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Expression of the Neurotrophin Receptor TrkB Is Associated With Unfavorable Outcome in Wilms’ Tumor

From the Division of Oncology and Biostatistics, The Children’s Hospital of Philadelphia, Philadelphia, PA.

Address reprint requests to Audrey E. Evans, MD, The Children’s Hospital of Philadelphia, Division of Oncology, ARC Room 902-D, 3516 Civic Center Blvd, Philadelphia, PA 19104; email: evansa{at}email.chop.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: 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.

PATIENTS AND METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
WILMS’ TUMOR (WT) or nephroblastoma is a pediatric tumor that arises from metanephric blastema.¹ It is thought to result from aberrant developmental processes within the kidney. Malignant rhabdoid tumor, which is characterized by poor outcome, is another renal tumor that has sometimes been included in WT studies.² The current rate of cure in WT (> 90%) is the result of efforts of cooperative groups such as the National Wilms’ Tumor Study Group (NWTSG) and the International Society of Pediatric Oncology. These groups have focused their attention on reduction in the intensity of therapy to minimize treatment-related morbidity. The most important prognostic factors identified to date are histologic type, tumor stage, and age.^3,4 Diffuse anaplasia, which is present in 5% of WT specimens, is considered a powerful marker for adverse prognosis.^1,5 These clinical factors alone, however, are not sufficient to identify all patients at increased risk for relapse. To allow reduced treatment intensity and subsequent toxicity for low-risk patients as well as selection of children at an increased risk for relapse to undergo more intensive treatments, a search for tumor biologic factors that may provide additional prognostic power is warranted.

The molecular mechanisms that underlie the pathogenesis of WT are poorly understood. Because WT caricatures renal organogenesis, the expression of a number of growth factors, including insulin-like growth factor and platelet-derived growth factor, has been examined.^6-8 They are thought to contribute to tumor development by increasing proliferation and inhibiting terminal differentiation.

There is considerable interest in the role of neurotrophic growth factors and their receptors in the regulation of growth and differentiation in normal and neoplastic nerve cells. The expression of different members of the tyrosine kinase (Trk) family of receptors for neurotrophins has been correlated with clinical features and outcome in neuroblastomas and medulloblastomas.^9-11 Activation of the Trk receptors A, B, and C by their specific ligands, nerve growth factor (NGF), brain-derived nerve growth factor (BDNF) plus neurotrophin 4, and neurotropin 3, respectively, leads to a variety of biologic responses including differentiation, proliferation, and apoptosis dependent on the cellular environment.¹² In addition to full-length transcripts, Trk genes are subject to alternative splicing events that lead to the generation of several isoforms for each Trk species. The functional significance of these splice variants is not completely clear, but it has been postulated that the truncated forms of TrkB and C inhibit signaling when coexpressed with full-length TrkB and C receptors.^13,14

Although most studies of Trk expression have focused on the CNS and peripheral nervous system, it is now known that all of the Trk receptors also are expressed in extraneural tissues including the rat and mouse kidneys.^13,14 The specific roles of the neurotrophin receptors and ligands in the development of nonneural organs are not yet known, however. It has been suggested that neurotrophins and their receptors also may be involved in the pathogenesis of some WTs.^15,16 The p75 low-affinity nerve growth factor receptor has been identified on epithelial WT cells in culture,¹⁶ and it has been demonstrated that high-affinity Trk receptors are expressed at distinct sites during the development of the rodent kidney¹⁷ and in several localizations in a series of 10 WTs.¹⁵

