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

我们要求对这笔赠款进行补充，以最大限度地实现最初的目标，并在 特别是能够使用特定的目标1重新定义神经母细胞瘤的风险分层 儿童肿瘤学会(COG)。 补助金将用于赠款具体目标1的工作，即： 具体目的1.在高危NB中确定端粒维持的关系 机制(TMM)，即端粒酶表达与交替端粒维持(ALT) 表型、临床结局、MYCN基因组扩增、11q缺失和ATRX 突变。低TERT表达与低/中风险患者的良好结局相关 NB(阶段1、2、4S)。相比之下，高危NB中低/阴性TERT的表达 在治疗难治性肿瘤患者中观察到。与儿童基金会合作 肿瘤组(COG)我们将根据TMM对高危4期NBS进行分类，并确定 TMM与临床转归及肿瘤分子特征的关系 A.在已知ATRX基因的高危4期NBS中，评估TERT和TERC 根据TMM定义肿瘤亚型的表达、C环含量和端粒含量： 1)高端粒酶，2)ALT=端粒酶阴性/C环，3)EST=端粒酶低/C环 不是。确定TMM表型与ATRX突变、端粒含量、 和临床结果。 B.确认TERT和C环表达为NB预后标记物 原发肿瘤。 C.比较端粒酶阳性和ALT的全基因组RNA表达

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