臺灣博碩士論文加值系統

背景：口腔癌為全球常見且重要的癌症之一，特別是在台灣男性族群中，其發生率與死亡率居高不下，對醫療照護與公共衛生造成沉重負擔。口腔潛在惡性病變（oral potentially malignant disorders, OPMDs），如白斑、紅斑及扁平苔癬，雖屬良性病變，但具較高的惡性轉化風險。吸菸、飲酒及嚼檳榔為口腔癌及頭頸癌的主要致病因子，但這些行為與口腔白斑、癌症發生及死亡率之間的關聯，可能受基因變異、表觀遺傳變化及血清生物標誌物等因素的交互影響。因此，單一層面的研究難以全面掌握致病機制，亟需結合大規模健康資料庫與分子流行病學，深入探討其間的關聯。
方法：本研究結合台灣癌症登記資料庫（TCR）與全民健康保險研究資料庫（NHIRD）進行大數據分析，探討吸菸、飲酒與嚼檳榔等生活習慣與頭頸癌、口腔癌死亡率風險的關係。此外，我們以健康對照者、口腔白斑患者及口腔癌患者為對象，運用分子流行病學，分析三項生物標誌物於不同族群間的差異：（1）DNA甲基化程度（以LINE-1作為指標）；（2）血清葉酸濃度；（3）單碳代謝相關基因多形性（如MTHFR rs1801133與rs1801131等）。
結果：研究顯示，單獨嚼檳榔顯著增加頭頸癌總體死亡風險（aIRR = 1.44）與癌症特異性死亡風險（aIRR = 1.51）。性別及腫瘤部位分層後，男女及不同頭頸癌部位（口腔癌、口咽癌）皆達統計顯著。口腔癌患者中，具吸菸、飲酒及嚼檳榔三項習慣者之總體及癌症特定死亡風險顯著上升，特別是舌癌（aIRR = 1.36與1.23）。此外，分子層面分析的結果顯示LINE-1甲基化程度在白斑組最高，其次為口腔癌組，對照組最低，三組差異顯著（p < 0.001）。血清葉酸濃度雖有降低趨勢，但組間差異不顯著（p = 0.250）。特定單碳代謝基因型，如MTHFR rs1801133 TT，相較於CC，顯著降低口腔癌風險（aOR = 0.17, p = 0.025）。
結論：本研究整合分子層級與健康資料庫分析，深化對口腔癌發生風險及死亡率風險影響因子的理解，並提供預防、早期偵測及個人化治療策略的科學依據。

Background: Oral cancer is one of the most common and significant cancers globally, particularly prevalent among Taiwanese men, with persistently high incidence and mortality rates. Oral potentially malignant disorders (OPMDs), such as leukoplakia, erythroplakia, and lichen planus, although classified as benign, carry a heightened risk of malignant transformation. Traditional risk factors for oral cancer include cigarette smoking, alcohol drinking, and betel nut chewing. However, the associations between these habits, oral leukoplakia, cancer incidence, and mortality may be modulated by genetic variations, epigenetic alterations, and serum biomarkers. Thus, a comprehensive understanding of these complex interactions necessitates an integrative approach combining large-scale health databases with molecular epidemiology.
Methods: This study utilized data from the Taiwan Cancer Registry (TCR) and the National Health Insurance Research Database (NHIRD) to examine the associations between lifestyle habits — cigarette smoking, alcohol drinking, and betel quid chewing — and the risks of mortality from head and neck cancers, including oral cancer. Additionally, molecular epidemiological analyses were conducted among healthy controls, oral leukoplakia patients, and oral cancer patients, focusing on three biomarkers: (1) DNA methylation level (assessed via LINE-1 methylation), (2) serum folate concentration, and (3) polymorphisms in one-carbon metabolism genes (including MTHFR rs1801133 and rs1801131).
Results: Betel nut chewing alone significantly increased overall mortality (aIRR = 1.44) and cancer-specific mortality (aIRR = 1.51) in head and neck cancer patients. Stratified analyses by gender and tumor site revealed consistent and significant associations. Furthermore, among oral cancer patients, those with concurrent cigarette smoking, alcohol drinking, and betel nut chewing had significantly higher risks of both overall and cancer-specific mortality, especially in tongue cancer (aIRR = 1.36 and 1.23, respectively). At the molecular level, LINE-1 methylation was highest in the leukoplakia group, followed by the oral cancer group, and lowest in healthy controls, with statistically significant (p < 0.001). Serum folate levels showed a decreasing trend across groups but were not statistically significant (p = 0.250). Moreover, the MTHFR rs1801133 TT genotype was associated with a significantly reduced risk of oral cancer compared to the CC genotype (aOR = 0.17, p = 0.025).
Conclusion: This study integrates molecular epidemiology with population-based health databases, enhancing our understanding of factors influencing oral cancer risk and mortality. The findings provide valuable insights for developing preventive measures, early detection strategies, and personalized treatment approaches for oral cancer.