In this study, we examined the expression patterns of the neurotrophin receptors TrkA, B, C, and p75 low-affinity nerve growth factor receptor as well as their ligands NGF, BDNF, NT3, and NT4 in 39 WTs and 11 renal rhabdoid tumors. We also compared expression levels with clinical variables of known prognostic significance.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We studied tumor specimens from 39 children with WTs who had been diagnosed in the United States and Canada from 1990 to 1997. Thirty-one patients were identified at the Children’s Hospital of Philadelphia, and eight patients’ specimens were from the NWTSG Biological Specimens Bank. The selection of tumors for study was based on the availability of a sufficient amount of tumor tissue from which to prepare mRNA for reverse transcriptase polymerase chain reaction (RT-PCR) analysis. All WT diagnoses were confirmed by histologic assessment of a tumor specimen obtained at surgery. The histologic features were classified as described previously.¹ The tumors were classified according to the NWTSG criteria. Our study group consisted of seven stage I, 12 stage II, 12 stage III, and eight stage IV tumors ( Table 1). The median patient age was 54 months (range, 8 to 164 months). Twenty-seven tumors had a favorable histology and 12 tumors were anaplastic (10 tumors with diffuse anaplasia and two tumors with focal anaplasia). In addition to these 39 WT tumors, we included 11 renal rhabdoid tumors in the comparison of gene expression with tumor histology, but these patients were not included in the survival analysis. The patients were treated according to previously described protocols.^18,19 For surviving patients, the median follow-up period after diagnosis was 62 months (range, 25 to 119 months).

Semiquantitative RT-PCR
PCR was performed in a final volume of 10 µL containing 0.5 units of Taq gold polymerase, dNTP 200 µmol/L, and 0.4 µmol/L of each primer in a buffer consisting of KCl 50 mmol/L, Tris-HCl 10 mmol/L (pH 8.3), MgCl₂ 2.0 mmol/L, and 1 µL of the reverse transcriptase product (reverse transcribed total RNA). PCR primers were biotinylated and designed to bracket cDNA sequences that cross an intron-exon boundary in genomic DNA (sequences available on request). All samples were overlaid with mineral oil. Amplification was performed on a PTC-100 programmable thermal controller (MJ Research, Inc, Waltham, MA). The samples were denatured initially at 95°C for 12 minutes, followed by 20 cycle numbers with denaturation at 95°C for 30 seconds, annealing at 55°C for 30 seconds, and extension at 72°C for 90 seconds. The final cycle was followed by a 5-minute extension step at 72°C. The absence of contaminants was checked routinely by RT-PCR assays of negative control samples (no reverse transcriptase added) and H₂O controls. The housekeeping gene GAPD was coamplified as an internal standard control as described previously.²⁰

Analysis of Amplified Products
Each PCR sample (10 µL added to 2 µL of Ficoll dye reagent) was analyzed in parallel with a biotinylated molecular weight marker (Amersham, Arlington Heights, IL) on a nondenaturing 6% polyacrylamide gel. DNA was transferred to a Hybond N+ nylon membrane (Amersham) and immobilized by UV cross-linking. Detection of biotin-labeled DNA was performed according to the Southern Light protocol (Tropix, Bedford, MA). Quantification of RNA transcript expression was performed by densitometric analysis on x-ray films using Scion Image 1.55 software (Scion Corp, Frederick, MD). A modification of the GAPD primers (biotinylated-to-nonbiotinylated ratio, 1:49) allowed accurate quantification within the linear range of x-ray detection of both the target transcript and GAPD.²⁰ The expression of the target transcript was normalized by calculation of the ratio between the densitometric unit of the transcript and that of the internal control GAPD²⁰. A subset of samples was analyzed three times and the assay-to-assay variability was less than 15%.

