Chromosomal 17q21-ter gain in neuroblastoma is both a common and clinically significant occurrence. The oncogenic, insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) gene is located near the proximal edge of this region. We have previously reported that in 69 neuroblastoma samples, IGF2BP1 DNA copy number (increased in 84% of tumors), mRNA, and protein levels are significantly higher in stage 4 compared with stage 1 tumors. Moreover, clinical and experimental data pointed to a strong association of IGF2BP1 with the MYCN oncogene. From the late 1990s onwards, 17q gain and 1p deletions (either alone or both) have been speculated as essential precursors to the MYCN amplification. As the tumor suppressive, miR-34a is located within 1p and is known to directly target MYCN and putatively IGF2BP1 mRNAs (Targetminer website), in this study we analyzed the co-occurrence of IGF2BP1 gain, miR-34a loss and MYCN amplification) in 69 neuroblastomas. qPCR was utilized to assess copy number. Changes were found for IGF2BP1 (58 tumors), miR-34a (15) and MYCN (12). miR-34a was never completed deleted. Interestingly, in all (12/12) MYCN amplified tumors, miR-34a was partially lost. Whilst, IGF2BP1 was gained in 9/12 MYCN amplified tumors. IGF2BP1 and miR-34a were aberrant together only twice with the absence of MYCN amplification. Of the 17 patients that died, all but one had at least an IGF2BP1 or miR-34a change in copy number. This stage 4 patent also had low MYCN protein levels, comparable to the stage 1 patients, indicating an aggressive tumor not involving the MYCN pathway. may A second larger cohort is certainly required to confirm these important results. IGF2BP1 and miR-34a locus have aberrant copy numbers in the majority of neuroblastoma, most strikingly, in the patients that died. IGF2BP1 and miR-34a may just be representative DNA of the larger locus changes and not be the causative event in affected neuroblastoma, but because of their known roles in cancer, the above results are intriguing. Although further experimental data is required, we speculate that either IGF2BP1 or mir-34a oncogenic changes are required for the clonal expansion of MYCN amplified tumor cells in neuroblastoma, and that these factors are crucial in the ability for an increase in MYCN transcription to be oncogenic in neuroblastoma.
Citation Format: Jessica L. Bell, Stefan Hüttelmaier. IGF2BP1 and miR-34a genetic instability found in deadly neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-137.