© 1993 by Oxford University Press
Journal of the National Cancer Institute, Vol. 85, No. 5, 377-384,
March 3, 1993
© 1993 Oxford University Press
Lack of High-Affinity Nerve Growth Factor Receptors in Aggressive Neuroblastomas
Division of Hematology-Oncology, Department of Pediatrics, Childrens Hospital Los Angeles, University of Southern California School of Medicine Los Angeles
Department of Pathology, Childrens Hospital Los Angeles, University of Southern California School of Medicine Los Angeles
Division of Hematology-Oncology, Department of Pediatrics, Childrens Hospital Los Angeles and Department of Microbiology, University of Southern California School of Medicine
Statistical Center, CCG, Arcadia, Calif., and Department of Preventive Medicine, University of Southern California School of Medicine
Correspondence to: Robert C. Seeger, M.D., Division of Hematology-Oncology. MS #126, Childrens Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90054–0700.
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 neuro-blastoma. 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 amplificaton 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-mycproto-oncogene is amplified, is associated with tumor progression. [J Natl Cancer Inst 85:377–384, 1993]
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