RTKs/ERK信号通路与前列腺癌的关联分析及风险点生物功能的研究

Prostate cancer is the most commonly diagnosed cancer in western men, and incidence is rising rapidly in our country. Genetic factor plays a major role in prostate cancer and is an important factor for the developing of prostate cancer that shows individual difference. This project wants to perform an association analysis between RTKs/ERK signal pathway based on the previous research and prostate cancer, and study the molecular function of risk SNPs in this pathway. The detail methods are as follows: Association analysis is performed between SNPs in RTKs/ERK signal pathway and prostate cancer with large sample from ChinaPCa. After finding the risk alleles, the susceptible gene expression in tissue, and the impact of the risk allelic polymorphisms on gene expression and cell tumor behavior was studied with Luciferase-reporter-gene system.In addition,gene methylation, transcription factor and miRNA binding sites on these risk allelic polymorphisms are predicted by bioinformatics and verified by experiment, and the impact of these combination on target gene expression and cell tumor behavior was researched. This research can shed new lights on the relationship between the molecular function of this pathway and individual differences, and perform personal medical on clinic.

前列腺癌是欧洲老年男性常见的恶性肿瘤之一，我国的前列腺癌发病率越来越高。遗传因素是前列腺癌发生发展的重要因素，也是前列腺癌发生发展存在个体差异的主要原因。本项目开展对前期研究富集出的RTKs/ERK信号通路与前列腺癌进行关联分析，并对该通路内风险点的生物功能进行研究，总的技术路线为：在中国前列腺癌协作组（ChinaPCa）收集的大样本中对RTKs/ERK信号通路上基因的多态位点与前列腺癌关联分析，找出与前列腺癌相关的风险位点，了解风险点等位型对组织易感基因表达的影响，并通过荧光素酶报告基因转染研究这些风险位点多态性对基因表达变化和细胞肿瘤行为的影响，另外，通过生物信息学预测及实验验证不同功能区域风险点的多态性对DNA甲基化模式、转录因子或miRNA结合的影响，并研究这些影响对易感基因表达和细胞肿瘤行为的作用。从而更明确阐明这个通路的生物功能与个体差异的关系，更能指导临床进行个体化医疗。

遗传因素是导致前列腺癌（PCa）存在个体化差异的主要原因。我们围绕RTKs/ERK通路与PCa发生发展的个体差异相关，分别从以下方面开展研究：（1）RTKs/ERK通路风险位点多态性与PCa发生、进展的相关性；（2）PCa发生发展相关RTKs/ERK通路基因上风险位点多态性对生物功能的影响；（3）整合多步选择高通量数据集探究PCa的miRNA生物标记物；（4）去势抵抗前列腺癌的综合性网络模型的构建；（5）多性状与基因组多区域多位点关联分析模型的构建。大部分相关成果已发表或已申请软件著作权。