目錄
目錄 I
表目錄 IV
圖目錄 VI
中文摘要 VII
Abstract VIII
第一章 緒論 1
第一節 研究背景 1
第二節 研究動機 2
第三節 研究目的 2
第二章 文獻探討 3
第一節 癌症及頭頸癌的流行病學 3
第二節 口腔癌及口腔潛在惡性病變的流行病學 4
第三節 口腔癌及口腔潛在惡性病變的危險因子 5
第四節 DNA甲基化與口腔癌及口腔潛在惡性病變 7
第五節 血清葉酸濃度與口腔癌及口腔潛在惡性病變 8
第六節 單碳代謝基因多形性與口腔癌及口腔潛在惡性病變 8
第七節 影響頭頸癌與口腔癌死亡率的危險因子 9
第八節 研究問題 10
第九節 研究假說 10
第十節 研究架構 10
第三章 材料與方法 13
第一節 以全國性健康資料庫分析頭頸癌、口腔癌死亡率風險的危險因子 13
一、 資料來源 13
二、 變項定義 13
（一） 吸菸、飲酒及嚼檳榔等生活習慣與頭頸癌死亡率風險的研究 13
（二） 吸菸、飲酒及嚼檳榔等生活習慣與口腔癌死亡率風險的研究 14
三、 統計分析 14
（一） 吸菸、飲酒及嚼檳榔等生活習慣與頭頸癌死亡率風險的研究 14
（二） 吸菸、飲酒及嚼檳榔等生活習慣與口腔癌死亡率風險的研究 15
第二節 以分子流行病學方法分析口腔癌發生風險的危險因子 15
一、 收案對象與檢體採集 15
二、 全面DNA甲基化分析 16
三、 血清葉酸濃度分析 17
四、 單碳代謝基因多形性分析 17
五、 統計分析 18
六、 樣本數的估計 19
第四章 結果 21
第一節 以全國性健康資料庫分析頭頸癌、口腔癌死亡率風險的危險因子 21
一、 吸菸、飲酒及嚼檳榔等生活習慣與頭頸癌死亡率風險的相關性 21
二、 吸菸、飲酒及嚼檳榔等生活習慣與口腔癌死亡率風險的相關性 24
第二節 以分子流行病學方法分析口腔癌發生風險的危險因子 27
一、 DNA 甲基化、血清葉酸濃度與口腔癌及口腔白斑 27
二、 單碳代謝基因多形性與口腔癌及口腔白斑 28
第五章 討論 32
第一節 以全國性健康資料庫分析頭頸癌、口腔癌死亡率風險的危險因子 32
一、 吸菸、飲酒及嚼檳榔等生活習慣與頭頸癌死亡率風險的相關性 32
（一） 主要結果說明 32
（二） 頭頸癌死亡率與吸菸、飲酒、嚼檳榔習慣之相關性的討論與說明 32
二、 吸菸、飲酒及嚼檳榔等生活習慣與口腔癌死亡率風險的相關性 33
（一） 主要結果說明 33
（二） 口腔癌死亡率與吸菸、飲酒、嚼檳榔習慣之相關性的討論與說明 34
三、 研究優勢 35
四、 研究限制 35
五、 未來研究方向 35
第二節 以分子流行病學方法分析口腔癌發生風險的危險因子 36
一、 主要結果說明 36
二、 DNA甲基化與口腔癌及口腔白斑的討論與說明 36
三、 血清葉酸濃度與口腔癌及口腔白斑的討論與說明 37
四、 單碳代謝基因多形性與口腔癌及口腔白斑的討論與說明 37
五、 研究優勢 39
六、 研究限制 39
七、 未來研究方向 40
第六章 結論 41
第七章 參考文獻 42

