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研究生:梁瑞瑩
研究生(外文):Soi Ieng Leong
論文名稱:分子檢測方法應用於乳癌的診斷和治療
論文名稱(外文):The molecular assays used in breast cancer diagnosis and treatment
指導教授:李瑤玲唐海誼唐海誼引用關係
指導教授(外文):YAO-LING LEE
口試委員:李慶孝
口試日期:2023-07-04
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:醫學檢驗暨生物技術學系
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2023
畢業學年度:111
語文別:中文
論文頁數:39
中文關鍵詞:乳癌生物標記標靶治療多基因平台
外文關鍵詞:Breast cancerBiomarkersTargeted therapyMulti-gene platforms
DOI:10.6834/csmu202300182
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乳癌好發於全球,其發生率已超過肺癌成為第一位。基於生活型態、飲食文化差異,遲婚和晚生育,開發中國家其乳癌發生率與已開發國家的差異縮少。乳癌的診斷和治療發展是科學界頭號重要項目,病理學上使用TMN分期,Nottingham grading system等系統使報告內容更精準描述病程;隨後發展出乳癌亞型,由Perou et al. (2000)首次利用cDNA微陣列分析 (cDNA microarrays)對基因組進行分析,結合乳癌的生物標記 (IHC4),被公認的四種亞型為Luminal A、Luminal B、Her2-enriched 和Triple-negative breast cancer (TNBC)。結合乳癌治療和分型系統可發展出不同的治療藥物,包括荷爾蒙治療和標靶治療:荷爾蒙治療是為阻斷雌激素與帶有雌激素受體的腫瘤細胞之間的相互作用;標靶治療則針對HER2基因過度表達、PIK3CA基因突變和遺傳性因子BRCA 基因突變作為目標。對於藥物的抗藥性或是傳導路徑的突變已逐漸被做為研究的焦點,因此藉由多基因表達平台能更精準評估復發的風險和輔助治療的措施,四個多基因平台: Oncotype Dx、MammaPrint、EndoPredict和Prosigna (PAM50) 使乳癌在診斷和治療上更精準且更全面性,本文也會描述其使用的檢驗方法。
Breast cancer has become the commonest cancer worldwide, surpassing lung cancer in recent years. Different lifestyle habits, diet, culture, delayed marriage and childbirth, have contributed the increasing incidence of breast cancer, even in developing countries. The diagnosis and treatment of breast cancer have become a priority in the scientific field. Pathologists use TNM staging and the Nottingham grading system, which accurately describe the disease progression. Subsequently, breast cancer subtyping has been established. Perou et al. (2000) first used cDNA microarray analysis to study the genome, after multiple studies and integration with breast cancer biomarkers (IHC4). Four subtypes are now recognized: Luminal A, Luminal B, Her2-enriched, and Triple-negative breast cancer (TNBC). The combination of breast cancer treatment and subtyping systems has led to the development of different drug treatments, including hormone therapy and targeted therapy. Hormone therapy aims to block the interaction between estrogen with estrogen receptors in the tumor cell. Targeted therapy targets HER2 gene overexpression, PIK3CA and BRCA gene mutations. As drug resistance or pathway mutations gradually become a focus of research, the use of multi-gene expression can more accurately assess the risk of recurrence and assist in treatment measures. Four multi-gene platforms, Oncotype Dx, MammaPrint, EndoPredict, and Prosigna (PAM50), have made breast cancer diagnosis and treatment more accurate and comprehensive. This article will also describe the testing methods used.
中文摘要…………………………………………………………............................i
英文摘要…………………………………………………………............................ii
目錄…………………………………………………………....................................iii
表目錄…………………………………………………………................................v
圖目錄…………………………………………………………................................vi
第一章 乳癌介紹 1
1.1乳癌流行病學 1
1.2乳癌的危險因子 1
1.3 乳癌的易感基因 (Susceptibility genes) 2
第二章 乳癌的診斷 3
2.1臨床上乳癌的診斷 3
2.2傳統乳癌的病理學 3
2.3乳癌的亞型(Subtype) 4
2.4 乳癌相關的生物標記 6
2.5生物標記於乳癌診斷的應用 7
第三章 乳癌的治療與分子生物學應用的相關意義 8
3.1傳統的乳癌治療 8
3.2荷爾蒙治療Hormonal therapy 8
3.2.1阻斷雌激素的產生 9
3.2.2阻斷雌激素對ER+腫瘤細胞的作用 9
3.2.3荷爾蒙治療的難題 10
3.3標靶治療Target therapy 11
3.3.1 HER2基因過度表達 11
3.3.2 PIK3CA基因突變 12
3.3.3 遺傳性因子BRCA 基因突變 13
第四章 乳癌多基因平台 14
4.1 Oncotype Dx 14
4.2 MammaPrint 15
4.3 EndoPredict 17
4.4 Prosigna (PAM50) 18
第五章 分子生物學檢測方法 20
5.1螢光原位雜交Fluorescence in situ hybridization (FISH) 20
5.2 微陣列檢測Microarray 20
5.3 qRT-PCR (Quantitative reverse transcription PCR) 21
5.4 Nanostring 21
5.5 其它高通量分子檢測方法 22
第六章 總結 23
參考文獻 25
附錄 29

表目錄

表一、 高、中風險變異的易感基因 29
表二、THE BLOOM & RICHARDSON METHOD系統評分表 30
表三、乳癌亞型的特徵及其預後和治療方式 31
表四、荷爾蒙治療常用藥物TAMOXIFEN 和 FULVESTRANT抗藥機制 32
表五、測試結果列舉了乳腺癌HER2基因擴增評估中遇到的五種臨床情況 33

圖目錄
圖一、ESTROGEN RECEPTOR的作用機轉 34
圖二、HER2基因過度表達機轉圖 35
圖三、美國臨床腫瘤學會(ASCO)在2019年更新了ONCOTYPE DX分數指南 36
圖四、CH/GL患者只進行荷爾蒙治療和合併化學治療的統計對比 37
圖五、MAMMAPRINT晶片8個相同子陣列墊微陣列晶片 38
圖六、MRNA雜交複合物示意圖與其反應過程 39
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