In-UTR mutations in neuroblastoma: Functional consequences and therapeutic implications
Neuroblastoma (NB) is the cancer of the immature nerve cells. It affects mostly infants and children and, with the exception of brain tumors, is the most common solid tumor of the childhood, accounting for approximately 15% of all pediatric cancer deaths. Although some of the tumors dissolve spontaneously, for patients with high-risk neuroblastoma survival remains well below 40%, despite aggressive and rather debilitating therapy. This necessitates the development of new targeted therapies. One of the proteins proven to contribute to NB is a binding partner of the insulin-like growth factor (IGF1R). Most importantly, various drugs have been developed that inactivate IGF1R. This development raises the following key question: which NB patients could benefit from such drugs? We propose that one of the important sensitivity factors is naturally occurring genetic variations in the IGF1R gene. These variations do not affect the protein structure, but instead prevent silencing of the IGF1R gene by so-called microRNAs. Upon conclusion of this work, we will have established a positive correlation between genetic polymorphisms in the IGF1R gene, its production levels, and sensitivity to some of the better validated and clinically promising IGF1R-targeting drugs.