EARLY DETECTION OF URINARY BLADDER CANCER

描述（由申请人提供）：该项目的总体目标是开发新的生物标志物和诊断策略，用于早期检测隐匿性膀胱肿瘤及其从内皮内肿瘤前病变到浸润性癌症的进展。目前的建议是早期检测研究网络第一个周期进行的研究的延伸和合乎逻辑的继续。这些研究鉴定出了对膀胱癌发展至关重要的六个染色体区域，并为一类被称为“先导”的新型基因的存在提供了证据，这些基因的参与先于主要肿瘤抑制基因在癌症发展中的功能丧失。我们假设膀胱癌前病变的原位克隆扩增是由与已知主要肿瘤抑制因子（如RB1）相邻的先导基因的功能丧失引起的。我们利用短干扰RNA的体外研究提供了证据，证明这些基因功能的丧失对尿路上皮细胞的生长优势至关重要。因此，鉴定新的先导基因并研究它们在人类膀胱癌前病变早期隐匿阶段的参与，不仅可能为人类癌症的发展提供重要的机制线索，而且可能鉴定出一类新的早期检测标志物，能够检测人类癌症发展的临床和显微镜隐匿阶段。基于最近发现的致癌激酶STK15/BTAK/Aurora-A的扩增和过表达，我们还假设了膀胱癌进展的互补机制，该激酶参与调节染色体分离和中心体功能，并且最近能够破坏p53肿瘤抑制蛋白的稳定。在这项资助中，我们提出以下主要研究小组：

DESCRIPTION (provided by applicant): The overall goal of this project is to develop novel biomarkers and diagnostic strategies for the early detection of occult urinary bladder neoplasia and its progression from intraurothelial preneoplastic conditions to invasive cancer. The current proposal represents an extension and logical continuation of the studies performed during the first cycle of the Early Detection Research Network (EDRN). These studies have led to the identification of six chromosomal regions critical for the development of bladder cancer and have provided evidence for the existence of a novel class of genes referred to as "forerunners" whose involvement precedes the loss of function of major tumor suppressor genes in the development of cancer. We hypothesize that in situ clonal expansion of bladder preneoplasia is caused by loss of function of the forerunner genes mapping contiguously to known major tumor suppressors such as RB1. Our in vitro studies utilizing short interference RNA provide evidence that loss of function of these genes is critical for growth advantage of urothelial cells. Thus, the identification of novel forerunner genes and the investigation of their involvement in early occult phases of human bladder preneoplasia may not only provide important mechanistic clues to the development of human cancer but may also identify a novel class of early detection markers capable of detecting the clinically and microscopically occult phases of human cancer development. We also hypothesized a complementary mechanism of bladder cancer progression based on the amplification and overexpression of a recently identified oncogenic kinase STK15/BTAK/Aurora-A shown to be involved in regulating chromosomal segregation and centrosome function and more recently to be capable of destabilizing the p53 tumor suppressor protein. In this grant we propose the following major groups of studies: (1) Perform functional analyses and assessment of the already identified putative "forerunner genes" (ITM2B, P2RY5, and CHClL) located contiguously to RB1 as novel early detection biomarkers. Additionally, we propose to characterize other predicted forerunner gene harboring loci mapping on chromosomes 17p13 and 5q22-23 and to assess the candidate genes identified as biomarkers for bladder cancer detection. We will also investigate the contribution of genetic and epigenetic mechanisms in the functional inactivation of each of the genes to elucidate a comprehensive view of the role of forerunner genes in the malignant transformation process that will enhance our ability to detect forerunner genes and provide clinically relevant markers for early detection. (2) Extension of our studies on STK15/BTAK/Aurora-A and its interacting genes involved in the pathway as biomarkers for bladder cancer detection. (3) Combine the STK15/BTAK/Aurora-A and its regulatory partners with the forerunner genes in a panel of approximately 15 markers testing their ability to identify occult bladder neoplasia in a prospective validation trial. Since both major categories of novel genes, i.e. the forerunner genes and Aurora-A with its partners, appear to be universally involved in human carcinogenesis the completion of this project will have major relevance for early detection of other common human cancers.