MOLECULAR PROGRESSION MODEL FOR TRANSITIONAL CELL CARCINOMA

大多数肿瘤，包括膀胱癌，被认为是通过 一系列的临床组织病理学阶段。这种进步是 伴随着特定的遗传变化，包括激活 原癌基因和肿瘤抑制基因的丢失。最近，我们定义了 在膀胱进展早期发生的两个关键事件：（1）高的 染色体9p21丢失的发生率和较少发生率（2） 微卫星重复序列一种新的肿瘤抑制基因p16， 在9p21区域缺失。然而，染色体缺失的其他区域 和已知高频丢失区域中的其他关键基因仍然存在， 被识别。本提案中的研究旨在制定一项 膀胱癌进展的遗传模型， 新的分子检测策略。首先，各种病变包括， 将对侵袭前和侵袭性肿瘤进行测试，以确定新的区域， 损失（并核实已确定的损失区域）和微型卫星 改变以开发膀胱癌的分子进展模型。 第二，测绘研究将继续确定 14q和其他染色体臂上的假定肿瘤抑制基因位点， 损失的频率很高。最后，我们将继续开发检测方法， 可以检测尿液中微卫星的变化初步可行性 项目表明，这些研究将大大加快， 高通量荧光毛细管和芯片阵列的出现。一 上述研究的结合应该提供重要的洞察力， 与膀胱肿瘤进展相关的特定遗传变化， 最终导致新的肿瘤抑制基因的分离。 此外，建立高度敏感的微卫星重复序列， 在膀胱肿瘤中的应用将允许识别关键目标， 进一步发展分子检测方法。

Most neoplasms, including bladder cancer, are thought to progress through a series of clinical histopathological stages. This progression is accompanied by specific genetic changes which include activation of protooncogenes and loss of tumor suppressor genes. Recently, we defined two critical events that occur early in bladder progression: (1) a high incidence of loss on chromosome 9p21 and less often (2) instability of microsatellite repeats. A novel tumor suppressor gene, p16, is often deleted in the 9p21 region. However, other areas of chromosomal deletion and other critical genes in known regions of high frequency loss remain to be identified. Studies in this proposal are aimed at the development of a genetic model of bladder cancer progression and ultimately in developing new molecular detection strategies. First, a variety of lesions including, preinvasive and invasive tumor will be tested to identify new regions of loss (and verify established regions of loss) and microsatellite alterations to develop a molecular progression model for bladder cancer. Second, mapping studies will continue to identify the precise location of putative tumor suppressor gene loci on 14q and other chromosomal arms with a high frequency of loss. Finally, we will continue development of assays that can detect microsattelite alterations in urine. Initial feasibility projects demonstrate that these studies will be greatly accelerated with the advent of high throughput fluorescent capillary and chip arrays. A combination of the above studies should provide important insight into the specific genetic changes associated with bladder tumor progression and eventually lead to the isolation of novel tumor suppressor genes. Additionally, establishment of highly susceptible microsatellite repeats in bladder tumors will allow identification of critical targets for further development of molecular detection approaches.