Molecular Biology, Pathobiology, and Genetics Human rRNA Gene Clusters Are Recombinational Hotspots in Cancer

The gene that produces the precursor RNA transcript to the three largest structural rRNA molecules (rDNA) is present in multiple copies and organized into gene clusters. The 10 hu-man rDNA clusters represent <0.5 % of the diploid human ge-nome but are critically important for cellular viability. Individual genes within rDNA clusters possess very high levels of sequence identity with respect to each other and are pres-ent in high local concentration, making them ideal substrates for genomic rearrangement driven by dysregulated homolo-gous recombination. We recently developed a sensitive physi-cal assay capable of detecting recombination-mediated genomic restructuring in the rDNA by monitoring changes in lengths of the individual clusters. To prove that this dysre-gulated recombination is a potential driving force of genomic instability in human cancer, we assayed the rDNA for structur-al rearrangements in prospectively recruited adult patients with either lung or colorectal cancer, and pediatric patients with leukemia. We find that over half of the adult solid tumors show detectable rDNA rearrangements relative to either sur-rounding nontumor tissue or normal peripheral blood. In con-trast, we find a greatly reduced frequency of rDNA alterations in pediatric leukemia. This finding makes rDNA restructuring one of the most common chromosomal alterations in adult solid tumors, illustrates the dynamic plasticity of the human genome, and may prove to have either prognostic or predictive value in disease progression. [Cancer Res 2009;69(23):9096–104