Most human cancers including neuroblastomas are characterized by genomic abnormalities, which can be manifest as loss of one allele (loss of heterozygosity, LOH) or as allele-specific increases in copy number. Detection of LOH has been used to identify genomic regions that harbor tumor suppressor genes and to detect predisposition to drug resistance and relapse. We analyzed neuroblastoma tumors for areas of LOH and DNA copy number changes through genome-wide analysis of 10,000 SNPs distributed across all human chromosome arms with the Affymetrix Mapping 10K array. Paired blood and primary tumor samples from 24 children with high-risk neuroblastoma (median age diagnosis 3.3 years; 23/24 cases stage 4; 7/24 cases with MYCN amplification) were examined. The dChipSNP package, a bioinformatics tool that automates the detection of regions of LOH and copy number, was used to analyze the data. By combining genotyping with SNP quantitation, LOH events caused by hemizygous deletion were distinguished from those that occurred through copy-neutral events. The most commonly observed area of LOH was on Ch 11q (14/24 samples or 58%), which was reflected as a loss of copy number in 10/14 samples. In 8 of the samples that had LOH of the 11q arm, there was reciprocal 11p gain of copy number. Ten samples had LOH at 3p (9/10 also had 11q LOH), with 5 showing a corresponding copy number reduction. LOH was also seen on 1p (9/24), and 4p (6/24) with all but 3 samples exhibiting copy number reduction. Gain of copy number in 17q was seen in all 24 of the samples, including 10 samples that also had LOH of 17q. Seven samples also had 17p gain. Ch 7 had gain of copy number in 15/24 samples in the q arm with 11 of these showing copy number gain in the p arm also. There was almost perfect concordance between SNP array analysis and conventional genotyping data. The superb mapping power of SNP array analysis plus the detection of copy number changes makes this a superior platform compared to more conventional techniques. SNP array analysis not only readily identified multiple areas of LOH and copy number gain that have been reported individually in neuroblastoma tumors, but also provided new information regarding cases with LOH on Chs 3 and 11 that did not have copy number reduction, implying both hemizygous deletion and reduplication of the remaining allele. This work extends our preliminary observations that Ch 3p and 11q LOH often go together and presents novel information regarding Ch 7. In addition, some cases with Ch 17 gain also showed evidence for LOH. Further studies will be needed to analyze whether this is due to a preferential amplification of the gained allele rather than loss of an allele.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]