Clinical significance of genetic rearrangements in human neuroblastomas

Abstract

Human neuroblastomas are characterized cytogenetically by manifestations of gene amplification and by partial monosomy for the short arm of chromosome 1. Analysis of 646 neuroblastomas and 16 ganglioneuromas showed N-myc gene amplification in only seven of 169 (4%) with low stages of disease but in 138 of 436 (32%) with advanced stages of disease. N-myc amplification was seen in four of 41 (10%) stage IV-S tumors, and none of 16 ganglioneuromas. Analysis of patient survival by stage, age, and N-myc copy number indicate that N-myc amplification was highly correlated with rapid tumor progression, even in patients with low stages of disease. Partial monosomy of chromosome 1p can be more effectively detected by analysis of restriction fragment length polymorphisms to detect somatic loss of heterozygosity (LOH) for chromosome 1p, which is the molecular equivalent of chromosome deletion. Analysis of pairs of normal and tumor DNAs from patients with neuroblastoma demonstrated that 13 of 47 tumors (28%) had LOH at one or more loci on distal chromosome 1p; the region that shows LOH most consistently is between 1p36.1 and 1p36.3. LOH for 1p shows a highly significant correlation with N-myc amplification, suggesting that these two genetic events are related and characterize a genetically distinct subset of aggressive neuroblastomas.