表目錄
表一 文獻研究發現與口腔癌風險有關的單碳代謝基因多形性 18
表二 參與者的人口學統計特徵與臨床病理變項的分布 52
表三 頭頸癌患者的總體死亡風險和癌症特定死亡風險，單變項卜瓦松回歸模型 53
表四 具有吸菸、飲酒、嚼檳榔習慣的頭頸癌患者的總體死亡與癌症特定死亡的風險，多變項卜瓦松回歸模型 55
表五 具有吸菸、飲酒、嚼檳榔習慣的頭頸癌患者的總體死亡與癌症特定死亡的風險，多變項卜瓦松回歸模型，以性別做分層 56
表六 具有吸菸、飲酒、嚼檳榔習慣的頭頸癌患者的總體死亡與癌症特定死亡的風險，多變項卜瓦松回歸模型，以腫瘤位置做分層 57
表七 口腔癌患者的總體死亡風險，卜瓦松回歸模型 58
表八 口腔癌患者的癌症特定死亡風險，卜瓦松回歸模型 60
表九 具有吸菸、飲酒、嚼檳榔習慣的口腔癌患者的總體死亡風險，多變項卜瓦松回歸模型，以腫瘤部位做分層 62
表十 具有吸菸、飲酒、嚼檳榔習慣的口腔癌患者的癌症特定死亡風險 (口腔癌)，多變項卜瓦松回歸模型，以腫瘤部位做分層 63
表十一 研究對象的人口基本變項、生活習慣、葉酸濃度與LINE-1甲基化程度 64
表十二 葉酸濃度和LINE-1甲基化與口腔白斑和口腔癌風險的相關性 65
表十三 白斑病例組與對照組的單碳代謝相關基因分布比較 66
表十四 羅吉斯回歸分析單碳代謝基因變異與白斑風險的相關性 67
表十五 口腔癌病例組與對照組的單碳代謝相關基因分布比較 68
表十六 羅吉斯回歸分析單碳代謝基因變異與口腔癌風險的相關性 69
表十七 白斑病例組與口腔癌病例組的單碳代謝相關基因分布比較 70
表十八 羅吉斯回歸分析單碳代謝基因變異與口腔癌風險的相關性 71
表十九 病例組和對照組的單碳代謝相關基因與葉酸濃度分布比較 72
表二十 對照組中單碳代謝基因的等位基因（allele）與血清葉酸濃度的關係 73
表二十一 白斑組中單碳代謝基因的等位基因（allele）與血清葉酸濃度的關係 74
表二十二 口腔癌病例組中單碳代謝基因的等位基因（allele）與血清葉酸濃度的關係 75
表二十三 葉酸濃度與白斑風險的相關性---依單碳代謝基因變異分組 76
表二十四 葉酸濃度與口腔癌風險的相關性---依單碳代謝基因變異分組 77
表二十五 葉酸濃度與白斑病例組和口腔癌病例組口腔癌風險的相關性---依單碳代謝基因變異分組 78

圖目錄
圖一 研究架構：頭頸癌、口腔癌死亡率的危險因子 11
圖二 研究架構：口腔白斑、口腔癌發生的危險因子 12
圖三 頭頸癌患者研究族群篩選流程圖 22
圖四 口腔癌患者研究族群篩選流程圖 25

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