Genetic variants in the promoter region of the calcium‐sensing receptor gene are associated with its down‐regulation in neuroblastic tumors

Authors:
Publisher website
Google Scholar
Abstract
We have previously reported that the calcium‐sensing receptor (CaSR) is expressed in benign, differentiated neuroblastic tumors, and epigenetically silenced in undifferentiated, malignant cases. Furthermore, cinacalcet, an allosteric activator of the CaSR, reduces neuroblastoma tumor growth in preclinical models. However, to identify patients that might benefit from this treatment, a complete understanding of mechanisms governing CaSR expression in these tumors would be required. We have now analyzed two polymorphisms in the promoter region of theCASRgene (rs7652589 and rs1501899) by allelic discrimination in neuroblastoma patients and cell lines. Association of genotypes and haplotypes withCaSRmRNA levels andCASRpromoter P2 methylation status was determined. Data presented show that minor alleles rs7652589 and rs1501899, present either in homo‐ or heterozygosis, were correlated with reducedCaSRmRNA levels in matching primary tumors and this association was independent ofCASRpromoter P2 hypermethylation. Haplotype AA was independently associated with reducedCaSRexpression after adjusting by promoter P2 methylation status. These polymorphisms were identified in some ganglioneuromas in which CaSR expression is low despite exhibiting a high degree of differentiation. Furthermore, homozygous variants rs7652589 and rs1501899 were detected in SH‐SY5Y cells, which are devoid ofCaSRexpression in the absence of hypermethylation ofCASRpromoter P2. In summary, minor alleles rs7652589 and rs1501899 are associated with reduced CaSR expression in neuroblastic tumors and neuroblastoma cell lines in which theCASRgene promoter P2 is not hypermethylated. Therefore, they potentially represent an additional mechanism ofCASRtranscriptional regulation in this group of developmental malignancies.
Funding Information
  • Ministerio de Agricultura, Alimentación y Medio Ambiente (FISPI14/00040)

This publication has 43 references indexed in Scilit: