Expression of the neurotrophin receptor TrkB is associated with unfavorable outcome in Wilms' tumor.

Abstract

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.