Statistical Analysis
A two-sample t test was used to examine possible associations between clinical stages and the expression of the genes of interest. The Pearson’s correlation coefficient (r) and P value for each gene pair examined were calculated. The following variables were used to evaluate overall survival: age at diagnosis, tumor stage, tumor histology, expression of full-length TrkB mRNA (TrkBfull), and expression of a truncated form of the TrkB receptor (TrkBtrunc). The t test and Pearson’s correlation coefficient were used to identify possible significant associations between the clinical and biologic variables listed above. The relative risk of death was calculated by univariate and multivariate analysis using Cox regression analysis. Relapse-free survival data were determined by the Kaplan-Meier method, and differences between survival curves were calculated using the log-rank test. Because all variables had a normal distribution, survival curves were divided by median expression levels. Statistical analysis was performed with the STATA version 6.0 software (State Corp, College Station, TX).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Neurotrophin Receptors and Ligands are Expressed at Various Levels in WTs and Renal Rhabdoid Tumors
We used semiquantitative RT-PCR analysis to examine the expression of neurotrophin receptors TrkA, TrkB, TrkC, and p75 as well as their ligands NGF, BDNF, NT3, and NT4 in 39 WTs and 11 renal rhabdoid tumors. The clinical characteristics of the 39 WT patients are summarized in Table 1. Figure 1 demonstrates the expression of TrkA, TrkBfull, TrkBtrunc, and TrkC in six representative tumor samples. Expression levels of TrkA and TrkC were low in most of the tumors (median expression level, 0). High-level expression (defined as median expression level) of TrkA was detected in 70% of favorable WTs and 42% of anaplastic WTs, whereas high expression of TrkBfull was demonstrated in 56% of favorable WTs but 75% of anaplastic WTs ( Table 2). TrkBtrunc was detected at high levels in 89% of favorable WTs but in none of the anaplastic WTs. TrkC expression was high in 44% of favorable WTs and 50% of anaplastic WTs. In renal rhabdoid tumors, we did not detect any expression of TrkA, TrkBfull, or TrkC, but one of the rhabdoid tumors demonstrated high-level expression of TrkBtrunc. High-level expression of p75 was found frequently in all histologic types of tumors (59% of favorable WTs, 67% of anaplastic WTs, and 18% of rhabdoid tumors). The ligands NGF, NT3, and NT4 were found at high expression levels more frequently in favorable than in anaplastic WTs (70% v 58%, 81% v 33%, and 78% v 33%, respectively). High expression of BDNF was detected in 56% of favorable and 50% of anaplastic WTs. We detected high levels of NGF in 9% and BDNF in 36% of rhabdoid tumors, whereas NT3 and NT4 were only expressed at low levels.

View larger version (93K): [in this window] [in a new window]   Fig 1. RT-PCR of Trk receptor expression in WT. Representative example of semiquantitative RT-PCR showing expression levels of TrkA, TrkBfull, TrkBtrunc, and TrkC in six primary WTs. Tumors 1 through 3 have favorable histology, and tumors 4 through 6 have diffuse anaplastic histology. Expression of GAPD was used as an internal control.

Gene Expression and Survival
Cox regression analysis revealed that children with WTs that expressed high levels of full-length TrkB had a significantly greater risk of death than children with tumors that expressed little TrkBfull (hazard ratio, 9.7; P = .02) ( Table 3). Analysis of overall survival data revealed similar results (hazard ratio, 13.6; P = .01); only one patient relapsed in the group with favorable WTs. The 5-year relapse-free survival data of the 39 WT patients are summarized in Table 4. The 5-year relapse-free survival rate was 100% for patients with tumors that expressed low levels of TrkBfull and 65% for patients with tumors that expressed high levels of TrkBfull (log-rank test, P < .003) ( Fig 2A). Conversely, children with tumors that expressed high mRNA levels of a functionally inactive TrkBtrunc receptor had a greater chance of survival than children with low levels of TrkBtrunc (hazard ratio, 0.08; P = .005) (Table 3). The 5-year relapse-free survival rate was 95% for patients with high levels of TrkBtrunc and 68% for patients with low levels of TrkBtrunc (log-rank test, P = .01) (Fig 2B).

View larger version (14K): [in this window] [in a new window]   Fig 2. Relapse-free survival curves of patients with WT, according to expression of TrkBfull mRNA (A) TrkBtrunc mRNA (B), and histology (C). High expression of TrkBfull and TrkBtrunc was defined as expression greater than or equal to the median expression level; low expression was defined as expression less than the median expression level. The survival curves were analyzed by use of the log-rank test.

