title: Polymorphisms in the calcium-sensing receptor gene are associated with clinical outcome of neuroblastoma.
abstract: BACKGROUND
  Neuroblastic tumors include the neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. Clinical behavior of these developmental malignancies varies from regression to aggressive growth with metastatic dissemination. Several clinical, histological, genetic, and biological features are associated with this diversity of clinical presentations. The calcium-sensing receptor (CaSR) is a G-protein coupled receptor with a key role in calcium homeostasis. We have previously reported that it is expressed in benign, differentiated neuroblastic tumors, but silenced by genetic and epigenetic events in unfavorable neuroblastomas. We have now analyzed three functionally relevant polymorphisms clustered at the signal transduction region of the CaSR (rs1801725, rs1042636 and rs1801726) to assess if genetic variants producing a less active receptor are associated with more aggressive disease course.
  
  
  METHODS
  Polymorphisms were analyzed in DNA samples from 65 patients using specific Taqman Genotyping Assays.
  
  
  RESULTS
  Mildly inactivating variant rs1801725 was associated with clinical stage 4 (P = 0.002) and the histological subgroup of undifferentiated neuroblastomas (P = 0.046). Patients harboring this polymorphism had significantly lower overall (P = 0.022) and event-free survival (P = 0.01) rates than those who were homozygous for the most common allele among Caucasians. However, this single locus genotype was not independently associated with outcome in multivariate analyses. Conversely, the tri-locus haplotype TAC was independently associated with an increased risk of death in the entire cohort (Hazard Ratio = 2.45; 95% Confidence Interval [1.14-5.29]; P = 0.022) and also in patients diagnosed with neuroblastomas (Hazard Ratio = 2.74; 95% Confidence Interval [1.20-6.25]; P = 0.016).
  
  
  CONCLUSIONS
  The TAC haplotype includes the moderately inactivating variant rs1801725 and absence of the gain-of-function rs1042636 polymorphism. Thus, its association with metastatic disease and poor outcome would add to our previous data and further support that inactivation of the CaSR gene is a mechanism associated with neuroblastoma malignant behavior.
authors.affiliation: Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu and Fundació Sant Joan de Déu, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Masvidal
authors.forename: Raquel
authors.initials: R
authors.lastname: Iniesta
authors.forename: Carla
authors.initials: C
authors.lastname: Casalà
authors.forename: Patricia
authors.initials: P
authors.lastname: Galván
authors.forename: Eva
authors.initials: E
authors.lastname: Rodríguez
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lavarino
authors.forename: Jaume
authors.initials: J
authors.lastname: Mora
authors.forename: Carmen
authors.initials: C
authors.lastname: de Torres
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics*; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D055815:Young Adult
chemical_list: D044169:Receptors, Calcium-Sensing