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研究生:簡暉慈
研究生(外文):Huei Tzu Chien
論文名稱:以病患抽菸、嚼食檳榔狀態為基礎之口腔鱗狀上皮細胞癌基因體概覽
論文名稱(外文):Genomic profiles of oral squamous cell carcinomas based on patient's cigarette smoking and areca quid chewing status
指導教授:謝玲玲謝玲玲引用關係
指導教授(外文):L. L. Hsieh
學位類別:博士
校院名稱:長庚大學
系所名稱:生物醫學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
論文頁數:186
中文關鍵詞:口腔鱗狀上皮細胞癌失去異合性最小缺失區段套數變異
外文關鍵詞:oral squamous cell carcinomaloss of heterozygosityminimally deleted regioncopy number alteration
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口腔癌是台灣男性十大常見癌症的第四位,死亡率亦逐年增加。流行病學研究顯示抽菸、飲酒及嚼食檳榔是台灣地區口腔癌的主要危險因子。本論文以口腔癌個案之危險暴露因子為選樣依據,分別運用微衛星序列標記組及兩種單一核苷酸多形性微陣列晶片平台(SNP 500K及SNP 6.0)進行口腔癌腫瘤組織全基因體失去異合性及染色體套數變異分析,來探討台灣地區男性口腔鱗狀上皮細胞癌基因體變異概覽。利用400個微衛星序列標記分析63個男性口腔癌腫瘤基因體,歸納出32個最小缺失區段(minimally deleted region, MDR)。其中有六個MDR與個案抽菸習慣有關,腫瘤組織在其中一個MDR c7r2 (7q32.2-q35)區段有缺失的口腔癌個案,其無病存活率較差(p值為0.046)。,此外,發現10個MDR與對偶基因失衡(allelic imbalance, AI)指數具統計顯著相關性,其中的MDR c14r1 (14q24.2-q32.12)及c11r1 (11q13.4-q25)的缺失會協同降低個案的無病存活率(p值為0.004);而同時MDR c7r2的缺失會再度降低個案的無病存活率(p值為0.001)。
利用500K及SNP 6.0單一核苷酸多形性微陣列晶片分別分析26個及46個晚期口腔癌腫瘤組織染色體之套數變異情形,並以GISTIC分析法訂出套數變異屬非隨機之區段(FDR q-value < 0.25)。500K平台歸納出46個非隨機套數變異區段(14個套數增加與32個套數遺失區段);SNP 6.0平台獲得208個非隨機套數變異區段(48個套數增加與160個套數減少區段)。兩平台所顯示的共同區段有15個,分別為8個套數增加區段(3q26.1、7p11.2、11q13.3、13q22.1、15q11.2、17p13.3、18p11.23-p11.31及20p11.22)及7個套數遺失區段(1q21.1、6p21.33、7q31.3、12q14.1、14q11.2及15q11.2);其中與淋巴結轉移達統計顯著水準的變異區段為3q26.1及18p11.23-p11.31與15q11.2 (p值分別為0.029、0.030、0.021);與口腔癌個案預後達統計顯著水準的變異區段為14q11.2。進一步分別以CCND1及EGFR探針進行螢光原位雜交驗證其所歸屬之11q13.3及7p11.2套數變異,發現其一致性為0.82與0.79。
結論:本論文以全基因體微衛星序列標記失去異合性及單一核苷酸多形性微陣列晶片分析染色體套數變異初步歸納出台灣地區抽菸及嚼食檳榔致口腔癌之基因體變異特徵,有助於未來明晰台灣地區男性口腔癌之致病基因。

In Taiwan, oral cancer is the fourth leading cause of cancer death in men. The motality rate is still rising. Epidemiological studies have indicated that cigarette smoking, alcohol drinking and areca quid chewing are the major risk factors. In the present study, we used microsatellite markers and SNP array to explore the genomic aberration profiles of male oral cavity squamous cell carcinoma (OSCC) in Taiwan with a study design upon patient’s history of cigarette smoking and areca quid chewing. A systematic loss of heterozygosity (LOH) analysis was performed to define 32 minimally deleted regions (MDRs) in 63 male OSCCs using 400 polymorphic microsatellite markers. Six MDRs were found to be associated with cigarette smoking. Among these markers, a loss of MDR c7r2 (7q32.2-q35) was significantly associated with poor disease-free survival (DFS, p=0.046) and ten MDRs were associated with allelic imbalance (AI) in tumors. Among the latter, a loss of MDR c14r1 (14q24.2-q32.12) and c11r1 (11q13.4-q25) had a synergistic effect on poor DFS (p=0.004) and were able to reduce further the DFS rate in patients with MDR c7r2 loss (p=0.001). Seventy-two advanced-stage OSCCs were analysed using two microarray platforms (26 cases with Affymetrix SNP 500K and 46 cases with Affymetrix SNP 6.0) to identify regions for copy number alterations (CNAs). GISTIC (genomic identification of significant targets in cancer) was further applied to determine the regions which were not random event (FDR q-value <0.25). With this approach, 46 (14 gain and 32 loss) and 208 (48 gain and 160 loss) non-random regions were identified from 500K and SNP 6.0 plateform, respectively. Among them, 15 focal CNAs (8 gains (3q26.1, 7p11.2, 11q13.3, 13q22.1, 15q11.2, 17p13.3, 18p11.23-p11.31, and 20p11.22) and 7 losses (1q21.1, 6p21.33, 7q31.3, 12q14.1, 2 focal regions in 14q11.2, 15q11.2)) were common in these 2 plateforms. The clinicopathologic significances of these 15 CNAs were examined. Gain of 3q26.1 and 18p11.23-p11.31, and loss of 15q11.2 were correlated significantly with lymph node metastasis (p=0.029, 0.030, 0.021, respectively). Loss of two focal regions in 14q11.2 was significantly associated with disease- free and overall survival. Furthermore, amplification of 11q13.3 and 7p11.2 containing known oncogenes CCND1 and EGFR were confirmed by fluorescence in situ hybridization (FISH) with high concordance rate.
In conclusion, the results of whole-genome LOH and CNAs analysis provide useful clues for future exploring the pathogenic genes associated with OSCC tumorgenesis in Tawian.