After favorable WTs were excluded, high levels of TrkBfull still influenced survival of patients with anaplastic WTs ( Fig 3A and 3B). Nine patients with anaplastic WTs that expressed high levels of TrkBfull had a relapse-free 5-year-survival rate of 34%, whereas three patients with diffuse anaplastic WTs and low TrkBfull expression had a survival rate of 100%. However, probably because of the low numbers of patients in this subset analysis, the influence of TrkBfull on survival of anaplastic WT patients did not quite reach statistical significance (P = .06). Expression levels of BDNF and TrkBfull did not correlate with each other, but all WTs with high levels of TrkBfull also expressed the specific ligand BDNF. There was a significant correlation, however, between expression of BDNF and TrkBtrunc (r = .4; P = .003).

View larger version (15K): [in this window] [in a new window]   Fig 3. (A) Expression pattern of TrkBfull in favorable and anaplastic WTs. The expression of TrkBfull in WT was determined by RT-PCR, and it was normalized by calculation of the ratio between the densitometric unit of the TrkB transcript and that of the internal control, GAPD. ( surviving patients; dead patients.) (B) Relapse-free survival curves of patients with anaplastic WT according to expression of TrkBfull mRNA. The Kaplan-Meier curve was analyzed by use of the log-rank test. High expression of TrkBfull and TrkBtrunc was defined as expression greater than or equal to the median expression level; low expression was defined as expression less than the median expression level.

The tendency of surviving patients to express higher levels of NT3 only approached significance (hazard ratio, 0.159; P = .05). No significant associations of other neurotrophin receptors or ligands with survival were detected.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Neurotrophins and their receptors regulate cell proliferation, differentiation, and death of normal and neoplastic neuronal cells and also have been implicated in the pathology of WT.^15,16 Our studies indicate that high levels of Trk receptors are frequently expressed in WTs, which suggests a role of neurotrophin receptors and their ligands in the biology and/or pathogenesis of WT. In contrast, renal rhabdoid tumors demonstrated no expression of Trk receptors, which further suggests the different origin and pathology of renal rhabdoid tumors and WTs.

Relevance of TrkBfull and TrkBtrunc as Prognostic Factors in WT
In the present study, high levels of TrkBfull expression and low levels of TrkBtrunc expression strongly correlated with an unfavorable outcome of WT. The combined evaluation for TrkBfull and TrkBtrunc mRNA expression defined a clear high-risk group (TrkBfull mRNA high and TrkBtrunc mRNA low) with a prognostic power similar to that of tumor histology (by use of Kaplan-Meier analysis and the log-rank test) ( Fig 4). The established clinical prognostic factors alone are not sufficient to reliably define high- and low-risk groups of WT patients. A variety of biologic variables have been proposed as prognostic factors for WT. To date, only tumor-specific loss of heterozygosity at chromosome 16q or chromosome 1p have been evaluated as putative biologic factors of suggested prognostic significance.²¹ Our research indicates that the level of TrkBfull and TrkBtrunc mRNA expression is a new prognostic factor that provides complementary information in patients with WT.

View larger version (12K): [in this window] [in a new window]   Fig 4. Relapse-free survival curve according to expression of TrkBfull and TrkBtrunc mRNA combined. Survival was significantly worse in the group with high levels of TrkBfull and low levels of TrkBtrunc mRNA expression than in all other groups (P < .0001). High expression of TrkBfull and TrkBtrunc was defined as expression greater than or equal to the median expression level; low expression was defined as expression less than the median expression level. Groups: A, low TrkBfull and high TrkBtrunc (n = 9); B, low TrkBfull and low TrkBtrunc (n = 10); C, high TrkBfull and high TrkBtrunc (n = 11); D, high TrkBfull and low TrkBtrunc (n = 9).

