions of clinical GISTs and are therefore compelling models in which to characterize early transforming, progressing, and involuting mechanisms. Most of the microGISTs involute and fail to progress. Herein, we collected 43 microGISTs by retrospective archive screening and demonstrated that they were on a biological spectrum with clinical GISTs, as judged by morphologic considerations, key oncogenic mutations, gene expression profiles, and protein expression patterns. One subset KIT and PDGFRA mutations, as initiating events shared by clinical and microGISTs, per se are not, in and of themselves, biological mechanisms of aggressive behavior, and cytogenetic aberrations, such as 14q loss, 22q loss, 15q loss and 1p loss revealed by array comparative genome hybridization in microGISTs, are necessary, but not sufficient, in genetic progression towards GIST malignancy. By whole-genome amplification, we detected crucial GIST biomarkers (e.g., KIT, ANO1, PRKCQ, ETV1, SPRY4 and PROM1) being actively transcribed in microGISTs, representing early events. By construct mutagenesis functional test, immunofluorescence and mRNA in situ hybridization, we also demonstrated that a subset of microGISTs carrying certain types of mutations that could sensitize KIT receptor to KIT-ligand stimulation from smooth muscle cells, which supported early microGIST development. In involution, microGIST cells outstrip available KIT-ligand with resultant inhibition of AKT/S6 pathways. The mechanism of high-grade transformation in GIST then remains to be clarified. We aim to discover the key progression events by studying biphasic GISTs. The study group included 101 GISTs. Nineteen of these had been screened from 263 GISTs to represent the early stage of GIST high-grade transformation, characterized by juxtaposed low-grade and high-grade regions in the same tumor (so-called biphasic GISTs). Mutational analyses, fluorescence in situ hybridization (FISH), NanoString analyses, telomere analysis and gene expression profiling were done, followed by in silico analyses, cell line study, and immunohistochemical validation. Utilizing gene expression analysis, downregulation of SFRP1 was revealed to be the main event in GIST high-grade transformation (p = 0.013), accompanied by upregulation of EZH2. In silico analyses revealed that downregulation of SFRP1 was a common feature in GIST progression across several different series. Immunohistochemically, the expression of SFRP1 was validated to be significantly lower in high-grade GISTs (WHO risk group 3a or higher) than in lower-grade GISTs (p < 0.001), and attenuation/loss of SFRP1 was associated with GIST tumor progression (p < 0.001). By NanoString and FISH analyses, chromosomal 9/9p loss was the only recurrent large-scale chromosome aberration in biphasic GISTs, with a correlation with SFRP1 downregulation. Subclones containing chromosome 9/9p loss could be appreciated in the low-grade parts of biphasic GISTs. TP53 mutation, RB1 loss, KIT/PDGFRA mutation and alternative lengthening of telomeres did not play a significant role in GIST high-grade transformation. In conclusion, high-grade transformation of GISTs features SFRP1 downregulation and chromosome 9/9p loss. | en |
dc.description.provenance | Made available in DSpace on 2023-03-19T22:09:17Z (GMT). No. of bitstreams: 1 U0001-1205202217161400.pdf: 10775303 bytes, checksum: ddeabaca7a114b4257df84cfe6bd211c (MD5) Previous issue date: 2022 | en |
dc.description.tableofcontents | 論文口試委員審定書………………………………………………………………. I 誌謝…………………………………………………………………………………. II 中文摘要……………………………………………………………………………. III 英文摘要……………………………………………………………………………. V Chapter 1 Introduction…..……………………………………………………… 1 Chapter 2 Materials and Methods………………..…………………………….. 5 2.1 Tumor collection and morphology analysis…………………….. 5 2.2 Immunohistochemistry (IHC)…………………………………... 6 2.3 DNA extraction and whole genome amplification (WGA)...…... 8 2.4 Mutational analysis, confirmation and subcloning...…………… 10 2.5 Array comparative genomic hybridization (aCGH)….………… 11 2.6 Fluorescence in situ hybridization (FISH)………..…………….. 12 2.7 Detection of actively transcribed genomic regions…..…….…… 13 2.8 Functional tests and protein structural analysis………...…….… 14 2.9 Immunofluorescence (IF)………………………………….…… 16 2.10 Messenger RNA (mRNA) in situ hybridization (ISH)…..….… 16 2.11 Large-scale genetic aberrations and gene expression profiling.. 16 Chapter 3 Results………………………………………………………………... 20 3.1 Clinicopathological features of microGISTs and biphasic GISTs 20 3.2 Mutational analyses of microGISTs revealed distinct mutational patterns and novel mutations…………………………………… 21 3.3 MicroGISTs revealed similar large scale chromosomal changes and gene expression profiles to clinical GISTs……………….... 23 3.4 MicroGISTs interacted with nearby stromal environment…...… 24 3.5 Chromosomal 9/9p loss was the only frequently recurrent event in high-grade transformation of biphasic GISTs……………...... 25 3.6 Downregulation of SFRP1 expression was a key progression factor revealed by gene expression profiling (GEO GSE75479) and a common event in GIST progression across different series………………………………………………..