臺灣博碩士論文加值系統

中文摘要
鼻咽癌的發生率有明顯的種族及地理差異，它在世界上多數種族並不常見，但卻是華人好發的癌症，世界上多數國家鼻咽癌的年發生率少於每十萬人年1例，但在中國南方省份及東南亞地區，鼻咽癌卻是相當普遍的癌症型態。鼻咽癌是台灣地區常見癌症之一，根據衛生署編印的＜中華民國八十七年癌症登記報告＞之統計資料顯示，鼻咽癌的年齡標準化發生率及死亡率分居男性癌症發生及死亡的第八位與第七位，女性癌症發生及死亡的第十三位與第十一位，每十萬人年的年齡標準化發生率，男性約為8例，女性3.2例，男女發生率之性別比例介於2至3比1之間。從這些描述性流行病學資料顯示出鼻咽癌研究在台灣地區之重要性。
第一章的文獻探討中，簡要介紹鼻咽部位之解剖學、鼻咽癌之組織病理分類及臨床表現；並瀏覽鼻咽癌之描述性流行病學特徵，包括：地理與種族之變異，及性別與年齡特性；亦歸納整理過去文獻中所提及的多重危險因子，包括：環境危險因子之Epstein-Barr病毒（EB病毒）感染、廣東鹹魚及其它飲食因子、抽菸、與職業暴露…等，家族聚集傾向，及宿主本身之基因特性；並針對未來台灣地區之鼻咽癌研究提出建議。
與鼻咽癌相關之環境危險因子中，以EB病毒感染扮演著重要的角色，然而以往的研究大多數是橫斷性研究，少數的貫縱研究則是追蹤時間較短，而新發生之鼻咽癌個案數偏少，無法針對EB病毒感染與鼻咽癌發生相關的時序性爭議提供有利之證據。因此在第二章中，藉由以社區族群為基礎之世代追蹤研究結果，我們提供一強有利的科學證據，證明抗EB病毒外鞘抗原IgA抗體（VCA/IgA）及抗EB病毒DNA分解酶抗體（DNase），確實在鼻咽癌個案癌症發生的多年之前即可測得，顯示此兩種抗EB病毒血清抗體標記對於鼻咽癌的發生具有相當不錯的預測能力。這個研究的突破性發現如下：兩種抗EB病毒抗體皆為陰性的個案，發生鼻咽癌之累積危險性為每十萬人年11.2例，其中一種抗體呈現陽性者，累積危險性則達每十萬人年45例，兩種抗EB病毒抗體皆為陽性的個案，累積危險性則高達每十萬人年371例，明顯高於兩種抗體皆為陰性的個案。在進一步調整年齡及鼻咽癌家族病史的可能干擾作用之後，相對於兩種抗EB病毒抗體皆為陰性的個案，其中一種抗EB病毒抗體為陽性者，發生鼻咽癌的相對危險性即增為4倍，兩種抗EB病毒抗體皆為陽性者，相對危險性更增高為32.8倍，皆達到統計顯著性水準。研究結果顯示此兩種抗EB病毒血清抗體標記有助於高危險族群之鼻咽癌早期發現。
個體易感受性基因多型性與環境中的危險因子暴露，對癌症發生的共同作用亦是流行病學研究所關心的主題，第三章藉由一比一配對之病例對照研究，探討第一級異物代謝酵素 [包括：人類細胞色素（CYP）1A1基因] 及第二級異物代謝酵素 [包括：麩胺硫轉移酵素（GST）M1、T1、P1基因與氮乙醯基轉移酵素（NAT）2基因] 基因多型性與鼻咽癌發生的相關，在調整完可能的干擾因子之後，研究結果發現此五種異物代謝酵素基因多型性與鼻咽癌的發生均不具有相關，顯示這些酵素基因多型性並非台灣地區鼻咽癌發生之重要危險因子。
由於第二章的世代追蹤研究，於收案當時可用於族群大規模篩檢之抗EB病毒血清抗體標記尚少，因此僅針對兩種抗EB病毒血清抗體標記進行測定。為進一步探討多種抗EB病毒血清抗體標記組合用於早期預測鼻咽癌發生之可行性，在第四章的研究中，採重疊病例對照研究設計探討五種抗EB病毒血清抗體標記，包括：抗EB病毒外鞘抗原IgA抗體（VCA/IgA）、抗EB病毒核心抗原抗體（EBNA）1、抗胸腺核甘酶抗體（thymidine kinase，TKN）及抗潛伏膜蛋白抗體（LMP）2A與2B，以提供更多證據進一步釐清EB病毒感染與鼻咽癌發生之相關機制。研究結果發現：相對於抗EB病毒抗體為陰性的個案，VCA/IgA抗體為陽性者，發生鼻咽癌的相對危險性為34.6倍，EBNA1抗體為陽性者相對危險性為22.8倍，LMP2A抗體為陽性者相對危險性為16.9倍，LMP2B抗體為陽性者相對危險性為18倍，TKN抗體為陽性者相對危險性為6.9倍，皆達到統計顯著性水準。在重複性資料分析中，兩次測定皆為抗體陽性者相較於兩次測定皆為抗體陰性者，發生鼻咽癌的相對危險性高達63倍，且達到統計顯著性水準。而在預測模式分析中，則發現VCA/IgA、LMP 2A 或2B及EBNA1三種血清抗體標記的組合對於鼻咽癌的早期發現具有最佳的預測效度。