Role of TrkBfull in Tumor Biology
It is possible that the expression of different members of the Trk family serves as a marker for the cell of origin, but the receptor itself has no significant role in tumor biology. It is more likely that differential expression of Trk receptors and activation of their respective signal transduction pathways directly affects the biologic behavior of the cells, which leads to differentiation, survival, and/or proliferation. In neuroblastoma cells, expression of TrkBfull has been demonstrated preferentially in aggressive, MYCN-amplified tumors, and it also is associated with a poor prognosis.¹⁰ Activation of the BDNF/TrkB signaling pathway in neuroblastoma cells that express TrkBfull increases cell survival and cellular invasion through extracellular matrix proteins.^10,23 It also has been suggested that BDNF/TrkB may protect neuroblastoma cells from chemotherapy and thereby contribute to a more chemoresistant phenotype.^24,25 The specific roles of neurotrophin receptors in nonneuronal organs are not yet known. It remains to be determined whether higher expression levels of TrkBfull also contribute to the more chemoresistant phenotype of anaplastic WT. It may be that TrkBfull signaling promotes proliferation and/or survival of WT cells that lead to tumor progression. Tumors with functional TrkB may be particularly aggressive because high levels of TrkB provide a growth advantage and may protect them from chemotherapy.

Role of TrkBtrunc in Tumor Biology
It has been suggested that the truncated forms of TrkB and TrkC inhibit signaling when coexpressed with the full-length TrkB and TrkC receptors.^13,14 Whether this inhibition of neurotrophin signaling reflects a sequestration of ligand by the truncated receptor or direct inhibition of dimerization and autophosphorylation of full-length Trk isoforms is unclear. Expression of TrkBtrunc in WT may serve to exert a dominant negative effect on the signal transduction mechanism of TrkBfull. This would be similar to the inhibition of the wild-type platelet-derived growth factor receptor by coexpression of a truncated receptor.²⁶ Recent Northern blot analyses of embryonic rodent kidneys identified only the truncated form of the TrkB receptor.¹⁷ Truncated TrkB also seems preferentially expressed in more differentiated neuroblastomas (ganglioneuromas and ganglioneuroblastomas) with a good prognosis,¹⁰ which further suggests a favorable biologic effect of TrkBtrunc on tumor cells.

We conclude that histology, TrkBfull expression, and TrkBtrunc mRNA expression are the most powerful biologic predictors of clinical outcome in WT patients. Assessment of TrkB and TrkBtrunc expression in WT may provide complementary prognostic information, which in turn may help determine the most appropriate duration and intensity of treatment. More important, both of these factors may have roles in the pathogenesis of WT. Cells that express functional, full-length TrkB may be susceptible to proliferation and/or survival signaling that leads to WT progression. Currently we are investigating the effects of activation of the BDNF/TrkB signaling pathway in WT cells. Future therapeutic approaches may aim to antagonize the TrkB receptor signaling pathway to induce apoptosis and prevent chemotherapy resistance in these tumors. We strongly recommend the prospective assessment of TrkBfull and TrkBtrunc mRNA levels and the incorporation of TrkBfull and TrkBtrunc mRNA expression in future NWTSG clinical trials.

	ACKNOWLEDGMENTS

 
Supported by grants from the Deutsche Krebshilfe/Dr Mildred Scheel Stiftung (to A.E.), the Jeffrey Miller Neuro-Oncology Research Fund (to M.A.G.), grant no. NS 34514 from the National Institutes of Health (to G.M.B.), the Audrey E. Evans Endowed Chair (to G.M.B), and the National Wilms’ Tumor Study Group Biological Specimens Bank.

We thank Paul Grundy, MD, for the tumor samples from the NWTSG Biological Specimens Bank.

	REFERENCES

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Submitted May 1, 2000; accepted September 21, 2000.

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