Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study.

Abstract

We assessed tumor cell DNA content (ploidy) and N-myc gene copy number as predictors of long-term disease-free survival in 298 children with neuroblastoma. Diploid tumor stem lines were identified in 101 patients (34%), clonal hyperdiploid abnormalities in 194 (65%), and hypodiploid stem lines in three (1%). In children with widely disseminated tumors at diagnosis (stage D), ploidy had a highly age-dependent influence on prognosis. Among infants (less than 12 months) treated with cyclophosphamide-doxorubicin, hyperdiploidy was closely associated with long-term disease-free survival (greater than 90% of cases), while diploidy invariably predicted early treatment failure (P less than .001). Similarly, in children 12 to 24 months of age who were treated with cisplatin-teniposide and cyclophosphamide-doxorubicin, diploidy uniformly predicted early failure, whereas half of the children with hyperdiploidy achieved long-term disease-free survival (P less than .001). There was no relationship between ploidy and treatment outcome in children older than 24 months with stage D tumors who had a very low probability of long-term disease-free survival (less than 10%). N-myc gene amplification was detected in 37 (25%) of the 147 tumors tested, with the remainder showing single-copy levels of the gene. N-myc gene amplification was more frequent in diploid than in hyperdiploid tumors (23 of 57 v 14 of 87, P = .001) and predicted a high likelihood of early treatment failure. In children younger than 2 years with disseminated neuroblastoma, tumor cell ploidy and N-myc gene copy number provide complementary prognostic information that will distinguish patients who can be cured on current regimens from those who require new treatment strategies.

Cyclooxygenase inhibitors modulate the p53/HDM2 pathway and enhance chemotherapy-induced apoptosis in neuroblastoma

“…As amplification of the MYCN oncogene is an important prognostic factor in neuroblastoma (Look et al, 1991), we tested neuroblastoma cells with different MYCN status. COX inhibitors were able to induce dosedependent inhibition of cell growth in both MYCN amplified (IMR-5) and non-amplified (SK-N-AS, SK-N-SH, SH-SY5Y, SH-EP) neuroblastoma cell lines (Figure 1).…”

Interferon-? cooperates with retinoic acid and phorbol ester to induce differentiation and growth inhibition of human neuroblastoma cells

“…1,2 A number of prognostic parameters for the disease have been identified, including age, loss of heterozygosity at chromosome 1p36, DNA ploidy, histopathologic stage and amplification of the N-myc proto-oncogene. [3][4][5][6][7][8] The latter condition is strongly correlated with advanced disease, insensitivity to chemotherapy and poor outcome. 9 -12 N-myc and other members of the myc family encode transcription factors that control the expression of genes involved in cell growth, differentiation and survival.…”

Allelic imbalance on chromosome 5q predicts long-term survival in neuroblastoma

“…Endoreduplication would lead to an apparent increase in either the cut or uncut allele in tumour DNA compared with normal DNA, as we observed. Indeed, an extra chromosome 5 has been noted to occur in several neuroblastoma karyotypes (Kaneko et al, 1987;Hayashi et al, 1989;Look et al, 1991).…”

“…In 1983, Schwab et al determined that a gene termed N-myc, related to the protooncogene c-myc, was amplified in many human neuroblastoma cell lines (Schwab et al, 1983). Subsequent studies have shown that DNA amplification of this gene, found in about 25% of neuroblastomas, is associated with rapid progression of disease (Seeger et al, 1985;Look et al, 1991;Fong et al, 1992). In one study of neuroblastoma, DNA content, which grossly reflects chromosome number, was diploid (DNA index= 1) in 44%, near-diploid (DNA index 1.18) in 6%, near-triploid (DNA index= 1.25-1.68) in 48% and hypotetraploid (DNA index= 1.85) in 2% of 59 neuroblastoma tumours analysed (Bourhis et al, 1991).…”

“…Conversely, diploidy rarely occurs in localised disease, and it predicts a poor outcome in disseminated disease of infants (Look et al, 1984(Look et al, , 1991.…”