Abstract
BackgroundTrkA (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.MethodsDNA 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.ResultsThree 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.ConclusionsNTRK1 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.
Highlights
IntroductionTrkA (encoded by NTRK1 gene), the high-affinity tyrosine kinase receptor for neurotrophins, is involved in neural crest cell differentiation
TrkA, the high-affinity tyrosine kinase receptor for neurotrophins, is involved in neural crest cell differentiation
Among molecular factors influencing the clinical outcome of neuroblastoma, the expression of TrkA has been associated with favourable prognosis [3]
Summary
TrkA (encoded by NTRK1 gene), the high-affinity tyrosine kinase receptor for neurotrophins, is involved in neural crest cell differentiation. Neuroblastoma (NB), a tumour of the peripheral nervous system arising from embryonal neural crest cells (NCCs), is the foremost malignant neoplasm of neonate and infant [1]. It demonstrates considerable diversity in clinical behaviour, ranging from spontaneous regression or maturation to rapid progression despite aggressive therapy [2]. TrkA is a member of a Trk family of tyrosine kinase receptor for nerve growth factor (NGF) and other neurotrophins. TrkA primarily regulates growth, differentiation and programmed cell death of neurons in both peripheral and central nervous systems [4]. As previously reported, TrkA expression is a crucial factor for spontaneous regression of neuroblastoma [5]
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