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

Abstract

Neuroblastoma is the most common extracranial solid tumour of childhood. Amplification of the proto-oncogene, N-myc, confers a poor prognosis in neuroblastoma, while hyperdiploidy is associated with a favourable outcome. Little is known about the contribution of tumour-suppressor genes to the development or progression of neuroblastoma. We examined allelic imbalance at the locus of the tumour-suppressor gene, APC (adenomatous polyposis coli), on chromosome 5q using a polymerase chain reaction (PCR)-based assay. Nine of 24 (37.5%) informative neuroblastoma tumours showed allelic imbalance (AI) at this locus. Clinical data concerning N-myc amplification and DNA content were correlated with these results in the same patients. Allelic imbalance was found only in tumours containing a single copy of the N-myc gene and exhibiting hyperdiploidy. All nine patients with AI of chromosome 5q were alive after a median follow-up period of 46 months, while 7 of 15 (47%) of those lacking AI at this locus had died (P = 0.018). Allelic imbalance at three additional loci on chromosome 5 was demonstrated in tumours that exhibited AI at the APC locus, suggesting that endoreduplication of chromosome 5 had occurred. Fluorescent in situ hybridisation (FISH) analysis of tumour tissue from one patient exhibiting AI demonstrated two, three, four or six copies of the APC gene per cell, consistent with this hypothesis. These data suggest that allelic imbalance of chromosome 5 is involved in at least a subset of neuroblastomas and influences survival in patients with neuroblastoma.