Characterization of the Role of Chromosome 1p Deletion in MYCN-Amplified Neuroblastoma

Background
Neuroblastoma is the most common solid extracranial pediatric tumor that originates from uncommitted neural crest cells. High risk patients have an elevated likelihood of becoming resistant to chemotherapy regimens. To understand the underlying cause of this disease, researchers have developed mouse models mimicking neuroblastoma. However, mouse cells behave differently from human cells, suggesting that mouse models may not appropriately reflect how a human neuroblastoma will respond to therapy.  Others have attempted to sequence the genome of neuroblastoma samples to identify common mutations in genes that can potentially be targeted for therapy, but few have been found for this disease.  

Project Goal
We believe that since neuroblastoma (as with other pediatric tumors) presents earlier in life compared to adult tumors, multiple genetic changes need to occur at once. This happens when several genes on the same chromosome are lost or gained, which are common phenomena in neuroblastoma.

In our proposal, we plan to do the following:

1) Starting with adult skin cells from a healthy human patient, we will transform them into stem-like cells, differentiate these cells towards the neural crest lineage, delete a chromosomal region that is frequently lost in neuroblastoma patients and characterize their impact on neuroblastoma formation as well as chemotherapy resistance.

2) Investigate smaller regions within common sites of chromosomal deletions to identify new mutations that have not been discovered from sequencing efforts.  Successful completion of this project will develop a relevant humanized model of the disease and the identification of novel potential therapeutic targets of neuroblastoma.