Single Nucleotide Polymorphisms Of DNA Repair Genes: Linkage Disequilibrium And Genetic Susceptibility To Basal Cell Carcinoma And Lung Cancer

The studies of human function genomics and disease genomics have arrived in the field of polygenically disease. Cancers that etiology and mechanism are not completely clear has been considered as polygenically inherited disease. Single Nucleotide Polymorphisms (SNPs) are the variations at the nucleotide level of genome, which result diversity of DNA sequences. SNPs are new genetic markers of third generation and attractive tools for studying the associations between genomic regions and the diseases. Determining genetic susceptibilities to development of polygenically inherited diseases are the key elements. It is documented that approximately three to twenty genes may be involved in occurrence of polygenically inherited disease and that SNPs of these genes or specific combination (haplotype effects or effects of multiple genes within the same pathology pathway) of these SNPs may also be the most import risk factor for occurrence of the polygenically inherited disease.DNA in most cells is regularly damaged by endogenous and exogenous mutagens. Unrepaired damage may result in apoptosis or may lead to unregulated cell growth and cancer. DNA repair systems are responsible for maintaining the integrity of the genome and have a critical role in protecting against mutations that can lead to cancer. Absent or incorrect repair can initiate carcinogenesis. At least four pathways of DNA repair operate on specific types of damaged DNA, and each pathwayinvolves numerous molecules. Population-based association study (case-control study) is currently thought to be the most powerful approach to detect the susceptibility genes of polygenic disease. Novel, common nontruncating SNPs and associations between SNPs in DNA repair genes and cancer risk are being identified continuously. In the present thesis, we report the results from the investigations. l.Ten Single Nucleotide Polymorphisms of DNA repair genes on chromosome 19q13.2-3: Linkage disequilibrium and genetic susceptibility to basal cell carcinoma among Danes Caucasian; 2.The DNA repair gene ERCC2/ XPD polymorphism Argl56Arg (C22541A) and risk of lung cancer in a Chinese population; and 3. Polymorphisms of DNA repair genes. ERCC1 Asn118Asn (G19007A) and ERCC2/XPD Argl56Arg (C22541A) in a Northeastern Chinese population. This thesis of PhD consists of three parts.Part one:Single Nucleotide Polymorphisms of DNA repair genes on chromosome 19ql3.2-3: Linkage disequilibrium and genetic susceptibility to basal cell carcinoma among Danes CaucasianBasal cell carcinoma (BCC) of skin is the most common cancer in Caucasians. Basal cell carcinomas are caused by a combination of genetic and environmental factors. Variation of DNA repair capacity is a key element in determining susceptibility to cancer. The genetic susceptibility to basal cell carcinoma among Danish four groups was investigated in association studies with ten single nucleotide polymorphisms on chromosome 19ql3.2-3. The results shown a significant association between BCC and A allele of a polymorphism in ERCC1 exon4 [Asn118Asn(A19007G)] [AA versus GG, Odds ratio =12, 95% CI = 1.17-124, P (x2, two-sided)=0.019] and to a lesser extent with ERCC2/XPD exon6 [Argl56Arg(C22541A)] (P = 0.06) inpsoriasis patient group. This is in accordance with recent studies of a American population of BCC cases, which places two highly influential markers between those two genes. The analysis also confirmed that considerable linkage disequilibrium existed between SNPs both within genes and between genes in this region. The combined studies suggest that genetic variation in nucleotide excision repair is of importance for the development of basal cell carcinoma.Part two:The DNA repair gene ERCC2/ XPD polymorphism Arg156Arg (C22541A)and risk of lung cancer in a Chinese populationExcision repair cross-complementing group 2 (ERCC2)/Xeroderma pigmentosum complementation group D (XPD), a major DNA repair protein, is involved in nucleotide excision repair and basal transcription. To determine the effect of the ERCC2/XPD Argl56Arg (C22541A) at exon6 polymor...