前列腺癌遗传多态性风险位点功能及机制分析

发布时间：2018-03-13 22:20

本文选题：前列腺癌　切入点：雄激素受体　出处：《浙江大学》2016年博士论文　论文类型：学位论文

【摘要】：前列腺癌(Prostate Cancer, PCa)是男性最常见的恶性肿瘤之一。过去的研究已经初步揭示了雄激素及其受体(Androgen receptor, AR)通过结合雄激素反应元件(androgen-response elements,AREs)下游调控靶基因,参与前列腺癌发生发展的基本机制。由于大多数根据全基因组关联分析所识别的与前列腺癌风险相关的单核苷酸多态性(SNPs)都不位于蛋白编码区,因而这些SNPs影响前列腺癌风险的机制并不清楚。本研究中我们使用一系列的生物信息工具以及数据库为易感SNPs的分子机理提供了新的见解。我们对前期已经识别和证实的33个前列腺癌风险相关的SNPs进行了功能的深入分析。我们首先把这33个SNPs以及连锁不平衡区(LD)(r2≥0.5)的其它SNPs定位到基因组功能注释数据库,包括DNA元件百科全书(ENCODE)、UCSC所定义的11个基因组调控元件数据库以及通过ChIP-chip技术所定义的雄激素受体结合位点(AR)。然后再通过富集分析评估这些风险SNP区域是否富集到不同的注释系统。风险SNP区非偶然性地显著性富集在两个注释组,包括AR结合位点(P=0.003)以及FoxAl结合位点(P=0.05)。另外大约有三分之一(11个)的SNPs风险区域位于AR结合区域。风险SNPs在AR结合位点的显著性富集表明这些SNPs对于前列腺癌的发生可能起到很重要的作用,为未来功能研究提供了指导。同时为了检验雄激素受体结合位点序列变异与前列腺肿瘤的相关性,我们系统性的评估,fHH(Johns Hopkins Hospital)和CGEMS(Cancer Genetic Markers of Susceptibility)群体中在AR结合位点区域SNPs与前列腺肿瘤风险的相关性。我们的研究表明前列腺肿瘤相关SNPs位点显著性地富集于AR结合位点。同时,AR区域新发现的风险相关SNPs更容易显著性地重复出现。这一结果与我们前期计算的风险SNPs富集于AR结合区域的结果一致。最后,我们的研究结果表明与易感SNPs关联并由雄激素受体所介导的调节机制会影响前列腺肿瘤的风险。由于我们的研究结果主要根据生物信息分析所得,所得结果仍需进一步的实验验证和更深入的分子机理分析。鉴于前列腺癌的发生是一个漫长的过程,因此本项目组推断：正常前列腺组织AR结合位点序列遗传变异可能改变AR对靶点结合能力,影响雄激素及其受体AR对下游靶基因和融合基因的调控,导致个体前列腺癌发生发展差异。同时基于对前列腺癌SNPs的系统性分析,以及基因结构信息、转录因子结合位点信息、表观遗传信息、蛋白翻译后修饰信息、RNA编辑等信息,我们开发了SNP功能注释分析平台FunSNP (Functional Annotation System for SNP),以便为分子生物分析人员在进行疾病分析时提供更多有用的信息。
[Abstract]:Prostate cancer (Prostate Cancer PCa) is one of the most common malignancy in men. Past studies have revealed the androgen and its receptor (Androgen receptor, AR) by combining the androgen response element (androgen-response, elements, AREs) downstream target genes involved in basic pathogenesis of prostate cancer. Because most according to relevance analysis the genomic identification and prostate cancer risk associated SNPs (SNPs) are located in the protein encoding region, so the influence mechanism of SNPs risk of prostate cancer is unclear. In this study, we use a series of bioinformatics tools and databases for molecular mechanism of susceptibility to SNPs provides new insights we have. Identification of early and confirmed 33 prostate cancer risk related SNPs in-depth analysis function. We use this SNPs to 33 Area and linkage disequilibrium (LD) (R2 = 0.5) and the other SNPs mapped to the genome annotation database, including the Encyclopedia of DNA elements (ENCODE), UCSC has defined 11 genomic regulatory element database and ChIP-chip technology through the defined androgen receptor binding sites (AR). Then through the analysis and evaluation of these enrichment the risk of SNP region is enriched to different annotation system. The risk of SNP region of non accidental significant enrichment in the two note group, including AR binding sites (P=0.003) and FoxAl binding sites (P=0.05). In addition, there are about 1/3 (11) of the SNPs risk area is located in the AR binding domain of SNPs in significant risk. The binding site of AR enrichment suggest that these SNPs for prostate cancer may play a very important role, provides guidance for future research. At the same time in order to test the function of androgen receptor binding sites and sequence variation Correlation of prostate cancer, we evaluated the system of the fHH (Johns Hopkins Hospital) and CGEMS (Cancer Genetic Markers of Susceptibility) group associated loci region SNPs and prostate cancer risk with AR. Our study shows that prostate cancer related SNPs locus significantly enriched in the AR binding site. At the same time, the risks associated SNPs found AR region significantly more easily repeated. This result with our previous calculation of the risk of SNPs enriched in the AR binding region of the results. Finally, the results of our study show that with the susceptible SNPs Association and regulation mechanism mediated by the androgen receptor mediated will affect the risk of prostate cancer. Because we the research results mainly based on biological information analysis, analysis of the results still need further experimental verification and further molecular mechanism. In view of the development of prostate cancer Life is a long process, so the project group concluded: normal prostate tissue AR binding sequence genetic variants may alter the AR binding ability of the target, effect of androgen and its receptor AR regulates transcription of downstream target genes and fusion gene, led the development of prostate cancer. At the same time, individual difference analysis on prostate cancer SNPs based on the information and gene structure, transcription factor binding site information, epigenetic information, protein post-translational modification, RNA editing and other information, we have developed a SNP function annotation analysis platform FunSNP (Functional Annotation System for SNP), in order to analyze the molecular biology in disease analysis to provide more useful information.

【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R737.25

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