Oral Presentation Advances in Neuroblastoma Research Congress 2016

The FOXM1 target gene BIRC5 (survivin) is a top ranked dosage sensitive gene located on the common large copy number 17q gained segment in neuroblastoma. (#97)

Suzanne Vanhauwaert 1 , Geertrui Denecker 1 , Anneleen Beckers 1 , Daniel R Carter 2 , Givani Dewyn 1 , Els Janssens 1 , Glenn Marshall 2 , Shuning He 3 , Katleen De Preter 1 , Thomas Look 3 , Frank Speleman 1
  1. Center for Medical Genetics, Ghent University, Ghent, Belgium
  2. Children’s Cancer Institute, University of New South Wales Sydney, Sydney, Australia
  3. Department of Pediatric oncology, Dana farber Cancer Institue, Boston, USA

Neuroblastoma can be regarded as a copy number disease. Mutation burden is low while both focal and large copy number imbalances are observed in nearly all cases. Amongst these, 17q gain is the most frequent in high stage tumors.  In the TH-MYCN mouse model we observed dynamic upregulation of multiple 17q genes as measured in superior cervical and celiac ganglia and and/or full blown tumors which were harvested from TH-MYCN and wild type mice 1, 2 and 6 weeks after birth. Finally, for several of these genes we also observed strong negative correlation between expression levels and survival. These genes included TOP2A, BIRC5 and BRIP1 ranked as 3rd, 5th and 8th highest upregulated 17q genes, all of which are bona fide FOXM1 target genes. FOXM1 was recently identified as a major predictor of adverse outcomes across several human cancer types while we found FOXM1 as part of an embryonal stem cell signature marking patients with ultra high risk neuroblastoma. In keeping with this, the FOXM1 target gene BIRC5, implicated in cell division and apoptosis, is highly expressed during embryonic development as well as in several cancer types and correlated with poor survival in neuroblastoma patients. To establish the in vivo role of BIRC5, we created a BIRC5 stable zebrafish line by injection of dβh-BIRC5 in wild type zebrafish. While stable BIRC5 overexpressing lines did not develop tumors, our first results of injection of dβh-BIRC5 overexpression constructs in the offspring of dβh-MYCN zebrafish are indicative for accelerated neuroblastoma development. Also, BIRC5 inhibitors are already in clinical trials and currently we are testing for synergistic effects with TOP2A and BRIP1 inhibitors in vitro and in vivo. In conclusion, we provide evidence for dosage effects for several 17q genes as candidate cooperative drivers during neuroblastoma development and provide a novel dβh-BIRC5 overexpressing zebrafish model for future studies towards unraveling the enigmatic role of 17q gain in neuroblastoma biology and clinical behaviour.