在臨床和流行病學的研究中有足夠的證據指出慢性發炎和癌症有相關。發炎相關細胞素IL-1α、IL-1RN、IL-1β、IL-4、IL-6、IL-8、IL-10、TNF-α以及TGFβ-1在口腔鱗狀上皮細胞癌的形成可能扮演重要的角色。我們執行兩組以醫院為底的病例對照研究，探討發炎相關細胞素的九個基因，其十六點基因多型性與吃檳榔相關的口腔癌前病症和口腔鱗狀上皮細胞癌易感性之相關性，並且評估在不同的IL-1B C-511T/T-31C基因單套型與血漿中IL-1β蛋白表現量的相關性。第一組病例對照研究包含363名的口腔鱗狀上皮細胞癌病人和487名健康配對；而另一組病例對照研究所收集到的受試者均有吃檳榔的習慣，包含227名口腔鱗狀上皮細胞癌病人、116名口腔癌前病症病人和209名配對。所有的受試者是自2003年11月到2007年5月於高雄榮民總醫院收集完成，並以聚合酶連鎖反應-限制酶片段長度多型性(PCR-RFLP)或鐵克曼定量聚合酶連鎖反應(TaqMan real-time PCR)技術完成基因型的分析。此外，我們也透過性別、年齡以及吃檳榔、喝酒、抽煙的量做配對，選取口腔鱗狀上皮細胞癌病人、口腔癌前病症病人及配對各9人，利用酵素免疫分析法(ELISA)來測量血漿中IL-1β蛋白質的表現量。在單點分析中，當與健康配對比較時， IL-4 intron 3 VNTR變異基因型RP1RP2或 RP2RP2 (比RPRP1)(校正勝算比分別為0.67和0.65，95%信賴區間分別為0.45-0.99和0.45-0.95)、IL-8 -251TA或-251AA(比TT)基因型(校正勝算比分別為1.55和2.50，95%信賴區間分別為1.05-2.30和1.46-4.27)、IL-8 +781TT(比CC)基因型(校正勝算比為2.01; 95%信賴區間為1.11-3.63)以及TNFA -308GA合併-308AA(比GG)基因型(校正勝算比為0.40，95%信賴區間為0.25-0.66)與口腔鱗狀上皮細胞癌之易感性有相關。然而，在有嚼食檳榔習慣的族群中：IL-10 -819CC(比TT)基因型(校正勝算比為0.24，95%信賴區間為0.08-0.74)以及IL-10 -592CC(比AA) 基因型(校正勝算比為0.25，95%信賴區間為0.08-0.79)與配對比較時，可降低罹患口腔癌前病症的風險。此外，當與配對比較時IL-1RN intron 2 VNTR變異基因型2/2或1/2(比1/1)基因型(校正勝算比分別為0.11和0.48，95%信賴區間分別為0.01-0.97和0.27-0.87)、IL-1B -31TC(比TT)基因型(校正勝算比為1.82，95%信賴區間為1.14-2.92)、IL-8 -251AA(比TT)基因型(校正勝算比為1.92，95%信賴區間為1.01-3.66)、IL-8 +396GG(比TT)基因型(校正勝算比為2.18，95%信賴區間為1.12-4.21)以及TNFA -308GG合併-308GA(比GG)基因型(校正勝算比為0.46，95%信賴區間為0.27-0.79)與口腔鱗狀上皮細胞癌有顯著相關。再者，當與口腔癌前病症比較時IL-10 -819CC(比TT)基因型(校正勝算比為3.33，95%信賴區間為1.07-10.42)與口腔鱗狀上皮細胞癌有顯著相關。在健康配對的基因單套型分析中：當與健康配對比較時IL-4 -590C/RP2(比-590T/RP1)單套型(校正勝算比為0.69，95%信賴區間為0.49-0.98)和IL-8 –251A/+781T(比—251T/+781C)單套型(校正勝算比為1.57，95%信賴區間為1.19-2.06)與口腔鱗狀上皮細胞癌有顯著相關。然而，在有嚼食檳榔習慣者的族群中：IL-1B –511C/-31C(比–511C/-31T)單套型(校正勝算比為0.00，95%信賴區間為0.00-0.01)以及IL-10 –1082A/-819C/-592C(比–1082A/-819T/-592A)單套型(校正勝算比為0.66，95%信賴區間為0.44-0.98)當與配對比較時，可降低罹患口腔癌前病症的風險。另外，當與配對比較時IL-1 家族基因-889C/2/-511C/-31T、-889T/1/-511C/-31T和-889T/1/-511T/-31C(比-889C/1/-511C/-31T)單套型(校正勝算比為0.47，95%信賴區間為0.26-0.87; 校正勝算比為0.31，95%信賴區間為0.13-0.73; 校正勝算比為3.26，95%信賴區間為1.34-7.93)與口腔鱗狀上皮細胞癌有顯著相關。相反地， IL-1B -511T/-31T(比-511C/-31T)單套型(校正勝算比為0.34，95%信賴區間為0.12-0.97)以及IL-1 家族基因 -889T/1/-511C/-31T(比-889C/1/-511C/-31T)單套型(校正勝算比為0.27，95%信賴區間為0.10-0.71)當與口腔癌前病症比較時，可降低罹患口腔鱗狀上皮細胞癌的風險。最後在分層分析中，三個基因的共同效應(IL-8 T-251A、IL-4 intron 3 VNTR和TNFA G-308A)在男性、年齡大於五十歲者、福建人合併原住民、沒有吃檳榔者、不抽菸和菸抽多者或喝酒少和多者之間有顯著地增加罹患口腔鱗狀上皮細胞癌的危險。由結果可知基因與環境的共同效應會提高罹患口腔鱗狀上皮細胞癌的危險。而在酵素免疫分析法中，IL1-B -511T/-31C和IL1-B -511T/-31T單套型與IL1-B -511C/-31C合併IL1-B -511C/-31T單套型相比時，有吃檳榔的口腔鱗狀上皮細胞癌病患與口腔癌前病症病患的裡血漿中有較高的IL-1β蛋白表現。由本論文結果，我們發現IL-1RN、IL-4和TNFA的基因多型性在口腔鱗狀上皮細胞癌和吃檳榔習慣的口腔癌前病症是有降低罹癌危險性的功能，但是IL-8的基因多型性在口腔鱗狀上皮細胞癌和有吃檳榔習慣的口腔癌前病症是增加危險性的。另外，IL-1B 和IL-10的基因多型性在吃檳榔習慣的口腔鱗狀上皮細胞癌或口腔癌前病症中有相反的功能。此外，在血漿中的IL-1β蛋白表現是會與IL1-B C-511T/T-31C基因單套型的變異相關，但與疾病的狀態是無關的。

