LACK OF HIGH-AFFINITY NERVE GROWTH-FACTOR RECEPTORS IN AGGRESSIVE NEUROBLASTOMAS

Background: Neuroblastoma is a malignancy of the sympathetic nervous system. Nerve growth factor, which has a major role in development of the sympathetic nervous system, has high-affinity (gp140TRK-A) and low-affinity (gp75NGFR) cell-surface receptors. We recently reported preliminary study results showing a lack of gp140TRK-A receptors and rapid disease progression in neuroblastomas, particularly those with amplification of the N-myc (also known as MYCN) proto-oncogene. Purpose: This retrospective study was designed to determine if expression of nerve growth factor receptor messenger RNA (mRNA) was associated with biologic and clinical parameters and with survival in neuroblastoma. Methods: We obtained 80 untreated primary neuroblastomas that had been snap-frozen and stored after surgical excision. To determine expression of gp140TRK-A and gp75NGFR, we performed Northern blot analyses on total RNA from the specimens. Samples from the same specimens were examined for N-myc proto-oncogene amplification, RNA expression, and histologic differentiation, and clinical stage at diagnosis and survival were determined. Results: Of the 80 neuroblastomas, 65 (81%) expressed gp140TRK-A RNA. However, three (27%) of the 11 tumors with genomic amplification and high expression of N-myc RNA and 62 (90%) of the 69 without genomic amplification or detectable N-myc RNA expressed gp140TRK-A mRNA. The inverse relationship between gp140TRK-A mRNA and N-myc expression had high statistical significance (P<.0001). Of the 67 tumors assessable for histologic differentiation, the 13 lacking gp140TRK-A mRNA were histologically undifferentiated, whereas 19 (35%) of the 54 expressing it were differentiated (P = .041). Only 10 (53%) of the 19 metastatic (stage IV) tumors expressed gp140TRK-A mRNA, compared with 90% for other stages (P = .0003). Survival 2 years after diagnosis was 92%, 78%, and 14% for patients whose tumors expressed high, intermediate, and no gp140TRK-A mRNA, respectively (P<.0001). Univariate and multivariate analyses demonstrated that N-myc and gp140TRK-A expression of mRNA and clinical staging were independent predictors of survival. Expression of gp75NGFR mRNA did not correlate with gp140TRK-A mRNA expression, histologic differentiation, stage, or survival. Conclusions: The expression of gp140TRK-A mRNA correlates with distinct biologic and clinical subsets of neuroblastoma, which suggests a role for the high-affinity nerve growth factor receptors in determining the phenotype of neuroblastoma. The absence of gp140TRK-A mRNA expression, whether or not the N-myc proto-oncogene is amplified, is associated with tumor progression.