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研究生:李俊良
研究生(外文):Chun-Liang Li
論文名稱:甲狀腺乳突癌檢體中NTRK1基因重組及BRAF基因突變之分析
論文名稱(外文):Analysis of NTRK1 gene rearrangement and BRAF gene mutation in papillary thyroid carcinoma
指導教授:劉瑞川陳錦翠
指導教授(外文):Rue-Tsuan LiuJiin-Tsuey Cheng
學位類別:碩士
校院名稱:國立中山大學
系所名稱:生物科學系研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:50
中文關鍵詞:甲狀腺甲狀腺乳突癌
外文關鍵詞:5''raceBRAFNTRK1PTCthyroid
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甲狀腺乳突癌(PTC)形成與某些基因的突變與功能活化有密切的關係,其中包括會將基因轉譯成酪氨酸激酶受器(tyrosine kinase receptor)的RET及NTRK1致癌基因,另外還有RAS及BRAF基因。RET及NTRK1原致癌基因會轉譯成一個跨膜的酪氨酸激酶受器。神經生長因子會透過與NTRK1及RET受器結合而產生作用。在有些甲狀腺癌症檢體中,可發現有DNA重組現象而造成NTRK1及RET 5’端的部分被其他基因的調節區所取代了,而造成酪氨酸激酶持續活化,形成致癌基因。NTRK1致癌基因有4種重組型,是由至少三種基因分別與TRK酪氨酸激酶簇(tyrosine kinase domain)相結合所造成的結果,此三種基因分別為TPM3、TPR及TFG。本論文研究結果發現有一個檢體有NTRK1酪氨酸激酶簇(TK)之表現,但是卻不屬於過去文獻所報導之任一種NTRK1重組基因型。顯示這個檢體中可能有一個新的NTRK1重組基因型存在,因此,利用5'' RACE 的方法,以NTRK1特異性引子進行其5''端未知的序列之增幅選殖,得知此檢體的酪氨酸激酶簇的5''端有剪接異常的現象,造成帶有第9個intron之不正常轉錄產物。此外,在此檢體中我們也發現到因為異常剪接而缺少exon 9的NTRK1的野生型,稱做TRKAⅠ。研究結果顯示,利用TK區特異性引子去判斷在PTC檢體中是否有NTRK1異常轉錄產物存在,似乎是一個有效且可信的方法。
BRAF蛋白絲胺酸/蘇鞍酸激酶(serine/threonine kinase)基因的突變最近在人類的腫瘤中被廣泛的研究,特別是在黑色素瘤及甲狀腺乳突癌(PTC)中,而在良性及惡性甲狀腺腫瘤中,BRAF V599E的突變只發生在甲狀腺乳突癌(PTC)檢體中。本研究分析在甲狀腺腫瘤中BRAF的突變,並搭配之前我們在RAS,RET重組基因型及NTRK1重組基因型的研究,以期能對RAS/RAF/MEK/MAPK 訊息傳遞途徑相關基因的異常表現能有更進一步的了解。在105例的甲狀腺乳突癌的檢體中,發現有49例有 BRAF V599E 的突變存在(約47%),但在其他的甲狀腺腫瘤中,並沒有發現到有此突變的存在。另外,在我們的甲狀腺乳突癌(PTC)檢體中,RET重組基因、NTRK1重組基因與BRAF突變,彼此之間並不會有重疊出現的現象。此外,在我們101例甲狀腺乳突癌(PTC)檢體中,BRAF突變與病理症狀分析之間,包括年齡、性別、腫瘤大小、頸部淋巴結轉移、甲狀腺外擴散、遠端轉移以及癌症分期上,並沒有統計上的相關性存在。總而言之,在甲狀腺腫瘤中BRAF突變對甲狀腺乳突癌有高度的專一性,與文獻是相符合的;本研究亦顯示BRAF突變在台灣甲狀腺乳突癌中是突變率最高的致癌基因。
Activating mutations of genes coding for two different tyrosine kinase receptor, either RET or NTRK1 (also named TRKA), as well as of RAS or BRAF gene are associated with human thyroid papillary carcinoma (PTC). RET or NTRK1 protooncogene encodes a cell-surface transmembrane tyrosine kinase receptor with nerve growth factor as its lignand. Oncogenic potential of these two genes in thyrocytes results from replacement of their 5'' portion by regulatory parts of other genes, leading to constitutive activation of their tyrosine kinase activity. The four reported oncogenic rearrangements of NTRK1 (TRK) are the consequences of fusion of its tyrosine kinase domain with one of the three genes (TPM3 gene, TPR gene, TFG gene). In our previous study, a PTC sample was found to express the NTRK1 tyrosine kinase domain without harboring NTRK1 rearrangement. We, therefore, assumed that there might have a novel NTRK1 rearrangement in this sample. 5’RACE strategy was employed to clone the unknown 5’end. Sequence of the cloned DNA fragment demonstrated that it is an aberrant transcription product containing an unspliced intron 9. In addition, the variant of NTRK1 wild type termed TRKAⅠ, which lacks exon 9, was also detected in this particular specimen. We conclude that amplification of TK domain of NTRK1 may serve as a rapid screening method for the presence of NTRK1-related transcript in PTCs.
Mutations of the BRAF protein serine/threonine kinase gene have recently been identified in a variety of human cancers, especially in melanoma and papillary thyroid carcinomas. Among benign and malignant thyroid tumors, BRAF V599E mutations were reported to be restricted to papillary carcinomas. In this study, we analyzed mutations of BRAF in conjunction with our previous studies on RAS, RET rearrangement and NTRK1 rearrangement in PTCs to investigate genetic alterations in the RAS/RAF/MEK/MAPK kinase pathway. BRAF V599E mutations were detected in 49 of 105 (47%) PTCs but not in other type of thyroid tumor. There was no overlap between papillary carcinomas harboring RET rearrangement, NTRK1 rearrangement and BRAF mutations. Correlation between BRAF mutations and various clinicopathological parameters in 101 papillary carcinomas did not reveal any association with age, sex, tumor size, cervical lymph node metastasis, extrathyroidal extension, distant metastases and clinical stage. We conclude that BRAF mutations are restricted to papillary carcinomas in thyroid tumor. The overall frequencies in our study are in line with data previously reported. In Taiwan, BRAF mutation is the most prevalent oncogene in papillary thyroid carcinomas so far identified.
中文摘要 ………………………………………………………………2
英文摘要 ………………………………………………………………4
背景介紹 ………………………………………………………………6
材料與方法……………………………………………………………11
結果與討論……………………………………………………………20
參考資料………………………………………………………………26
圖表……………………………………………………………………32
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