Neuroblastoma: Effect of genetic factors on prognosis and treatment

Abstract

Background and Methods. Genetic analysis of tumor tissue has provided considerable insight into mechanisms of malignant transformation and progression. Neuroblastomas have been studied by cytogenetics, flow cytometry, and molecular genetic techniques, and these studies have identified several specific abnormalities that allow subclassification of these tumors into genetic/ clinical subtypes. Results and Discussion. Four genetic abnormalities have been identified that are characteristic of certain neuroblastomas. These include: (1) loss of heterozygosity (LOH) for the short arm of chromosome 1, including band lp36; (2) amplification of the N‐myc protooncogene; (3) hyperdiploidy, or near triploidy; and (4) defects in expression or function of the nerve growth factor receptor (NGFR). Abnormalities of the NGFR are found in virtually all neuroblastoma cell lines, and some primary tumors. The latter have not been studied extensively. Hyperdiploidy is associated with lower stages of disease and with a favorable outcome in infants. LOH for chromomors. The latter have not been studied extensively. Hyperdiploidy is associated with lower stages of disease and with a favorable outcome in infants. LOH for chromosome 1, band p36, and N‐myc amplification are more common in patients older than 1 year of age with advanced stages of disease. The latter two genetic abnormalities may be related, and LOH for 1p 36 may precede the development of amplification. When these abnormalities are combined with assessment of DNA content, three distinct genetic subsets of neuroblastomas can be identified. The first is characterized by a hyperdiploid or near‐triploid modal karyotype, with few if any cytogenetic rearrangements. These patients generally are younger than 1 year of age with localized disease and a good prognosis. The second has a near‐diploid karyotype, with no consistent abnormality identified currently. These patients generally are older with more advanced stages of disease that progress slowly and are often fatal. The third group has a near‐diploid or tetraploid karyotype, with deletions or LOH for lp36, amplification of N‐myc, or both. These patients generally are older with advanced stages of disease that rapidly are progressive. Thus, genetic analysis of neuroblastoma cells provides information that has prognostic significance and can direct a more appropriate choice of treatment.

Consolidation with a busulfan-containing regimen followed by stem cell transplantation in infants with poor prognosis stage 4 neuroblastoma

“…The bone was the site of recurrent disease in all of these patients and lesions were associated with bone marrow involvement in four. Their median age at the time of relapse was 22 months (range [21][22][23][24][25][26][27][28][29][30]. For the seven remaining patients, HDC was given as consolidation therapy immediately after first-line chemotherapy to six patients with an NMA tumor and to one patient with persistent bone metastases in spite of eight courses of conventional chemotherapy.…”

Altered expression of the MYCN oncogene modulates MRP gene expression and response to cytotoxic drugs in neuroblastoma cells

“…Neuroblastoma, a disease which arises from embryonal neural crest cells, is the most common solid tumour of infancy (Brodeur et al, 1992). The majority of patients present with widely disseminated disease at diagnosis and despite intensive regimens, the prognosis for such patients is poor, with 5 year survival rates of less than 40% (Stram et al, 1996).…”

“…The majority of patients present with widely disseminated disease at diagnosis and despite intensive regimens, the prognosis for such patients is poor, with 5 year survival rates of less than 40% (Stram et al, 1996). A number of prognostic factors have been identi®ed for this disease, with one of the most powerful being ampli®cation of the MYCN oncogene (Brodeur et al, 1992). Thus patients whose tumours display MYCN gene ampli®cation are at increased risk of early treatment failure, suggesting that the MYCN oncoprotein is closely linked to the drug resistant phenotype and disease progression of these tumours.…”

Detection of MYCN Amplification in Neuroblastoma using Competitive PCR Quantitation

“…A mplification of the MYCN oncogene in the pediatric tumor neuroblastoma is almost always associated with rapid tumor progression and poor outcome irrespective of tumor stage (Brodeur et al, 1992). The use of MYCN amplification as a prognostic indicator is of particular relevance in view of the clinical heterogeneity that is a characteristic feature of neuroblastoma: tumor phenotype may vary from a benign tumor requiring little or no treatment to a very aggressive malignancy that results in high mortality.…”