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

先行基因：一类新型膀胱癌早期检测标记物

• 批准号: 8135636
• 负责人: BOGDAN A CZERNIAK
• 金额: $ 31.33万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8135636
• 关键词: 13q14; 17p13; 3q22.1; Address; Apoptosis; BH3 Domain; Biological Assay; Biological Markers; Bladder; Carcinoma; Cell Proliferation; Cell Survival; Clinical; Clinical Trials; Clonal Expansion; Co-Immunoprecipitations; Collaborations; Contracts; DNA; Data; Detection; Development; Diagnostic; Disease; Early Diagnosis; Early identification; Epigenetic Process; Event; Genes; Genetic; Genetic Materials; Germ-Line Mutation; Goals; Grant; Growth; Hereditary Malignant Neoplasm; Human; Hypermethylation; In Situ; Invasive Lesion; Laboratories; Lesion; Letters; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Maps; Medical center; Methylation; Modeling; Molecular; Monitor; Mutation; Neoplasms; Nude Mice; Organ; Patient Monitoring; Patients; Phase; Play; Preneoplastic Conditions; Preventive Intervention; Promoter Regions; Proteins; RB1 gene; Research; Resected; Resolution; Risk Factors; Role; Sampling; Sensitivity and Specificity; Small Interfering RNA; Surface; TP53 gene; Testing; Tissues; Tumor Suppressor Proteins; Urine; Urothelial Cell; Urothelium; Validation; cancer recurrence; carcinogenesis; cohort; genome-wide; high risk; insight; mouse model; novel; novel marker; promoter; prospective; therapeutic target; tumor; yeast two hybrid system

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.

先行基因：一类新型膀胱癌早期检测标记物 识别与癌前病症发展相关的早期变化将提供 癌症发生早期事件的重要线索，有助于开发早期癌症的新标记物 隐匿性肿瘤的识别。我们进行了全基因组搜索以寻找遗传物质的丢失 对应于正常尿路上皮、原位癌前病变和侵袭性尿路上皮的多个 DNA 样本 从切除的人类膀胱的整个粘膜表面提取的癌。命中率分析 与癌前病变的生长优势相关，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 膀胱癌的发展包含一类独特的基因，称为先行者 (FR) 基因 参与前体条件的克隆扩增。我们将精力集中在其中一项上 区域，其中包含模型肿瘤抑制因子 RB1。我们使用高分辨率全器官绘图 SNP，有助于识别三个位置候选 FR 基因（ITM2B、P2RY5 和 CHC1L） 连续映射到 RB1。我们还提供证据表明它们的失活可能对于 癌前病变的发展。使用同一区域的组合遗传和表观遗传作图 我们已经鉴定了一个与 RB1 (GPR38) 相邻的额外 FR 基因。表达、突变和 甲基化分析表明，至少有两个原型 FR 基因（ITM2B 和 GPR38）经常被 膀胱癌中存在甲基化，并且可以在排泄的尿液样本中检测到它们的甲基化。这个提议 描述了我们持续研究的重点是原型 FR 基因 (ITM2B) 的作用和功能 与 RB1 相邻。我们的初步数据表明该基因在控制细胞增殖中发挥着关键作用 肿瘤前克隆并且在膀胱癌中经常被甲基化。因此，除了功能性 我们建议将频繁甲基化的 FR 基因与其他甲基化标记结合使用的研究 膀胱癌的检测。我们研究的具体目的如下： 具体目的 1. 明确 FR 基因 (ITM2B) 在膀胱癌中的作用和功能。具体目标 2. 识别有效的甲基化 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 膀胱癌复发高风险患者前瞻性队列中的生物标志物甲基化组。