【作者】 尹娇杨；

【导师】 李继承；

【作者基本信息】 浙江大学 ， 细胞生物学， 2005， 博士

【摘要】 目前,人类功能基因组学及疾病基因组学已进入多基因疾病研究领域,而癌症被认为是多基因疾病,病因及发病机制尚不完全清楚。单核苷酸多态(SingleNucleotide Polymorphism,SNP)主要指由基因组核苷酸水平上的变异引起的DNA序列的多样性,是受到高度重视的新一代遗传标志,将构成今后基因组学研究的主要工具。DNA修复系统基因已被作为候选的癌症易感基因。基于人群相关研究的关联分析被认为是研究多基因疾病易感基因的有效策略。一些普通的及新的DNA修复基因单核苷酸多态与癌症发生风险的关联已经被或正在被验证。本文研究了人类染色体19q13.2-3区域DNA修复等基因十个SNPs:连锁不平衡及其与基底细胞癌的遗传易感性和核苷酸切除修复基因一个SNP与肺癌的发生风险,并揭示了核苷酸切除修复基因两个SNPs在蒙古人种与高加索人种之间的差异。本研究共分三个部分。浙江大学博士学位论文第一部分:丹麦高加索人染色体19ql3.2一3区域DNA修复等基因单核昔酸多态: 连锁不平衡及其与基底细胞癌易感性研究 皮肤基底细胞癌(Basal een carcinoma, BCC)是高加索群体中最普通的癌症,它是由于遗传因素与环境因素相互作用所引起。DNA修复能力的变异在决定癌发易感性上是一个关键因素。我们研究了丹麦四组人群染色体19ql3.2一3区域DNA修复等基因10个SNPs及其单体型与BCC的关联及其遗传易感性。研究结果表明:在银屑病群体中,DNA修复基因ERcc 1 exon4[A snll8Asn(A19007G)1 AA基因型纯合子个体比GG基因型纯合子个体有12倍高的BcC发生风险【AA versus Gq OR=12,95%Cl=1.17一124,尸(xZ,two一sided)=0.019],且其次为nNA修复基因ERCCZ/x卫D exon6[Argl 56A招(C2254lA)](P=o.o6)。研究分析也证实了:这个亚区域的基因内及基因间的SNPs之间存在着极大的连锁不平衡。这与我们在美国BCC群体的研究结果相一致:19号染色体这个亚区域与BCC发生相关联。我们的研究结果提示:丹麦银屑病群体中,DNA修复基因ERCC 1 exon4【Asnl一8Asn(A一goo7G)]A等位基因SNP与增加BCC发生易感性相关联。人类染色体19ql3.2一3亚区域:其基因内及基因间的S刊甲s之间存在着极大的连锁不平衡,是BCC发生的易感性区域。DNA修复系统基因;核昔酸切除修复基因ERCCI及ERCCZ/XPD的变异在BCC发生中起着重要作用。这两个基因也可作为对于其它普通癌症发生易感性研究的候选基因。这是第一次在丹麦群体中报道了ERCCI exon4[Asnll8Asn(A19o07G)l单核普酸多态与基底细胞癌发生易感性之间有意义的关联。应进一步进行较大样本群体的及以正常人群作为对照组的研究以证实这个发现。浙江大学博士学位论文第二部分中国人DNA修复基因ERCCZ仄PDA馆156A花(C2254lA)单核昔酸 多态与肺癌发生风险 切除修复交叉互补2组(E RccZ)/着色性干皮病互补D组(xPD)是主要的DNA修复蛋白,它参加于核昔酸切除修复和基础转录过程。为了探索中国人DNA修复基因ERccZ/x卫D Aigl 56A塔(C 2254lA)单核昔酸多态与肺癌发生风险的关联,我们设计了以医院为基础的病例一对照研究:149名新诊断的且未进行化疗与放疗的肺癌患者,137名正常对照,对照组与之年龄(士3岁)、性别和民族相配对。所有个体均为无亲缘关系的中国汉族。全部研究组中,ERccZ/x卫D Argl 56Arg(C 22541A)多态等位基因频率分布:病例组与对照组之间无显著性差异(P=O.74)。分层分析时发现:携带有ERCCZ/xpD Argl56Arg(C 22541A)A变异等位基因个体可增加1.65倍患肺腺癌风险(A刀AC versus cC,adjusted oR=1.65,95%CI=l .09一2.50)(P=0.02)。分析吸烟史与基因型之间的关系:在从不吸烟组中发现,携带有1个或2个 ERCCZ/X卫D Argl 56Arg(C 2254lA)A变异等位基因个体可增加2.49倍患肺癌(OR声2.49,95%CI=l .10一5.64Xp二0.03)及5.6倍患肺腺癌(0R=5.60,95%Cl=1.52,20.56)(尸=0.005)的风险,相似的结果在吸烟组中没有被发现。研究结果提示了可能的基因和环境的相互作用。但由于亚组中相对小数目的群体,发现受到限制。这是第一次报道了ERCCZ/X卫D为gl56A堪(C 2254lA)单核昔酸多态与肺癌发生风险之间有意义的关联。我们的研究结果提示:在这个研究的中国群体中,ERCCZ/xpD Aigl 56A堪(C 22541A)A变异等位基因是肺腺癌发生的风险标记及在从不吸烟者中增加了肺癌的发生风险,为了证实这个发现,进一步较大样本群体的研究是需要的。更多还原

【Abstract】 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更多还原