Genomic stability and instability in different neuroepithelial tumors. A role for chromosome structure?

Summary

Selected childhood and adult neoplasm exemplify fundamental differences in their propensity for genomic change. DNA replication is essential for the formation of neuroepithelial tumors, probably because the genome can be remodeled. Nonetheless, several differentiated and stable childhood neoplasms retain their nuclear controls for differentiation. In contrast, rapidly arising gliomas often show a variety of phenotypic changes. Genomic plasticity and instability allow gliomas to flexibly adapt to new environments. Gene changes (in DNA) can be limited in childhood tumors whereas more widespread genetic changes in malignant gliomas indicate a fundamental alteration in many chromosome regions. Can such regions be defined? We used one repeated DNA sequence (TTAGGG)n, present at the end of all normal human chromosomes, to investigate chromosome termini in more detail. Pulsed-field gel electrophoresis showed this region can be unusually variable, as several other multilocus probes did not reveal comparable changes. Because telomeres form unique chromosomal structures, and are thought to provide essential signals to position chromosomes in the interphase nucleus, it was pertinent to assess these regions by in situ hybridization. Many telomeric domains localized at variable as well as interior nuclear positions in glioma cells. These positions, which are presumably abnormal, may be generated by the DNA variants observed. Such position changes may contribute to the more general ‘disorder’ observed in glioma nuclei. Other chromosome domains with a unique DNA-protein structure may define additional genomic loci that are preferentially modified in neoplasia. A fundamental understanding of chromosome structure should clarify the problem of multilocus instability in glioblastoma.