Alternate Telomere Maintenance Mechanisms in High Risk Neuroblastoma as Prognostic Indicators and Therapeutic Targets Yr 1 to 5

高风险神经母细胞瘤中的替代端粒维持机制作为第 1 至 5 年的预后指标和治疗目标

• 批准号: 10366253
• 负责人: CHARLES Patrick REYNOLDS
• 金额: $ 6万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-29 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10366253
• 关键词: 11q; ATRX gene; Clinical; Collaborations; Expressed Sequence Tags; Genetic Transcription; Genomics; Genotype; Grant; MYCN gene; Molecular; Mutation; Neuroblastoma; Outcome; Patients; Pediatric Oncology Group; Phenotype; Primary Neoplasm; Prognostic Marker; Refractory; Risk; Telomerase; Telomere Maintenance; Validation; Work; base; genome-wide; high risk; risk stratification; telomere; therapeutic target; tumor

We request a supplement for this grant to enable optimal completion of the original aims, and in particular to enable using specific Aim 1 to re-define risk stratification for neuroblastoma within the Children’s Oncology Group (COG). The supplement will be used for work on Specific Aim 1 of the grant, which is: Specific Aim 1. In high-risk NB determine the relationship of telomere maintenance mechanisms (TMM), i.e. telomerase expression vs. alternate telomere maintenance (ALT) phenotype, to clinical outcome, MYCN genomic amplification, 11q deletions, and ATRX mutations. Low TERT expression is associated with favorable outcome in low/intermediate risk NB (stages 1, 2, 4S). By contrast, low/negative TERT expression in high-risk NB has been observed in patients with treatment-refractory tumors. In collaboration with the Children’s Oncology Group (COG) we will categorize high-risk stage 4 NBs by TMM and determine the relationship of TMM to clinical outcome and tumor molecular features. A. In high-risk stage 4 NBs for which ATRX genotype is known assess TERT and TERC expression, C-circle content, and telomere content to define subsets of tumors based on TMM: 1) telomerase-high, 2) ALT = telomerase negative/c-circle +, 3) EST = telomerase-low/C-circle negative. Determine the association of TMM phenotype with ATRX mutations, telomere content, and clinical outcome. B. Confirm TERT and C-circle expression as NB prognostic markers in a validation set of primary tumors. C. Compare genome-wide RNA expression of telomerase-positive and ALT

我们要求该赠款的补充，以实现最佳的原始目标，并在 特定要使用特定目标1重新定义神经母细胞瘤的风险分层 儿童肿瘤学小组（COG）。 该补充剂将用于赠款的特定目标1的工作，即： 特定目标1。在高风险中，NB确定端粒维护的关系 机制（TMM），即端粒酶表达与替代端粒维护（ALT） 表型，临床结果，MYCN基因组扩增，11Q缺失和ATRX 突变。低/中级风险中的低TERT表达与有利的结果有关 NB（第1、2、4s阶段）。相比之下，高风险NB中的低/负TERT表达已经 在治疗难治性肿瘤患者中观察到。与孩子们合作 肿瘤学组（COG）我们将按TMM分类高风险阶段4 NBS并确定 TMM与临床结果和肿瘤分子特征的关系。 答：在高风险阶段4 NB中，ATRX基因型是已知的评估和TERC 表达，C圈含量和端粒含量以基于TMM定义肿瘤的亚集： 1）端粒酶高，2）alt =端粒酶负/c-cird +，3）est =端粒酶 - 低/c-cirvle 消极的。确定TMM表型与ATRX突变，端粒含量的关联， 和临床结果。 B.在验证集中确认TERT和C-CIRCLE表达 原发性肿瘤。 C.比较端粒酶阳性和ALT的全基因组RNA表达