The origin of chromosome imbalances in neuroblastoma

Many recurrent large-scale chromosome abnormalities associated with poor clinical outcomes have been identified in neuroblastoma, a pediatric tumor that accounts for 15% of childhood cancer deaths. We have previously used high-resolution oligonucleotide array comparative genomic hybridization to map 461 chromosome breakpoints leading to large-scale chromosome imbalances in 56 primary neuroblastoma tumors and cell lines. Here, we analyze the distribution of DNA sequence elements and genomic landmarks found within these breakpoint intervals and in 15,800 randomly generated intervals of similar size. The most consistent finding was that neuroblastoma chromosome breakpoints occur preferentially in GC-rich regions of the genome. It is not unsurprising that these regions have fewer (AT)(n) microsatellite repeat sequences. In addition, chromosome breakpoints occurring in neuroblastoma also appeared to be preferentially associated with ancestral chromosome breakpoint regions on several chromosomes, suggesting that such sites also act as hotspots for chromosome rearrangement in somatic cells. Very little evidence for the enrichment of Alu and other types of repeats in breakpoint intervals was obtained. Overall, our results are consistent with a mechanistic model involving nonhomologous end joining of DNA double-strand breaks that have been generated in a nonrandom manner.