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dc.contributor.authorHuang, Yi- Hsinen_US
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dc.description.abstract乳癌是一種由多重因子造成的疾病,根據研究發現大約有百分之五到百分之十的女性乳癌是來自遺傳,在這些家族性乳癌患者有五成是在四十歲以前就發生乳癌屬於早發性乳癌。1990年Mary-Claire King 發現在17號染色體上確實有與乳癌密切關聯的基因存在,1994年於17號染色體上發現了BRCA1基因,1995年發現了第二各乳癌基因BRCA 2。其他遺傳性乳癌相關的基因有TP53、PTEN/MMAC等,但以BRCA1及BRCA2為最主要的影響因子。 BRCA2 有27 exons,其中以第11 exon 為最大的exon,BRCA2可經由exon 11 上的BRC repeat domain 直接和Rad51結合, 藉此控制RAD 51的聚合狀態,進行受損DNA的修補以達成維持DNA穩定的功能,所以推測exon 11的突變可能與乳癌形成有關。因此為了探討BRCA2 exon 11 在母犬乳腺腫瘤中是否有核苷酸的突變的情況,實驗組的樣本是由國立中興大學獸醫教學醫院診斷為犬乳腺腫瘤並以外科切除下來的乳腺組織,以隨機取樣的方式挑選,而對照組則是挑選正常犬的乳腺組織。將四隻正常犬乳腺組織之BRCA2 exon 11核苷酸序列,和Bignel l997年所發表之犬BRCA2 exon11 mRNA序列 (GenBank number: Z75664) 及Ochiai等人2001年發表了犬BRCA2全長序列 (GenBank:AB043895) 比對,於2414位置發現核苷酸有變異 (G2414A) 。分別將乳腺腫瘤犬隻的BRCA2 exon 11全長共4521bp的核苷酸序列,與本實驗所定序出的正常犬隻BRCA2 exon 11進行序列比對分析,發現一共有19個single nucleotide polymorphisms ( SNPs )。在這些核苷酸變異中,以A511C及A2414G發生的比例最高為54.5 % (6/11) ,其餘SNP發生比例皆為9.1 % (1/11) ,屬於零星發生的變異。而究竟這些核苷酸變異是否會影響蛋白質的功能而導致腫瘤形成,或只是單純性非致病性的SNP,仍需要更多的研究去釐清。zh_TW
dc.description.abstractMammary gland tumors (MGT) are caused by a complex combination of genetic and environmental factors. Several genes are known to be involvid in human breast cancer. Mutated forms of BRCA1 and BRCA2 are found in 40% of families with histories of early onset breast cancer and ovarian cancer. BRCA2 plays an essential role in the repair of double-strand DNA breaks via BRC repeats in exon 11 to regulate the action of the RAD51 recombinase. Loss of RAD51 function would result in accumulation of DNA damage and thus would increase the risk of cancer. In the mouse model, the deletion of several BRC repeats has been shown to lead to cancer, but the role of BRCA2 in canine MGT carcinogenesis remains unclear . In this study, the nucleotide sequences of exon 11, the largest exon of BRCA2 gene, form several canine MGTs were analyzed. Samples, including 4 normal canine breast tissue samples and 11 MGT samples, were obtained from Veterinary Medicine Teaching Hospital of National Chung-Hsing University. Exon 11, consisting of 4521 base pairs, was amplified from genomic DNA isolated from mammary gland tissue by polymerase chain reaction, and the authenticity of resulting products was determined by DNA sequencing. We compared our sequences with published sequences from GenBank (accession No. Z75664) and (accession No. AB043895), and found one nucleotide variation G2414A (Arg805Lys) existing in all mammary gland samples we analyzed, form both normal and MGT specimens. Moreover, in MGT samples, 19 signal nucleotide polymorphisms (SNPs), widely distributed in BRCA2 exon 11, were found and silent mutations and missence mutations constituted 31.5 % and 68.5 % of those SNPs, respectively. Most interestingly, point mutations at nucleotide 511 and 2414 existed in 6 out of 11 samples (54.5 %), whereas other mutations were found in 1/11 (9.1 %) of MGT samples. Further studies are required for elucidating the significance of those mutations of BRCA2 exon 11 in canine MGT carcinogenesis.en_US
dc.description.tableofcontents中文摘要 i 英文摘要 ii 目次 iii 表目次 v 圖目次 vi 第一章 緒言 1 第二章 文獻探討 2 第一節 犬乳腺腫瘤之探討 2 一、犬乳腺腫瘤之流行病學 2 二、乳腺腫瘤之致病因素 3 三、犬乳腺腫瘤之組織病理學分類 5 四、犬乳腺腫瘤之臨床表現 5 五、犬乳腺腫瘤之分期 6 六、犬乳腺腫瘤之治療 6 七、犬乳腺腫瘤的預後因子 8 第二節 基因BRCA2 之探討 12 一、遺傳性乳癌基因之介紹 12 二、BRCA1 基因之簡介 12 三、BRCA2 基因之簡介 13 四、RAD 51基因之簡介 14 五、BRCA2 基因之功能 15 六、BRCA2 基因突變和乳腺腫瘤之相關性 15 七、BRCA2 基因於犬乳腺腫瘤之研究 18 第三節 研究目的 20 第三章 材料與方法 21 第一節 樣本的採樣 21 一、實驗樣本來源 21 二、犬正常乳腺與腫瘤組織之處理 21 三、組織切片製作 21 第二節 聚合酶連鎖反應 ( POLYMERASE CHAIN REACTION, PCR ) 23 一、DNA的萃取 23 二、特異性引子的設計 24 三、聚合酶連鎖反應之條件 (Polymerase chain reaction, PCR) 27 四、瓊酯凝膠電泳 (Agarose Gel Electrophoresis) 檢測PCR產物 28 五、限制酵素切割確定 29 第三節 PCR產物純化、接合與轉形 (transformation) 作用 30 一、PCR產物纯化 30 二、接合反應 (ligation) 30 三、勝任細胞 (competent cells) 的製備 30 四、轉型作用 ( transformation ) 31 五、含轉形基因菌體的篩檢 32 六、質體 DNA 的萃取 32 七、限制酵素切割確認質體DNA 33 八、核酸定序 33 第四章 結果 34 第一節 犬BRCA2基因 exon 11 PCR電泳分析 34 一、PCR產物轉殖至pGEM®-T easy vector 34 二、PCR增幅犬BRCA2 exon 11片段 36 第二節 正常犬之BRCA2 exon 11核苷酸及胺基酸序列分析 38 第三節 犬乳腺腫瘤BRCA2 exon 11核苷酸及胺基酸序列之分析 43 第五章 討論 46 參考文獻 50 附錄 57zh_TW
dc.subjectmammary tumorsen_US
dc.title乳癌基因BRCA 2第11外顯子在犬乳腺腫瘤 之核酸序列分析zh_TW
dc.titleThe Nucleic Acid Sequence Analysis of Breast Cancer Susceptibility Gene 2 Exon 11 in Canine Mammary Tumorsen_US
dc.typeThesis and Dissertationzh_TW
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