Contact:
Professor Murray Norris
Email: mnorris@ccia.unsw.edu.au

The majority of patients with neuroblastoma present with widely disseminated disease at diagnosis and despite highly intensive treatment regimens, the prognosis for such patients is dismal. A number of prognostic markers have been identified for this disease and one of the most powerful is MYCN oncogene amplification, which can be demonstrated in 25-30% of primary untreated neuroblastomas.

Numerous reports have confirmed the association between MYCN amplification and rapid tumour progression, advanced clinical stage and poor outcome. MYCN regulates numerous genes mediating cell behaviour; however those genes necessary or sufficient for tumorigenesis have remained elusive. We have sought to identify pathways downstream of MYCN that are required for neuroblastoma initiation and maintenance, as these represent potential candidates for therapeutic intervention.

N-ethyl-N-nitrosurea (ENU) was discovered in the 1970s to be a powerful compound that causes mutations in DNA. ENU works by creating DNA adducts that cause heritable mutations during DNA replication and mutations occur at a rate of approximately 1 base every 1000 bases. ENU screening processes employ a phenotype-driven methodology that assumes no bias towards any gene or pathway, and as such are a powerful tool for elucidating new molecules that are important to the disease of interest.

In collaboration with the Walter and Eliza Hall Institute (Victoria), we have undertaken a large ENU mutagenesis screen in order to identify co-factors that are responsible for mediating the oncogenic effects of MYCN in neuroblastoma tumorigenesis. We have generated a founder line with a significant heritable increase in tumour latency and we will use this, and other lines showing heritable delays in tumorigenesis, to identify the responsible genes by a combination of mapping and next-generation sequencing. This forward genetic screen offers the potential to discover critical cellular genes whose loss of function results in a reduction of neuroblastoma tumorigenesis, and as such may provide novel pathways for therapeutic targeting in this disease.

External Collaborators: Doug Hilton and Ben Kile, Walter and Eliza Hall Institute, VIC