Eggert A, Grotzer M A, Ikegaki N, Zhao H, Cnaan A, Brodeur G M, Evans A E
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
J Clin Oncol. 2001 Feb 1;19(3):689-96. doi: 10.1200/JCO.2001.19.3.689.
Neurotrophins and their receptors regulate the proliferation, differentiation, and death of neuronal cells, and they have been implicated in the pathogenesis and prognosis of neuroblastomas and medulloblastomas. Tyrosine kinase (Trk) receptors also are expressed in extraneural tissues.
To study the role of neurotrophin receptors and ligands in Wilms' tumor (WT), we determined their expression by semiquantitative duplex reverse transcriptase polymerase chain reaction in 39 patients with primary WT. Comparison of mRNA expression levels with clinical variables was performed by use of Cox regression analysis.
Children with WT that expressed high levels of full-length TrkB mRNA (TrkBfull) had a significantly greater risk of death than children whose tumors had little or no TrkBfull expression (hazard ratio, 9.7; P =.02). The 5-year relapse-free survival was 100% versus 65% for patients with low versus high tumor expression of TrkBfull (P <.003). Conversely, children with tumors that expressed high mRNA levels of a functionally inactive truncated TrkB receptor (TrkBtrunc) had a greater chance of survival than children with low levels of TrkBtrunc (hazard ratio, 0.08; P =.005). The 5-year relapse-free survival was 95% versus 68% for patients with high versus low levels of TrkBtrunc (P =.01). The hazard ratios for TrkBfull and TrkBtrunc remained significant after they were adjusted for tumor stage (P =.01 and P =.017, respectively). All WTs with high levels of TrkB expression also expressed the brain-derived nerve growth factor ligand.
Expression of TrkBfull in WT is associated with worse outcome, perhaps because it provides an autocrine survival pathway. Conversely, TrkBtrunc expression is associated with excellent outcome, perhaps as a result of a dominant negative effect.
神经营养因子及其受体调节神经元细胞的增殖、分化和死亡，并且它们与神经母细胞瘤和髓母细胞瘤的发病机制及预后有关。酪氨酸激酶（Trk）受体也在外周组织中表达。
为了研究神经营养因子受体和配体在肾母细胞瘤（WT）中的作用，我们通过半定量双重逆转录聚合酶链反应确定了39例原发性WT患者中它们的表达情况。通过Cox回归分析比较mRNA表达水平与临床变量。
WT中全长TrkB mRNA（TrkBfull）表达水平高的儿童死亡风险明显高于肿瘤TrkBfull表达很少或无表达的儿童（风险比，9.7；P = 0.02）。TrkBfull肿瘤表达低与高的患者5年无复发生存率分别为100%和65%（P < 0.003）。相反，肿瘤中功能性无活性截短TrkB受体（TrkBtrunc）mRNA水平高的儿童比TrkBtrunc水平低的儿童生存机会更大（风险比，0.08；P = 0.005）。TrkBtrunc水平高与低的患者5年无复发生存率分别为95%和68%（P = 0.01）。在根据肿瘤分期进行调整后，TrkBfull和TrkBtrunc的风险比仍然显著（分别为P = 0.01和P = 0.017）。所有TrkB表达水平高的WT也表达脑源性神经生长因子配体。
WT中TrkBfull的表达与较差的预后相关，可能是因为它提供了一条自分泌生存途径。相反，TrkBtrunc的表达与良好的预后相关，可能是由于显性负效应。
