Deletion of Chromosome 1p Loci and Microsatellite Instability in Neuroblastomas Analyzed with Short-tandem Repeat Polymorphisms

We have analyzed DNA from 46 neuroblastoma tumors of all clinical stages and five ganglioneuroma tumors together with corresponding control DNA for loss of heterozygosity (LOH) on the distal 1p chromosomal region (1p-LOH). The markers used for the analyses were genetically mapped DNA polymorphisms detectable with PCR analysis. In general, there was concordance among aggressive tumor stage, 1p deletion, and N-myc amplification, although exceptions were found. Twelve (26%) of the 46 neuroblastoma tumors displayed 1p-LOH, 11 being stage 4 and 1 stage 2 (which progressed subsequently to stage 4), whereas 10 stage 4 tumors showed no 1p-LOH. Of 12 neuroblastomas shown to have N-myc amplification, 10 had 1p-LOH. In 8 cases it was possible to test for parental origin of the chromosome involved in 1p-LOH. No significant correlation between LOH and paternal or maternal allele was found. Commonly deleted loci in the distal 1p region in the neuroblastoma tumors indicated that the region for a tentative neuroblastoma tumor suppressor gene is defined proximally by marker D1S244 and distally by marker D1S80. One striking feature of three stage 2 neuroblastomas and one of the stage 3 tumors was the presence in the tumor DNA of alleles not present in the constitutional DNA of the patients, i.e., microsatellite instability. The significance of this phenomenon in localized neuroblastoma tumors remains to be clarified. Aggressive neuroblastoma in young children (younger than 2 years of age) seems to be a homogenous disorder consistently showing concomitant 1p-LOH and N-myc amplification. In the majority of unfavorable neuroblastoma in older children, however, neither 1p-LOH nor N-myc amplification could be detected. This indicates that neuroblastoma in older children is a biologically more heterogenous disorder in which genetic alterations other than deletions of chromosome 1p and amplification of N-myc also may contribute to tumorigenesis.