title: c.1810C>T polymorphism of NTRK1 gene is associated with reduced survival in neuroblastoma patients.
abstract: BACKGROUND
  TrkA (encoded by NTRK1 gene), the high-affinity tyrosine kinase receptor for neurotrophins, is involved in neural crest cell differentiation. Its expression has been reported to be associated with a favourable prognosis in neuroblastoma. Therefore, the entire coding sequence of NTRK1 gene has been analysed in order to identify mutations and/or polymorphisms which may alter TrkA receptor expression.
  
  
  METHODS
  DNA was extracted from neuroblastomas of 55 Polish and 114 Italian patients and from peripheral blood leukocytes of 158 healthy controls. Denaturing High-Performance Liquid Chromatography (DHPLC) and Single-Strand Conformation Polymorphism (SSCP) analysis were used to screen for sequence variants. Genetic changes were confirmed by direct sequencing and correlated with biological and clinical data.
  
  
  RESULTS
  Three previously reported and nine new single nucleotide polymorphisms were detected. c.1810C>T polymorphism present in 8.7% of cases was found to be an independent marker of disease recurrence (OR = 13.3; p = 0.009) associated with lower survival rates (HR = 4.45 p = 0.041). c.1810C>T polymorphism's unfavourable prognostic value was most significant in patients under 18 months of age with no MYCN amplification (HR = 26; p = 0.008). In-silico analysis of the c.1810C>T polymorphism suggests that the substitution of the corresponding amino acid residue within the conservative region of the tyrosine kinase domain might theoretically interfere with the functioning of the TrkA protein.
  
  
  CONCLUSIONS
  NTRK1 c.1810C>T polymorphism appears to be a new independent prognostic factor of poor outcome in neuroblastoma, especially in children under 18 months of age with no MYCN amplification.
authors.affiliation: Department of Biology and Genetics, Medical University of Gdańsk, Debinki 1, 80-211 Gdańsk, Poland. b.lipska@gumed.edu.pl
authors.forename: Beata S
authors.initials: BS
authors.lastname: Lipska
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Drozynska
authors.forename: Paola
authors.initials: P
authors.lastname: Scaruffi
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.forename: Ewa
authors.initials: E
authors.lastname: Izycka-Swieszewska
authors.forename: Szymon
authors.initials: S
authors.lastname: Zietkiewicz
authors.forename: Anna
authors.initials: A
authors.lastname: Balcerska
authors.forename: Danuta
authors.initials: D
authors.lastname: Perek
authors.forename: Alicja
authors.initials: A
authors.lastname: Chybicka
authors.forename: Wojciech
authors.initials: W
authors.lastname: Biernat
authors.forename: Janusz
authors.initials: J
authors.lastname: Limon
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality*; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D017434:Protein Structure, Tertiary; D020917:Receptor, trkA / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein
chemical_list: D014408:Biomarkers, Tumor; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D020917:Receptor, trkA