臺灣博碩士論文加值系統

因c-kit基因突變引起的KIT蛋白持續活化，在犬肥大細胞瘤 (mast cell tumors) 的腫瘤生成中扮演著重要角色。而帶有c-kit基因突變的犬肥大細胞瘤較容易對於酪胺酸激酶抑制劑 (tyrosine kinase inhibitors) 的治療有反應。本實驗目的為研究犬肥大細胞瘤c-kit基因的突變盛行率和它們的臨床相關性。本研究使用來自49隻肥大細胞瘤患犬的55個樣本。以聚合酶鏈鎖反應 (polymerase chain reaction) 增幅c-kit基因之第8，9，11 和17外顯子 (exon) 後，進行瓊脂糖凝膠電泳和自動定序。在55個犬肥大細胞瘤樣本發現10個突變 (18.2%)。在這些突變中， 4個突變 (7.2%) 位於第8外顯子，6個 (10.9%) 內部串聯重複突變 (internal tandem duplications, ITDs) 位於第11外顯子。並且發現同一隻患犬的原發位與局部轉移之區域淋巴結有相同的ITD (ITD 1711-1766)。第11外顯子內部串聯重複突變與改良式Patnaik高分級 (high grade) 顯著相關 (P=0.027)。再者，c-kit 基因突變與較短的總體存活時間 (overall survival time) 顯著相關 (P=0.05)。然而，分層分析與迴歸分析結果顯示總體存活時間與c-kit基因突變無關，僅與組織分級呈負相關。總結來說，總體存活時間與c-kit基因突變的顯著相關是來自同時存在組織分級這個干擾因子下所造成的高估。本研究在c-kit基因第8外顯子中發現了一個新的錯義突變(missense mutation) c.1274 C>T。此突變的活化情形與臨床相關性有待未來的研究繼續探討。

The c-kit mutations induced the constitutively activated KIT protein and played an important role in tumorigenesis of canine mast cell tumors (MCTs). The MCTs harboring c-kit mutation were more likely to respond to the treatment of tyrosine kinase inhibitors (TKIs). The aim of this study is to investigate the prevalence of c-kit mutation and their clinical significance in canine MCTs. Fifty-five specimens from 49 dogs were included in this study. Exons 8, 9, 11 and 17 of c-kit were amplified by polymerase chain reaction (PCR) followed by agarose gel electrophoresis and automated sequencing. Ten mutations were identified in the 55 canine MCT specimens (18.2%). Among these mutations, four (7.2%) mutations were located in exon 8, and 6 (10.9%) internal tandem duplications (ITDs) were located in exon 11. The concordance of the ITD1711-1766 from the primary lesion and locally metastatic lymph node was identified in one dog. The exon 11 ITDs were significant associated with modified Patnaik’s high grade (P= 0.027). The c-kit mutation was significantly associated with the shorter overall survival time (OST) (P=0.05). However, the results of stratification and regression analysis indicated that the OST was not associated with the c-kit mutation, but was negatively associated with the histologic grade. In conclusion, the significant association between the OST and the c-kit mutation was overestimated from the influence of the confounding factor, histologic grade. A novel missense mutation, c.1274 C>T was identified in the exon 8 of c-kit. Further studies were warrant to determine the activating status and clinical relevance of this mutation.

致謝 i
摘要 ii
Abstract iii
Contents iv
List of Tables vi
List of Figures vii
Chapter 1. Introduction 1
Chapter 2. Materials and Methods 6
2.1. Animals 6
2.2. Sample collection 10
2.3. Genomic DNA isolation 10
2.4. Measurement of the DNA concentration and DNA quality 11
2.5. Amplification of glyceraldehydes-3-phosphate dehydrogenase (GAPDH) 11
2.6. Amplification of c-kit exon 8, 9, 11 and exon 17 of canine MCTs 12
2.7. Cloning and transformation of the multiple-bands PCR product 15
2.8. Colony analysis 15
2.9. Sequencing of the c-kit exon 8, 9, 11 and exon 17 of canine MCTs 16
2.10. Statistical analysis 17
Chapter 3. Results 18
3.1. Patients 18
3.2. Amplification of GAPDH and c-kit exon 8,9,11 and 17 19
3.3. The c-kit mutation and polymorphism 22
3.4. The association between the mutation status and the clinicopathologic features 27
3.5. The clinical response to the treatment and survival data of the mutational cases 27
3.6. The association between c-kit mutation and grade 30
3.7. Survival analysis 32
Chapter 4. Discussion 38
References 47

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