MOLECULAR PROGRESSION MODEL FOR TRANSITIONAL CELL CARCINOMA

大多数肿瘤，包括膀胱癌，被认为是通过 一系列临床组织病理学分期。这一进程是 伴随着特定的基因变化，包括激活 原癌基因与肿瘤抑制基因的丢失。最近，我们定义了 发生在膀胱进展早期的两个关键事件：(1)高潮 染色体9p21丢失的发生率和较少发生(2) 微卫星重复。一种新的肿瘤抑制基因p16经常 在9p21区域删除。然而，其他区域的染色体缺失 而在已知的高频丢失区域中的其他关键基因仍然 被指认出来。这项提案中的研究旨在开发一种 膀胱癌进展和最终发展的遗传模型 新的分子检测策略。首先，各种损伤，包括， 将对侵袭前和侵袭性肿瘤进行测试，以确定新的区域 丢失(并验证已建立的丢失区域)和微卫星 为了建立膀胱癌的分子进展模型而进行的改变。 第二，测绘研究将继续确定 14Q和其他染色体臂上可能的抑癌基因座 高频率的损失。最后，我们将继续发展检测方法。 可以检测到尿液中微卫星的变化。初步可行性 项目表明，这些研究将随着 高通量荧光毛细管和芯片阵列的出现。一个 以上研究的结合应该会为我们提供重要的见解 与膀胱癌进展和预后相关的特异性基因改变 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 将允许识别关键靶点以治疗膀胱肿瘤 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.