Neuroblastoma is a common and often fatal childhood malignancy of the peripheral nervous system. There is marked heterogeneity in disease presentation; clinical course and outcome. However, the majority of patients have locally aggressive and/or metastatic disease that is often refractory to intensive multimodal therapies. Clinical variables such as age at diagnosis, disease stage and histopathologic grade are important in distinguishing between these divergent phenotypes, but biological and genetic features of the tumor provide critical additional prognostic information. Our group and others have identified nonrandom genomic alterations that occur in specific subsets of cases. Thus, we hypothesize that the pattern of somatically acquired genomic alterations present at diagnosis in primary neuroblastomas can independently predict clinical course and disease outcome. We will test this hypothesis through a prospective and systematic analysis of genomic-based candidate prognostic markers in all neuroblastoma patients enrolled on Children's Oncology Group (COG) clinical trials. In addition, we plan to identify new genetic alterations critical to the development of the highly malignant subset of neuroblastomas. First, we will determine the independent prognostic significance of allelic alterations at chromosome bands 1p36, 11q23, 14q32 and 17q23-25 when these variables are entered into a multivariate analysis, individually and in combinations, with all current prognostic variables. Second, we will develop a microarray-based molecular diagnostic approach for neuroblastoma by using a customized cDNA-based neuroblastoma-specific """"""""chip"""""""". This array should provide a standardized approach to sensitive, specific and reproducible detection of clinically relevant tumor-specific alterations. Third, we will identify novel prognostic markers critical to the development of high-risk disease. We will perform clinical correlative studies in a prospectively identified group of 150 representative cases to determine the clinical significance of recently described genomic alterations. Promising candidate markers would then by analyzed in the full patient cohort. In addition, we will perform genome-wide expression profiling designed to identify the unique patterns of gene expression present in strictly defined clinicobiological subsets. The successful completion of the proposed research will allow us to unequivocally define the genetic alterations present in human neuroblastoma and to use these data to predict clinical phenotype and response to treatment. These studies will therefore provide the infrastructure necessary to apply tumor- specific data to treatment planning algorithms for future patients with neuroblastoma, and thus this project may contribute to improved survival probabilities. It is also expected that these studies will identify novel genes and/or pathways that are unique to the high-risk subset of tumors. It is expected that these will be of prognostic importance and serve as specific targets for developmental therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087847-02
Application #
6618021
Study Section
Special Emphasis Panel (ZRG1-CONC (01))
Program Officer
Lively, Tracy (LUGO)
Project Start
2002-08-01
Project End
2007-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$239,816
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Balamuth, Naomi J; Wood, Andrew; Wang, Qun et al. (2010) Serial transcriptome analysis and cross-species integration identifies centromere-associated protein E as a novel neuroblastoma target. Cancer Res 70:2749-58
Diskin, Sharon J; Hou, Cuiping; Glessner, Joseph T et al. (2009) Copy number variation at 1q21.1 associated with neuroblastoma. Nature 459:987-91
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Attiyeh, Edward F; Diskin, Sharon J; Attiyeh, Marc A et al. (2009) Genomic copy number determination in cancer cells from single nucleotide polymorphism microarrays based on quantitative genotyping corrected for aneuploidy. Genome Res 19:276-83
Mosse, Yael P; Laudenslager, Marci; Longo, Luca et al. (2008) Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455:930-5
Fredlund, Erik; Ringner, Markus; Maris, John M et al. (2008) High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc Natl Acad Sci U S A 105:14094-9
Cole, Kristina A; Attiyeh, Edward F; Mosse, Yael P et al. (2008) A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene. Mol Cancer Res 6:735-42
Raabe, E H; Laudenslager, M; Winter, C et al. (2008) Prevalence and functional consequence of PHOX2B mutations in neuroblastoma. Oncogene 27:469-76
Mosse, Yael P; Diskin, Sharon J; Wasserman, Nora et al. (2007) Neuroblastomas have distinct genomic DNA profiles that predict clinical phenotype and regional gene expression. Genes Chromosomes Cancer 46:936-49

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