Genetic determinants of gene expression phenotypes in aggressive prostate cancer

描述（由申请人提供）： 调节变异被认为在形成个体之间的表型差异中起重要作用，因此也很可能影响疾病易感性和进展。在这项研究中，我们建议利用表达QTL定位和共表达基因网络分析来识别和表征负责前列腺癌侵袭性表型的候选基因和遗传变异。我们的假设是，大多数前列腺癌侵袭性表型的遗传变异对候选基因表达具有调节作用，只有通过检查原发组织（此处为前列腺）才能完全理解调节性SNP。为了验证这一假设，我们将使用一个案例-案例研究设计，并通过整合DNA序列变异和基因表达与临床性状信息，应用一种创新而可行的方法。四个具体目标是：1。利用基于表达遗传学的eQTL作图方法鉴定新的攻击性相关候选SNP; 2.利用基于整合系统遗传学的网络分析方法鉴定新的攻击性相关候选SNP; 3.对于目标1和2中鉴定的新的候选SNP，进行额外的基于关联的研究以确认它们与前列腺癌的侵袭性相关表型的关联;以及4.通过精细定位鉴定候选eSNP，认识到目标3中鉴定的候选eSNP将最有可能与eSNP连锁不平衡。了解侵袭性表型的遗传机制将对预防策略、预后和潜在的靶向治疗产生重大影响。 公共卫生相关性： 前列腺癌可以是相对无害的或极具侵略性的。本研究的目的是确定和表征前列腺癌侵袭性（临床上更显着）形式的遗传原因。了解侵袭性疾病的遗传机制将对预防策略，预后和潜在的靶向治疗产生重大影响。

DESCRIPTION (provided by applicant): The regulatory variation is believed to play an important role in shaping phenotypic differences among individuals and thus is also very likely to influence disease susceptibility and progression. In this study, we propose to take advantage of the expression QTL mapping and co-expressed gene network analysis to identify and characterize candidate genes and genetic variants that are responsible for aggressive phenotype of prostate cancer. Our hypothesis is that most genetic variants responsible for an aggressive phenotype of prostate cancer have regulatory effect on candidate gene expression and complete understanding of regulatory SNPs can only be achieved by examining primary tissue (here, prostate). To test this hypothesis, we will use a case-case study design and apply an innovative yet feasible approach by integrating DNA sequence variation and gene expression with clinical trait information. The four Specific Aims are: 1. Identify novel aggressiveness-related candidate SNPs by utilizing an expression genetics-based eQTL mapping approach; 2, Identify novel aggressiveness-related candidate SNPs by utilizing an integrative systems genetics-based network analysis approach; 3. For the novel candidate SNPs identified in Aims 1 and 2, perform additional association-based studies to confirm their association with an aggressiveness-related phenotype for prostate cancer; and 4. Identify candidate causal-SNPs by fine mapping, recognizing that the candidate eSNPs identified in Aim 3 will most likely be in linkage disequilibrium with the causal-SNPs. Understanding genetic mechanisms underlying the aggressive phenotype will have significant impact on prevention strategies, prognosis and potentially targeted therapy. PUBLIC HEALTH RELEVANCE: Prostate cancer can be relatively harmless or extremely aggressive. The goal of this study is to identify and characterize genetic causes of the aggressive (clinically more significant) form of prostate cancer. An understanding the genetic mechanism underlying the aggressive disease will have a significant impact on prevention strategies, prognosis and potentially targeted therapy.