Forerunner Genes: A Novel Class of Early Detection Markers for Bladder Cancer

先导基因：一类新的膀胱癌早期检测标记物 识别与癌前状态发展相关的早期变化将提供 癌变早期事件的重要线索，有助于开发早期癌症的新标记物 隐匿性肿瘤的鉴别。我们对遗传物质的丢失进行了全基因组搜索 与正常尿路上皮、原位癌前病变和侵袭性病变相对应的多个DNA样本 从切除的人膀胱的整个粘膜表面提取的癌。命中率分析 癌前病变的生长优势使我们能够识别六个染色体区域 映射到3q22.1、5q22.2-5q23.3、9q22.12、10q26.1、13q14和17p13，这可能对 膀胱癌的发生，并包含一类独特的基因，称为前体(FR)基因 参与克隆扩增的前体条件。我们将我们的努力集中在其中一项上 区域，其中包含一个模型肿瘤抑制因子RB1。我们使用了高分辨率的全器官标测 SNPs，这有助于识别三个位置候选FR基因(ITM2B、P2RY5和CHC1L) 连续映射到RB1。我们还提供了证据表明，它们的失活很可能是 癌前病变的发展。利用同一区域的联合遗传和表观遗传作图 我们又发现了一个与RB1(GPR38)相邻的FR基因。表达，突变，和 甲基化分析表明，至少两个原型FR基因(ITM2B和GPR38)经常 在膀胱癌中甲基化，其甲基化可在尿液样本中检测到。这项建议 描述了我们对原型FR基因(ITM2B)的作用和功能的持续研究 与RB1相邻。我们的初步数据表明，该基因在控制肿瘤细胞增殖中起关键作用。 癌前克隆，在膀胱癌中经常发生甲基化。因此，除了功能上的 我们建议使用频繁甲基化的FR基因与其他甲基化标记相结合的研究 膀胱癌的检测。我们研究的具体目标如下：具体目标1.明确 FR基因(ITM2B)在膀胱癌中的作用和功能具体目标2.确定有效的甲基化 一组基因，包括用于检测尿液中膀胱癌的FR基因。具体目标3.验证 膀胱癌复发高危人群中生物标记物甲基化的研究。

Forerunner Genes: A Novel Class of Early Detection Markers for Bladder Cancer Identification of early changes associated with the development of preneoplastic conditions would provide important clue on early events of carcinogenesis and could aid in the development of novel markers for early identification of occult neoplasia. We performed genome-wide search for losses of genetic material on multiple DNA samples corresponding to normal urothelium, in situ preneoplastic lesions, and invasive carcinoma extracted from the entire mucosal surface of resected human bladders. The analysis of hits associated with growth advantage of preneoplastic lesions allowed us to identify six chromosomal regions mapping to 3q22.1,5q22.2-5q23.3,9q22.12, 10q26.1, 13q14,and 17p13 that may be critical for the development of bladder cancer and contain a distinct class of genes referred to as forerunner (FR) genes involved in the clonal expansion of precursor conditions. We concentrated our efforts on one of these regions, which contain a model tumor suppressor RB1. We used high-resolution whole-organ mapping with SNPs, which facilitated the identification of three positional candidate FR genes (ITM2B, P2RY5and CHC1L) mapping contiguously to RB1. We also provide evidence that their inactivation is likely to be critical for the development of preneoplastic lesions. Using combined genetic and epigenetic mapping of the same region we have identified an additional FR gene contiguous to RB1 (GPR38). The expression, mutational, and methylation analyses showed that at least two of the prototypic FR genes (ITM2B and GPR38) are frequently methylated in bladder cancer and their methylation can be detected in voided urine samples. This proposal describes our continuing studies focused on the role and function of the prototypic FR gene (ITM2B) contiguous to RB1. Our preliminary data implicate that this gene plays a key role in controlling proliferation of preneoplastic clone and is frequently methylated in bladder cancer. Therefore, in addition to the functional studies we propose to use the frequently methylated FR genes combined with other methylation markers for the detection of bladder cancer. The specific aims for our study are as follows: Specific Aim 1. Clarify the role and function of the FR gene (ITM2B) in bladder cancer. Specific Aim 2. Identify an effective methylation panel of genes, including FR genes for detecting bladder cancer in urine. Specific Aim 3. Validate the methylation panel of biomarkers in a prospective cohort of patients at high risk of bladder cancer recurrence.