ABSTRACT
Nasopharyngeal carcinoma (NPC) is rare in most populations of the world, but prevalent in some ethnic groups. It is most common in southern China and Southeast Asia. In Taiwan, NPC is also a frequent cancer. According to the statistical data from Department of Health in 1998, NPC is the eighth leading cause of cancer incidence and the seventh leading cause of cancer death in males. The age-standardized incidence rate for male and female is 8 and 3.2 per 100,000, respectively. The sex ratio of male to female is about 2-3 to 1. These epidemiological findings suggested that NPC is an important issue in Taiwan.
In the Chapter 1 of the thesis, the anatomy of the nasopharynx, histopathology and clinical manifestation of NPC are briefly reviewed. Descriptive epidemiology (including geographic variation, ethnic variation, gender and age patterns) and a constellation of risk factors (environmental factors, familial aggregation, and host factors) of NPC are also reviewed.
Although EBV has been suggested as the strongest environmental risk factor for NPC in previous studies, the association was corroborated mostly in cross-sectional observational studies. The temporal relationship between EBV and NPC has never been addressed. The results from a population-based cohort study described in Chapter 2 provided strong evidence that IgA antibodies against EBV capsid antigen (VCA/IgA) and neutralizing antibodies against EBV DNase are predictive of NPC. The cumulative risk of NPC was 11.2 per 100,000 person-years for subjects who tested positive for neither serologic marker, 45.0 per 100,000 person-years for those who had one marker, and 371.0 per 100,000 person-years for those who had both markers. After adjustment for age and the presence or absence of a family history of NPC, the relative risk of NPC was 32.8 for subjects with both markers (95 percent confidence interval, 7.3 to 147.2; P<0.001) and 4.0 for subjects with one marker (95 percent confidence interval, 1.6 to 10.2; P=0.003), as compared with subjects with neither marker. The measurement of these two anti-EBV markers may be useful for the early detection of NPC in high-risk populations.
In earlier studies, both genetic and environmental factors were purported to account for the development of NPC. The relationships of genetic polymorphisms of some Phase I and Phase II xenobiotic-metabolizing enzymes to occurrence of NPC cases were therefore disentangled using a case-control study in Chapter 3. No association with risk of NPC was noted in this study, however, when genotypes of CYP1A1, GSTM1, GSTT1, GSTP1, and NAT2 were evaluated. The result suggested that the polymorphisms of these xenobiotic-metabolizing enzymes might not play a role in the development of NPC among Taiwanese population.
In Chapter 4 of the thesis, a nested case-control study was further designed to identify an optimal combination of five EBV serologic markers for predicting early NPC cases. The odds ratio (OR) of NPC was 34.6 (95% CI, 10.5 to 114; P<0.0001) for subjects positive for anti-EBV VCA/IgA, 16.9 (95% CI, 3.6 to 78.4; P<0.001) for anti-EBV LMP2A, 18.0 (95% CI, 3.9 to 83.3; P<0.001) for anti-EBV LMP2B, 22.8 (95% CI, 6.7 to 77.5; P<0.0001) for anti-EBV EBNA1, and 6.9 (95% CI, 2.8 to 17.2; P<0.0001) for anti-EBV TKN. In serial analysis, compared with subjects who tested negative for these antibodies in the fist and second assay, the OR of developing NPC was 63.0 (95% CI, 7.9 to 1353; P<0.0001) for subjects who had any marker in both assays. The subjects who had had continuously high titer of EBV antibodies were at increased risk of NPC. The combination of serologic markers of anti-EBV VCA/IgA, LMP2A or 2B, and EBNA1 (Predictive validity, 0.9; Sensitivity, 0.85; Specificity, 0.88) is good predictor for early detection of NPC.

CONTENTS
中文摘要……………………………………………………………………….. I
Abstract………………………………………………………………………… IV
Chapter 1. Epidemiological Characteristics and Risk Factors of Nasopharyngeal Carcinoma……………………………………… 1
Abstract………………………………………………………………. 2
Introduction………………………………………………………….. 4
Epidemiological Characteristics of NPC…………………………… 9
Conclusions and Future Perspectives……………………………… 29
References……………………………………………………………. 31
Chapter 2. Serologic Markers of Epstein—Barr Virus Infection and Nasopharyngeal Carcinoma－A Prospective Study……………. 56
Abstract………………………………………………………………. 57
Introduction………………………………………………………….. 59
Materials and Methods……………………………………………… 61
Results………………………………………………………………... 66
Discussion……………………………………………………………. 69
References……………………………………………………………. 71
Chapter 3. Genetic Polymorphisms of Phase I and Phase II Xenobiotic-Metabolizing Enzymes and Nasopharyngeal Carcinoma－A Case-Control Study………………………………………….. 79
Abstract………………………………………………………………. 80
Introduction………………………………………………………….. 82
Materials and Methods……………………………………………… 85
Results………………………………………………………………... 89
Discussion……………………………………………………………. 91
References……………………………………………………………. 93
Chapter 4. Selection of Serologic Markers of Epstein—Barr virus Infection for the Early Detection of Nasopharyngeal Carcinoma－A Nested Case-Control Study………………………………….. 101
Abstract………………………………………………………………. 102
Introduction………………………………………………………….. 105
Materials and Methods……………………………………………… 111
Results………………………………………………………………... 118
Discussion……………………………………………………………. 123
References……………………………………………………………. 126

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