Enhanced expression of the cellular oncogene MYCN and progression of human neuroblastoma

A central issue in cancer research is how tumors evolve and acquire a more aggressive phenotype. It is a widely discussed hypothesis that tumor cell populations progress by evolutionary change as a result of the generation of a variant cell through genomic instability followed by selection of particular variant clones having a growth advantage within the particular tissue environment. Genetic instability appears to be characteristic of neoplastic cells, but no consistent increase in instability seems to accompany progression of the malignant phenotype of the tumor. It is reasonable to assume that quantitative or qualitative changes of cellular oncogenes contribute to the emergence of more malignant phenotypes. Although any one of the molecular changes of cellular oncogenes identified over the past years is a good candidate as an element in progression, amplification appears particularly frequently as a correlate to advanced tumor stage. The fact that amplification does not show up in all progressing tumors of a particular type, for instance in only 50% of advanced-stage neuroblastomas, is often construed as speaking against a role in progression. One should be aware, however, that it is the enhanced expression of a gene consequent to amplification and not amplification per se that affects the cellular phenotype. There are alternative molecular pathways by which expression of a particular gene may become deregulated. During the past decade much information has accrued about genetic alterations in tumor cells. The activation of the oncogenic potential of cellular genes can take different routes among which mutational alteration, translocation and amplification predominate. In particular, amplification has found its way to practical use due to its association with more aggressively growing types of human cancer. MYCN amplification in neuroblastoma is a paradigm for the prognostic significance of oncogene alteration, and at the same time has represented the clinical debut of oncogene research. The full significance of oncogene amplification as a predictor for poor prognosis became clear with the more recent identification of amplified ERBB2 in aggressively growing breast cancers. The state of the art is that amplified cellular oncogenes define cancer patients who have a poor prognosis and require a specific therapeutic regimen.