目 錄
長庚大學博士學位論文指導教授推薦書
長庚大學博士學位論文口試委員會審定書
長庚大學博士論文著作授權書 - iii -
誌謝 - iv -
中文摘要 - v -
英文摘要 - vii -
目錄 - ix -
表目錄 - x -
圖目錄 - xii -
第一章 緒論 - 1 -
1.1 前言 - 1 -
1.2 口腔癌的流行病學特徵 - 2 -
1.3基因變異與基因體不穩定 - 4 -
1.4染色體不穩定 - 6 -
1.5抽菸及嚼食檳榔致口腔癌之相關研究 - 10 -
1.6口腔癌基因體變異研究 - 14 -
第二章 研究目的 - 21 -
第三章 研究材料與方法 - 22 -
3.1研究個案 - 24 -
3.2實驗方法 - 26 -
3.3資料分析 - 46 -
第四章 研究結果 - 48 -
4.1微衛星序列標記分析口腔癌腫瘤基因體失去異合性 - 48 -
4.2腫瘤組織最小缺失區段候選基因失去異合性分析 - 55 -
4.3 GeneChip® Human Mapping 500K Array口腔癌腫瘤組
織基因體套數變異分析 - 59 -
4.4 Affymetrix® Genome-Wide Human SNP Array 6.0口腔
癌腫瘤組織基因體套數變異分析 - 61 -
4.5 500K array及SNP 6.0兩平台口腔癌腫瘤組織共同非隨
機套數變異區段分析 - 63 -
4.6口腔癌腫瘤組織染色體套數變異區段候選標的腫瘤基
因分析 - 64 -
第五章 討論 - 67 -
5.1口腔癌腫瘤組織基因體微衛星序列標記失去異合性概
觀 - 67 -
5.2台灣地區男性口腔鱗狀上皮細胞癌全基因體套數變異
分析 - 74 -
第六章 結論 - 84 -
參考文獻 - 158 -


表目錄
表1 微衛星序列失去異合性分析之口腔癌個案臨床基本特徵 - 91 -
表2 以500K或SNP 6.0微陣列晶片分析之口腔癌個案臨床
基本特徵 - 92 -
表3 以候選標的基因進行失去異合性分析之口腔癌個案臨床
基本特徵 - 93 -
表4 口腔癌腫瘤基因體失去異合性與臨床病理變項達統計顯
著水準之微衛星序列標記 - 94 -
表5 口腔癌腫瘤基因體失去異合性與口腔癌危險因子達統計
顯著水準之微衛星序列標記 - 97 -
表6 口腔癌腫瘤基因體微衛星序列標記失去異合性分析之最
小缺失區段(minimally deleted region,MDR) - 98 -
表7 口腔癌腫瘤基因體微衛星序列標記失去異合性分析中與
對偶基因失衡(allelic imbalance, AI)指數具統計顯著相關性之
最小缺失區段 - 101 -
表8 口腔癌腫瘤基因體微衛星序列標記失去異合性分析中與
染色體不穩定(chromosomal instability,CIN)具統計顯著相關性
之最小缺失區段 - 102 -
表9 口腔癌腫瘤基因體微衛星序列標記失去異合性分析中與
口腔癌危險因子具統計顯著相關性之最小缺失區段 - 103 -
表10 口腔癌腫瘤基因體微衛星序列標記失去異合性分析中與
口腔癌臨床病理特徵具統計顯著相關性之最小缺失區段 - 104 -
表11 口腔癌染色體不穩定與個案無病存活率之Cox多變項迴
歸分析 - 105 -
表12 口腔癌腫瘤基因MDR缺失與個案無病存活率聯合效應
之Cox單變項迴歸分析 - 106 -
表13 口腔癌腫瘤基因體MDR缺失與對個案無病存活率之
Cox多變項迴歸分析 - 107 -
表14 口腔癌腫瘤組織FOXN3基因失去異合性與個案預後之
相關性 - 108 -
表15 500K微陣列晶片分析口腔癌腫瘤組織染色體套數增加
(gain)屬非隨機之區段 - 109 -
表16 500K微陣列晶片分析口腔癌腫瘤組織染色體套數遺失
(loss)屬非隨機之區段 - 111 -
表17 SNP 6.0微陣列晶片分析口腔癌腫瘤組織染色體套數增
加(gain)屬非隨機之區段 - 113 -
表18 SNP 6.0微陣列晶片分析口腔癌腫瘤組織染色體套數遺
失(loss)屬非隨機之區段 - 117 -
表19 500K及SNP6.0微陣列晶片二平台分析口腔癌腫瘤組織
染色體套數變異達統計顯著水準之共同區段 - 127 -
表20口腔癌腫瘤組織染色體套數變異與臨床病理變項達統計
顯著水準之區段 - 128 -
表21口腔癌腫瘤組織染色體14q11.2區段套數變異與個案存
活率之Cox多變項迴歸分析 - 129 -
表22 微陣列晶片分析染色體11q13.2區段之基因套數與FISH
偵測CCND1基因套數之一致性(N=62) - 130 -
表23 微陣列晶片分析7p11.2區段之基因套數與FISH偵測
EGFR基因套數之一致性(N=52) - 131 -


