Identification of Genes for Predicting Prognosis in Pediatric Cancers

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Neuroblastomas are cancers of neural crest origin with variable prognoses depending on age at presentation, stage, histology, presence of MYCN amplification, chromosomal ploidy, and deletion status of 1p36. Very little is known of the molecular mechanisms that confer good or poor prognosis in this and other malignancies. We have demonstrated that cancers can be diagnosed on the basis of gene expression profiling using cDNA microarrays and sophisticated pattern recognition algorithms such as Artificial Neural Networks. The Oncogenomics Section has expanded this study in collaboration with the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) group to perform more extensive genomic analysis using next generation whole genome, exome and transcriptome sequencing on a series of clinically annotated neuroblastoma samples. With these methods we are identifying somatic mutations, and tumor-specific expression patterns, or fingerprints, that uniquely identify a poor prognostic group, as well as those associated with specific genetic aberrations including MYCN amplification. By these techniques, we hope to classify genomic profiles that correlate with prognosis and hence identify the genes that confer these biological properties. Once we have narrowed down the list of genes that defines a particular cancer or diagnostic or prognostic group cluster to a minimum number, we will translate our findings to the patient for example develop multiplex PCR-based assays for diagnostic purposes in the clinic. Isotope-coded affinity tags (ICAT), stable isotope labeling by amino acids in cell culture (SILAC) and phospho-proteomic analysis allows the quantitative measurement of protein expression levels and the phosphorylation status in different cell types and tissues. In these methods proteins from two samples can be compared by chemically labeling both samples with the light and heavy isotopic forms of a reagent respectively. With this and other proteomic method we plan to sequence and identify up to 3000-4000 differentially expressed proteins between tumors with poor (death) and good (event free survival > 3yrs) outcome. These proteins and their phosphorylation status indicates potential targets for therapy, diagnostic and prognostic markers for high-risk patients as well as provide important clues on the biology of these tumors that fail to respond to conventional therapy.