Evaluations of N-myc gene amplification and DNA ploidy are complementary, and the combined determination of these two factors may be one of the most powerful prognostic indicators in neuroblastoma.
Gene amplification and rearrangements are discussed through review of recent work on the N-myc gene in neuroblastoma and the epidermal growth factor receptor (EGFR) gene in glioblastoma.
To study the regulation of N-myc, we have subcloned fragments of the 5' flanking region of the human N-myc gene upstream of the chloramphenicol acetyl transferase (CAT) reporter gene, and assayed for promoter activity in transient transfections into neuroblastoma and other cell lines.
Multivariate analysis showed that the INSS stage (stage 4 vs other stages) and International Neuroblastoma Pathology Classification histology (unfavourable vs favourable) were significantly and independently associated with the survival of patients undergoing treatment, stratified by age, stage and MYCN amplification (P=0.0002 and P=0.0051, respectively).
Thus, telomere-dependent chromosomal instability is highly prevalent in NB, and may contribute to the complexity of genomic alterations as well as therapy resistance in the absence of MYCN amplification and in this tumor type.
In this study, gene expression profiling was performed on 103 neuroblastoma (NB) tumors, stages 1-4 with and without MYCN amplification, using cDNA microarrays containing 42,578 elements.
Recent studies suggest that a multiplicity of genomic alterations contributes to neuroblastoma, the most frequent and well studied being deletion of the short arm of chromosome 1 and amplification of N-MYC.
Four neuroblastoma xenograft samples derived from cell lines with known N-myc gene copy number were also evaluated, as were 7 samples of non-small cell lung cancer (NSCLC) tumors with known Skp2 gene amplification.
These data, combined with the relatively high incidence of neuroblastoma reported in partial trisomy 2p patients, support the notion that MYCN duplication should be added to the growing list of genetic factors associated with an increased risk of neuroblastoma.
Neuroblastoma harbours a variety of genetic changes, including a high frequency of MYCN amplification, loss of heterozygosity at 1p36 and 11q, and gain of genetic material from 17q, all of which have been implicated in the pathogenesis of neuroblastoma.
A missense SNP in exon 10 of the CASP8 gene SNP D302H was associated with worse overall and event-free survival in patients with MYCN-amplified neuroblastoma tumors.
Targeted ALK(F1174L) and MYCN coexpression revealed a strong synergism in inducing neuroblastoma with minimal chromosomal aberrations, suggesting that fewer secondary hits are required for tumor induction if both oncoproteins are targeted.