Poster Presentation Advances in Neuroblastoma Research Congress 2016

IGF2BP1 harbours prognostic significance by gene gain, diverse expression and interplay with MYCN   (#231)

Jessica L Bell 1 , Turlapati Raseswari 1 , Tao Liu 2 , Bernard Atmadibrata 2 , Daniel Carter 2 , Glenn Marshall 2 , Johannes H Schulte 3 , Stefan Hüttelmaier 1
  1. Martin Luther University (Halle), Halle (Saale), Germany
  2. Children's Cancer Institute , Sydney, Australia
  3. Department of Pediatrics, Charité Medical School, Berlin, Germany

Previous reports have shown chromosomal 17q21-ter gain in neuroblastoma is both a common and highly prognostic event. The oncofetal, Insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1), is located near the proximal edge of this gained region. IGF2BP1 is also essential for neurocrest migration during development. This study analyzes the DNA copy number and expression of the IGF2BP1 gene in neuroblastoma, and importantly dissects the molecular interplay of the IGF2BP1 and MYCN oncogenes. In two microarray datasets, 77-100 % of tumours had substantial IGF2BP1 mRNA expression. High IGF2BP1 transcript abundance was significantly associated with stage 4 tumours (p = 0.019, 1.1e-06), and decreased patient survival (both p < 0.0001)(1). Additionally, IGF2BP1 was also associated with MYCN gene-amplification and MYCN mRNA abundance. In the 69 neuroblastoma samples IGF2BP1 DNA copy number (increased in 84 % of tumours), mRNA and protein abundance were significantly higher in stage 4 as compared to stage 1 tumours. Importantly, IGF2BP1 protein levels were associated with lower overall patient survival (p = 0.012) and positively correlated with MYCN mRNA, even when excluding MYCN amplified tumours. Although widely expressed in neuroblastoma tumours, the other protein family members IGF2BP2 and IGF2BP3, failed to clearly demonstrate any prognostic trend. In vitro, IGF2BP1 clearly affected MYCN expression and neuroblastoma cell survival. Moreover, we have evidence showing MYCN promotes IGF2BP1 expression, including that the MYCN protein binds the IGF2BP1 promoter, and also that IGF2BP1 is significantly upregulated in precancer cells in a MYCN-driven neuroblastoma mouse model. IGF2BP1 is also expressed highest in cell lines with MYCN amplification. In conclusion, IGF2BP1 was expressed in the majority of neuroblastoma specimens analyzed and was associated with lower overall patient survival and MYCN-abundance. These data demonstrate, for the first-time, IGF2BP1 as a potential oncogene and biomarker in neuroblastoma, which has an important role within MYCN-driven carcinogenesis.

  1. IGF2BP1 harbors prognostic significance by gene gain and diverse expression in neuroblastoma. Bell JL, Turlapati R, Liu T, Schulte JH, Hüttelmaier S. J Clin Oncol. 2015 Apr 10;33(11):1285-93. doi: 10.1200/JCO.2014.55.9880. Epub 2015 Mar 9. PMID: 25753434