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，以最佳地完成最初的目标

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