…………… 26 3.7 Validation of SFRP1 and p16 expression by immunohisto- chemistry…………………………………..………………….… 27 Chapter 4 Discussion…………………………………………………………….. 29 4.1 The microGISTs……………….………………………………... 29 4.1.1 MicroGISTs share morphologic and IHC features with clinical GISTs but the cytomorphology cannot predict tumor involution…………………………………………… 30 4.1.2 MicroGISTs show similar but distinct mutational pattern compared with clinical GISTs…………………………...… 34 4.1.3 Nursing effect of SCF plays a role in early GIST tumorigenesis……………………………………………… 37 4.1.4 MicroGISTs share with clinical GISTs similar large scale chromosomal aberrations and gene expression……………. 39 4.1.5 WT microGISTs…………………………………………… 41 4.2 The biphasic GISTs………….…………………………………. 42 4.2.1 Chromosome 9/9p loss is the sole recurrent cytogenetic event in GIST high grade transformation………………….. 43 4.2.2 SFRP downregulation is a key factor in GIST high grade transformation………………………………..……………. 45 Chapter 5 Conclusion…..……………………………………………………….. 48 References ………………..……………………………………………………….. 49 Figure 1 An illustration of the project concept…………………….……….….. 62 Figure 2 Quality control of WGA reactions………………………….………... 63 Figure 3 Morphological patterns of microGISTs……………………………… 64 Figure 4 Immunohistochemistry of microGISTs………………………………. 65 Figure 5 The relationship of microGIST cells and smooth muscle cells………. 66 Figure 6 PI3K survival pathway markers in microGISTs………….………….. 67 Figure 7 SDHB immunostaining in microGISTs……………………………… 68 Figure 8 Morphological features of biphasic GISTs………..…………………. 69 Figure 9 Mutational analyses of microGISTs………………………………….. 70 Figure 10 Functional tests of novel mutations in microGISTs………………….. 72 Figure 11 Protein structure analyses of novel mutation in microGISTs..………. 73 Figure 12 Large scale chromosomal changes of microGISTs….………………. 74 Figure 13 Large scale chromosomal changes analyzed by FISH in different regions in the same microGIST……………………….……………... 75 Figure 14 Actively transcribed genomic regions detected by Agilent SurePrint G3 Microarray Human Custom 2x415K array analysis…………….... 76 Figure 15 Spatial relationship between microGIST cells and adjacent smooth muscle cells…………………………………………………………... 77 Figure 16 MicroGISTs interacted with nearby stromal environment…………... 78 Figure 17 MicroGIST cells, smooth muscle cells and SCF……………………... 79 Figure 18 The pattern of SCF secretion revealed by mRNA ISH…………..…... 80 Figure 19 Large-scale chromosomal variations in biphasic GISTs by NanoString nCounterTM analysis………………….………………... 81 Figure 20 Platform adequacy evaluation: comparison between different GEP platforms by gene rank tests………………………………………..... 82 Figure 21 Gene expression profiles in biphasic GISTs………………….……... 83 Figure 22 By gene expression profiles, in silico analyses of online datasets revealed that downregulation of SFRP1 expression………………..... 85 Figure 23 Transcription level of SFRP1 in archived samples and cell lines…..... 86 Figure 24 Validation of SFRP1 expression in biphasic GISTs by immunohisto- chemistry……………………………………..…………………..…... 87 Figure 25 Trend analysis of SFRP1 expression in additional conventional GIST samples……………………………………………………………..... 89 Figure 26 Summary of progression events in GISTs…………………….……... 90 Table 1 Antibodies used in immunohistochemistry (IHC)……………...……….. 91 Table 2 Sequencing primers for KIT and PDGFRA genes…………………….... 92 Table 3 Functional mutation prediction of novel microGIST point mutations.…. 93 Table 4 Clinical and pathological data of the biphasic GISTs…………………… 94 Table 5 Mitotic counts, Ki-67 proliferative indices and large-scale chromosomal aberrations in biphasic GISTs…………………………………………… 96 Table 6 Immunohistochemistry (IHC) of SFRP1, p16, MAX and ATRX in biphasic GISTs………………………………………………………...… 97 Table 7 Comparison of upregulated genes in clinical GISTs (by gene expression profiling) and microGISTs (by pseudoamplified genes)………………… 98 Table 8 Immunohistochemical expression of p16 in cases with and without 9/9p loss in biphasic GISTs…………………………………………………… 99 | |
dc.language.iso | en | |
dc.title | 腸胃道間質腫瘤之致病機轉: 從早期發展至高惡性度轉變 | zh_TW |
dc.title | Pathogenesis Of Gastrointestinal Stromal Tumors: From Early Development To High-Grade Transformation | en |
dc.type | Thesis | |
dc.date.schoolyear | 110-2 | |
dc.description.degree | 博士 | |
dc.contributor.author-orcid | 0000-0001-8903-6082 | |
dc.contributor.oralexamcommittee | 吳振都(Chen-Tu Wu),成佳憲(Chia-Hsien Cheng),郭冠廷(Kuan-Ting Kuo),謝明書(Min-Shu Hsieh) | |
dc.subject.keyword | 腸胃道間質腫瘤(GIST),微小腸胃道間質腫瘤(microGISTs),KIT,PDGFRA,全基因體複製,SFRP1,染色體9/9p, | zh_TW |
dc.subject.keyword | gastrointestinal stromal tumor (GIST),microscopic GISTs (microGISTs),KIT,PDGFRA,whole-genome amplification,SFRP1,chromosome 9/9p, | en |
dc.relation.page | 99 | |
dc.identifier.doi | 10.6342/NTU202200766 | |
dc.rights.note | 同意授權(限校園內公開) | |
dc.date.accepted | 2022-05-13 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 病理學研究所 | zh_TW |
dc.date.embargo-lift | 2022-06-14 | - |
顯示於系所單位: | 病理學科所 |
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