Clinical implications of oncogene activation in human neuroblastomas

Amplification of the oncogene N-myc has been identified in almost all human neuroblastoma cell lines tested. Eighty-nine primary neuroblastomas from untreated patients were studied to determine the frequency and clinical significance of N-myc amplification. Tumor DNA was analyzed by hybridization with the radiolabeled probe pNB-1 for N-myc. Amplification (3-300 copies) of the N-myc gene was found in 34 of the 89 tumors (38%). Amplification was not found in 8 Stage I or 5 Stage IV-S tumors, but it was found in 2 of 16 with Stage II, 13 of 20 with Stage III, and 19 of 40 with Stage IV tumors (P less than 0.01). Correlation of N-myc amplification with progression-free survival (PFS) indicated that N-myc amplification was associated with a worse prognosis (P less than 0.0001). The PFS at 18 months was 70%, 30%, and 5% for patients whose tumors had 1, 3-10, and more than 10 copies, respectively. Even within individual stages, the presence of N-myc amplification correlated with rapid progression. For instance, of 16 patients with Stage II disease, the 2 with N-myc amplification developed progressive disease rapidly, whereas only 1 of 14 without amplification progressed (P = 0.03). Similarly, those with Stage III and IV disease whose tumors have multiple copies of N-myc had a substantially worse prognosis. The correlation between N-myc amplification and age at diagnosis was also analyzed. Although N-myc amplification was detected in only 4 of 28 infants less than 1 year of age, compared to 30 of 61 older patients (P less than 0.005), this difference disappeared when corrected for disease stage. The results suggest that N-myc amplification is a powerful prognostic indicator, and that this gene may play an important role in the progression of certain neuroblastomas.