Genetics of Germline Gene Expression Phenotype in Aggressive Prostate Cancer

描述(申请人提供)：前列腺癌的严重程度从相对良性到极具侵袭性。一些前列腺癌生长缓慢，几乎没有临床症状。在这些情况下，患者最常死于前列腺癌，而不是前列腺癌。侵袭性癌症迅速扩散到淋巴结、其他器官，尤其是骨骼。死亡通常是由这种癌症的侵袭性行为引起的。因此，迫切需要确定那些侵袭性疾病的高危个体，因为这可能对前列腺癌的临床治疗产生重大影响。遗传学被认为在决定前列腺癌风险和前列腺癌预后方面发挥着重要作用。事实证明，连锁分析和基因关联研究等传统方法在识别前列腺癌相关基因方面不太成功。我们认为基因表达谱可以是基因型的产物，侵袭性特征基因可能是通过一个或多个遗传性状产生的，这些性状可能代表着发生更严重前列腺癌的危险因素。因此，我们假设基因表达的变异强烈影响前列腺癌的肿瘤行为和临床结果。基因表达水平可以作为遗传标记的替代品，这些遗传标记可以定位导致基因表达变化和肿瘤侵袭性的基因变异。本研究的具体目的有三个：1)。识别和验证一组在侵袭性较强的前列腺癌患者和侵袭性较弱的前列腺癌患者之间非恶性组织中差异表达的标志性转录本；来绘制这些签名转录本的遗传决定因素。3)。研究选定的候选基因及其在侵袭性前列腺癌中的作用。为了完成这些，我们将调查所有已知的人类基因在前列腺癌患者正常非恶性组织中的表达。我们将评估侵袭性更强的癌症患者和侵袭性较弱的癌症患者之间的遗传表达差异，并确定一组标志性基因，这些基因可能被用作预测侵袭性前列腺癌的遗传标记。我们将以单核苷酸多态为遗传标记，以基因表达水平为数量性状，研究这些标志性基因的遗传决定因素。我们还将通过进行大规模的基因关联研究来探索这些标志性基因在侵袭性前列腺癌中的作用。这项拟议的研究将帮助我们确定前列腺癌侵袭性行为的遗传风险因素和标志物。更重要的是，对遗传基因表达特征的表征可以指向筛查、预防和治疗研究的目标。

DESCRIPTION (provided by applicant): Prostate cancer ranges in severity from relatively benign to extremely aggressive. Some prostate cancers are slow growing, causing few clinical symptoms. In these cases, a patient will most often die with prostate cancer rather than from prostate cancer. Aggressive cancers spread rapidly to the lymph nodes, other organs and in particular, bone. Death usually results from aggressive behavior of this form of cancer. Therefore, there is a critical need to identify those individuals at high risk for aggressive disease as this could have a significant impact on the clinical management of prostate cancer. Genetics is believed to play an important role in determining prostate cancer risk and outcome of prostate cancer. Conventional methods such as linkage analysis and gene association study have proved less successful in identifying genes responsible for prostate cancer. We believe that gene expression profiles can be a product of genotype, and the aggressiveness signature genes may arise through a heritable trait or traits that may represent a risk factor for developing more severe form of prostate cancer. Therefore, we hypothesize that variation in gene expression strongly influences tumor behavior and clinical outcome of prostate cancer. The levels of gene expression function as surrogates for genetic markers that can map the gene variants which underlie both the gene-expression changes and tumor aggressiveness. There are three specific aims for this study: 1). To identify and validate a set of signature transcripts that are differentially expressed in non-malignant tissues between patients with more aggressive and patients with less aggressive prostate cancer; 2). To map genetic determinants of these signature transcripts. 3). To characterize selected candidate genes and their roles in aggressive prostate cancer. To accomplish these, we will survey all known human genes for their expression in normal non-malignant tissues of prostate cancer patients. We will evaluate the inherited expression difference between patients with more aggressive cancer and patients with less aggressive cancer and identify a set of signature genes that may be used as genetic markers for prediction of aggressive prostate cancer. We will investigate genetic determinants of these signature genes using single nucleotide polymorphisms as genetic markers and gene expression level as quantitative trait. We will also explore the role of these signature genes in aggressive prostate cancer by performing large scale gene association study. The proposed study will help us identify genetic risk factors and markers responsible for aggressive behavior of prostate cancer. More importantly, characterization of inherited gene expression signature could point to targets for screening, preventive and therapeutic studies.