DNA修復機制能防止DNA損傷的形成並維持基因體的完整性，其中最重要的一類為具有能辨識多種DNA損傷的核

DNA repair mechanisms counteract the formation of deleterious DNA lesions and maintain genomic integrity. Nucleotide excision repair (NER) is an important DNA repair pathway because of its extraordinarily large substrate specificity. P53 protein regulates NER pathway in a transcription-dependent or transcription-independent manner. Inherited polymorphisms of NER pathway genes (XPC, HR23B, XPA, DDB2, XPB, XPD, ERCC1, XPF, and XPG) and TP53 gene may contribute to individual variations in genetic susceptibility to OSCC and correlate with the prognosis of 204 OSCC patients. We carried out a hospital-based case-control study to investigate the association of 25 various polymorphisms of nine NER pathway genes and TP53 gene with the risk for OSCC. There were 34 newly diagnosed OSCC patients and 135 frequency-matched controls without BQ chewing and smoking habit as well as 313 newly diagnosed OSCC patients with BQ chewing or smoking habit and 312 frequency-matched controls being recruited between November 2003 and July 2007 at Kaoshiung Veterans General Hospital. Genotyping was performed using the PCR-RFLP techniques or TaqMan real-time PCR method. The significant association between polymorphisms of NER pathway genes and OSCC risk was mainly found among subjects with BQ chewing or smoking habit. In the single locus analysis, GA and AA genotypes of ERCC1 G-641A (AOR, 0.64; 95% CI, 0.45-0.93 and AOR, 0.48; 95% CI, 0.29-0.79, respectively; p for trend, 0.002), CT genotype of XPF C-850T (AOR, 1.53; 95% CI, 1.08-2.18; p for trend, 0.014), as well as GG genotype of XPB A-1039G (AOR, 0.51; 95% CI, 0.26-0.98; p for trend 0.034) were significantly associated with the risk of OSCC. Furthermore, -641G/ -425T or -641G/ -425C haplotype of ERCC1 (AORs, 1.34; 95% CI, 1.02-1.77 and AOR, 1.56; 95% CI, 1.18-2.07, respectively; p for trend 0.002) as well as -850T/ -247T and -850T/ -247C haplotype of XPF (AOR, 1.45; 95% CI, 1.09-1.94 for; p for trend 0.016) were strongly associated with the risk of OSCC. A trend toward increased risk of OSCC was observed when people with the increasing number of at risk genotypes in the combined analyses of nine NER pathway genes with (p for trend, <0.001) or without (p for trend 0.001) TP53 gene. Finally, in the stratification analysis, the combined effects of nine NER pathway genes had a significantly increased risk of OSCC among younger group (≦50 years old), Fukienece population, BQ chewers, light smokers, or light drinkers. Besides, in the prognosis analysis of 204 OSCC patients, HR23B A-823C, polymorphisms of XPA gene, XPD C-643G, XPG C787G, and the number of at risk genotypes of NER pathway genes were associated with pathologic stage, T classification, or N classification. The association between NER genetic polymorphisms and survival of patients was only found in XPA C-1778T polymorphism. These results suggested that the single polymorphism of XPB A-1039G, ERCC1 G-641A and XPF C-850T, the joint effect of genetic polymorphisms of NER pathway genes, and gene-environment combined effect were associated with the risk of OSCC. Furthermore, in the analysis of NER genetic polymorphisms and prognosis of OSCC, we found polymorphisms of XPA gene might be a prognostic factor for OSCC.

Chapter 1 General Introduction --------------------------------------------------------------------------------------------------------------- 1
1.1 Backgrounds and Significance ----------------------------------------------------------------------------------------------------------- 2
1.2 Specific Aims ---------------------------------------------------------------------------------------------------------------------------------- 12
1.3 References ------------------------------------------------------------------------------------------------------------------------------------ 13
Chapter 2 The Relation of Polymorphisms in DNA Repair Genes to OSCC Risk: A Case-Control Study. -------------- 18
2.1 Summary ---------------------------------------------------------------------------------------------------------------------------------------- 19
2.2 Introduction ------------------------------------------------------------------------------------------------------------------------------------- 20
2.3 Patients and Methods ------------------------------------------------------------------------------------------------------------------------ 34
2.4 Results ------------------------------------------------------------------------------------------------------------------------------------------- 41
2.5 Discussion -------------------------------------------------------------------------------------------------------------------------------------- 55
2.6 References ------------------------------------------------------------------------------------------------------------------------------------- 63
2.7 Tables -------------------------------------------------------------------------------------------------------------------------------------------- 72
2.8 Figures and Figure Legends -------------------------------------------------------------------------------------------------------------- 119
Chapter 3 Future Perspective ------------------------------------------------------------------------------------------------------------------- 126
3.1 Specific Aims ----------------------------------------------------------------------------------------------------------------------------------- 127
3.2 Experimental Designs ----------------------------------------------------------------------------------------------------------------------- 129
Appendix ---------------------------------------------------------------------------------------------------------------------------------------------- 131

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