Department of Biology and Genetics, Medical University of Gdańsk, Debinki 1, 80-211 Gdańsk, Poland.
BMC Cancer. 2009 Dec 13;9:436. doi: 10.1186/1471-2407-9-436.
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.
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.
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.
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.
TrkA（由 NTRK1 基因编码）是神经营养因子的高亲和力酪氨酸激酶受体，参与神经嵴细胞分化。已有报道称其表达与神经母细胞瘤的预后良好相关。因此，分析了 NTRK1 基因的整个编码序列，以确定可能改变 TrkA 受体表达的突变和/或多态性。
从 55 名波兰患者和 114 名意大利患者的神经母细胞瘤以及 158 名健康对照者的外周血白细胞中提取 DNA。采用变性高效液相色谱法（DHPLC）和单链构象多态性（SSCP）分析筛选序列变异。通过直接测序证实遗传变化，并与生物学和临床数据相关联。
检测到三个先前报道的和九个新的单核苷酸多态性。在 8.7%的病例中发现存在 c.1810C>T 多态性，是疾病复发的独立标志物（OR=13.3；p=0.009），与较低的生存率相关（HR=4.45，p=0.041）。在无 MYCN 扩增的 18 个月以下的患者中，c.1810C>T 多态性的不良预后价值最为显著（HR=26；p=0.008）。c.1810C>T 多态性的体内分析表明，在保守的酪氨酸激酶结构域内相应氨基酸残基的取代，理论上可能干扰 TrkA 蛋白的功能。
NTRK1 c.1810C>T 多态性似乎是神经母细胞瘤不良预后的一个新的独立预后因素，尤其是在无 MYCN 扩增的 18 个月以下的儿童中。