圖目錄
圖1 口腔癌腫瘤組織微衛星序列標記失去異合性之頻率二相
分布圖 - 132 -
圖2 以高解析熔解曲線分析法(HRM analysis)鑑別基因型及失
去異合性代表圖 - 133 -
圖3 利用引子延展法(primer extension)暨解離式高效能液相層
析儀(denaturing high performance liquid chromatography, DHPLC)
分析標的基因失去異合性之代表圖 - 134 -
圖4 以Vysis公司之CCND1探針進行FISH分析11q13.2區
段之染色體套數代表圖 - 135 -
圖5 口腔癌腫瘤組織微衛星序列標記分析各染色體臂失去異
合性頻率 - 136 -
圖6 口腔癌腫瘤基因體微衛星序列標記分析對偶基因失衡指
數(AI index)分布圖 - 137 -
圖7口腔癌腫瘤組織微衛星序列標記失去異合性分析之最小缺
失區段(MDR) - 138 -
圖8 口腔癌腫瘤基因體微衛星序列標記失去異合性分析之MDR
分布圖 - 139 -
圖9 口腔癌腫瘤組織在微衛星序列標記失去異合性分析之最
小缺失區段發生缺失之區段數分布圖 - 140 -
圖10 口腔癌微衛星序列標記失去異合性分析之對偶基因失衡
與個案無病存活率之相關性 - 141 -
圖11 口腔癌微衛星序列標記失去異合性分析之最小缺失區段
與個案無病存活率之相關性 - 142 -
圖12 口腔癌微衛星序列標記失去異合性分析之單一MDR區
段內單一標記失去異合性與個案無病存活率之相關性 - 143 -
圖13 口腔癌微衛星序列標記失去異合性分析之雙MDR區段
內標記與失去異合性個案無病存活率之相關性 - 144 -
圖14 口腔癌腫瘤組織FOXN3基因失去異合性與臨床預後之
相關性 - 145 -
圖15 500K微陣列晶片分析之口腔癌腫瘤組織各染色體套數變
異片段分布圖(N=26) - 146 -
圖16 500K微陣列晶片分析之口腔癌腫瘤組織各染色體套數變
異頻率(A:套數增加; B:套數遺失) (N=26) - 147 -
圖17 500K微陣列晶片分析之口腔癌腫瘤組織各染色體log2 ratio
分布圖 - 148 -
圖18 口腔癌500K微陣列晶片分析之腫瘤組織各染色體套數
增加屬非隨機之區段 - 149 -
圖19 口腔癌500K微陣列晶片分析之腫瘤組織各染色體套數
遺失屬非隨機之區段 - 150 -
圖20 SNP 6.0微陣列晶片分析之口腔癌腫瘤組織各染色體套數
變異片段分布圖(N=46) - 151 -
圖21 SNP 6.0微陣列晶片分析之口腔癌腫瘤組織各染色體套數
變異頻率(A:套數增加; B:套數遺失) (N=46) - 152 -
圖22 SNP 6.0微陣列晶片分析之口腔癌腫瘤組織各染色體log2 ratio分布圖 - 153 -
圖23口腔癌SNP 6.0微陣列晶片分析之腫瘤組織各染色體套
數增加屬非隨機之區段 - 154 -
圖24口腔癌SNP 6.0微陣列晶片分析之腫瘤組織各染色體套
數遺失屬非隨機之區段 - 155 -
圖25口腔癌腫瘤組織14q11.2(a,b)區段遺失染色體套數變異
與個案存活率分析 - 156 -
圖26口腔癌腫瘤組織染色體套數變異區之基因參與腫瘤特異
訊息路徑KEGG pathway in cancer之分析圖 - 157 -


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