Clinical and epidemiological studies support a strong association between chronic inflammation and cancer. Inflammatory related cytokines, such as IL-1α, IL-1RN, IL-1β, IL-4, IL-6, IL-8, IL-10, TNF-α and TGFβ-1, might play important role in carcinogenesis of oral squamous cell carcinoma (OSCC). Two case-control studies were carried out to evaluate the association of 16 various polymorphisms of 9 inflammatory-related genes with the risk for OSCC and the risk for betel quid (BQ)-related oral precancer lesions (OPL) and BQ-related OSCC. Then the association between various IL-1B C-511T/T-31C haplotypes with plasma levels of IL-1β was evaluated. One case-contol study included 363 OSCC case patients and 487 healthy controls as well as the other case-control study included 227 BQ-related OSCC cases, 116 BQ-related OPL patients and 209 BQ-related controls. All subjects were recruited and genotyped by use of the PCR-RFLP techniques or TaqMan real-time PCR method from November 2003 and May 2007 at Kaohsiung Veterans General Hospital. Then, 9 OSCC case patients, 9 OPL patients, and 9 controls were selected and matched on sex, age as well as the quantity of BQ-chewing, alcohol drinking, and cigarette smoking for evaluation of plasma levels of IL-1β by use of ELISA. In the single locus analysis, the variant genotype of RP1RP2 or RP2RP2 (VS. RP1RP1) of IL-4 intron 3 VNTR (AOR = 0.67, 95% CI = 0.45-0.99; AOR = 0.65, 95% CI = 0.45-0.95), TA or AA (VS. TT) genotype of IL-8 T-251A (AOR = 1.55, 95% CI = 1.05-2.30; AOR = 2.50, 95% CI = 1.46-4.27), TT (VS. CC) genotype of IL-8 C+781T (AOR = 2.01; 95% CI = 1.11-3.63), and GA combined with AA (VS. GG) genotype of TNFA G-308A (AOR = 0.40; 95% CI = 0.25-0.66) were associated with risk of OSCC, as compare with those genotypes of healthy controls. However, CC (VS. TT) genotype of IL-10 T-819C (AOR = 0.24, 95% CI = 0.08-0.74) and CC (VS. AA) genotype of IL-10 A-592C (AOR = 0.25, 95% CI = 0.08-0.79) were significantly associated with reduced risk of BQ-related OPL, as compared with those genotypes of BQ controls. In addition, the variant genotype of 2/2 or 1/2 (VS. 1/1) of IL-1RN intron2 VNTR (AOR = 0.11, 95% CI = 0.01-0.97; AOR = 0.48, 95% CI = 0.27-0.87), TC (VS TT) genotype of IL-1B T-31C (AOR = 1.82, 95% CI = 1.14-2.92), AA (VS. TT) genotype of IL-8 T-251A (AOR = 1.92, 95% CI = 1.01-3.66), GG (VS. TT) genotype of IL-8 T+396G (AOR = 2.18; 95% CI = 1.12-4.21), and GA combined with AA (VS. GG) genotype of TNFA G-308A (AOR = 0.46, 95% CI = 0.27-0.79) were significantly related with risk of BQ-related OSCC, as compared with BQ controls. Moreover, CC (VS. TT) genotype of IL-10 T-819C (AOR = 3.33, 95% CI = 1.07-10.42) was associated with increased risk of BQ-related OSCC, as compared with those genotypes of BQ-related OPL. In the haplotype analysis, -590C/RP2 (VS. -590T/RP1) haplotype of IL-4 (AOR = 0.69; 95% CI = 0.49-0.98) and -251A/+781T (VS. -251T/+781C) haplotype of IL-8 (AOR = 1.57, 95% CI = 1.19-2.06) were related with risk of OSCC, as compared with those haplotypes of healthy controls. However, -511C/-31C (VS. -511C/-31T) haplotype of IL-1B (AOR = 0.00, 95% CI = 0.00-0.01) and -1082A/-819C/-592C (VS. -1082A/-819T/-592A) haplotype of IL-10 (AOR = 0.66, 95% CI = 0.44-0.98) were strongly associated with reduced risk of BQ-related OPL, as compared with those genotypes BQ controls. In addition, -889C/2/-511C/-31T or -889T/1/-511C/-31T or -889T/1/-511T/-31C (VS. -889C/1/-511C/-31T) haplotypes of IL-1 family genes (AOR = 0.47, 95% CI = 0.26-0.87; AOR = 0.31, 95% CI = 0.13-0.73; AOR = 3.26; 95% CI = 1.34-7.93) were associated with risk of BQ-related OSCC, as compared with those genotypes of BQ controls. On the contrary, -511T/-31T (VS. -511C/-31T) haplotype of IL-1B (AOR = 0.34, 95% CI = 0.12-0.97) and -889T/1/-511C/-31T (VS. -889C/1/-511C/-31T) haplotype of IL-1 family genes (AOR = 0.27, 95% CI = 0.10-0.71) were associated with reduced risk of BQ-related OSCC, as compared with those haplotypes of BQ-related OPL. Finally, in the stratification analysis, the combined effects of three genes (IL-8 T-251A, IL-4 intron 3 VNTR and TNFA G-308A) had a significantly increased risk of OSCC among male, older group (＞50 years old), Fukienece combined with Aborigine population, never-BQ chewers, never as well as heavy smokers, or light and heavy drinkers, compared with healthy controls. The results suggested that gene-environment combined effect were associated with the risk of OSCC. In ELISA assay, plasma IL-1β levels in BQ-related OSCC and OPL were found significantly higher than those in haplotypes for IL-1B -511T/-31C and IL-1B -511T/-31T compared with the combined effects of IL-1B -511C/-31C and IL-1B -511C/-31T. In conclusion, polymorphisms of IL-1RN, IL-4 and TNFA were associated with the decreased risk of OSCC or BQ-related OPL, but IL-8 was with increased risk of OSCC or BQ-related OPL. Furthermore, polymorphisms of IL-1B and IL-10 had contrary effect between BQ-related OSCC and OPL. Additionally, plasma levels of IL-1β was correlated with various IL-1B C-511T/T-31C haplotypes but not with correlated with the status of disease.

Contents

Chapter 1 General Introduction 1
1.1 Backgrounds and Significance 2
1.2 Specific Aims 9
1.3 References 10
Chapter 2 Association of Genetic Polymorphisms of Inflammatory Related Cytokine Genes with the Risk of Oral Cancer 28
2.1 Introduction 29
2.2 Patients and Methods 37
2.3 Results 41
2.4 Discussion 46
2.5 References 51
Chapter 3 Association of Genetic Polymorphisms of Inflammatory Related Cytokine Genes with the Risk of Betel Quid-related Oral Precancer and Oral Cancer 69
3.1 Introduction 70
3.2 Patients and Methods 71
3.3 Results 77
3.4 Discussion 83
3.5 References 89
Chapter 4 Association of Haplotypes and Plasma Levels of IL-1β with the Rsik of Betel Quid-related Oral Cancer, Oral Precancer and Controls 109
4.1 Summary 110
4.2 Introduction 111
4.3 Patients and Methods 112
4.4 Results 115
4.5 Discussion 116
4.6 References 118
Tables 121
Figures and Figure Legends 157

Chapter 5 Future Perspective. 164
5.1 Specific Aims 165
5.2 Experimental Designs 167

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