gms | German Medical Science

Introduction: High-resolution, genome-wide mapping of exact boundaries of chromosomal alterations should facilitate the localization and identification of genes involved in gliomagenesis and may characterize genetic subgroups of human gliomas.

Methods and Materials: We have performed such mapping using microarray-based comparative genomic hybridization technology to profile copy number alterations across 42,000 mapped human cDNA clones, in a series of 54 gliomas of varying histogenesis and tumor grade.

Results: This gene-by-gene analysis demonstrated the power of the created maps to precisely localize and size target regions and new recurrent regions of gene copy number change in these tumors. We have identified novel, common minimally altered regions in a subset of gliomas. The focal and informative nature of these recurrent regions can be best appreciated by consideration of the peak amplitude of recurrence of individual gene alterations within a region. We have discovered five minimally deleted regions, harboring deletions in putative tumor suppressor genes (TOPORS, FANCG, RAD51, TP53BP1, and BIK) within their peak profile, not previously reported in gliomas. Finally, our study has revealed recurrent patterns of occurrence of distinct chromosomal aberrations as well as their interrelationships, and shows that gliomas can be clustered into distinct genetic subgroups. A subset of alterations was shown predominantly associated with either astrocytic or oligodendrocytic tumor phenotypes. This suggests that some gene alterations during gliomagenesis may be primarily shared within histological subgroups, while others may be beyond the morphological boundaries of tumor phenotype.

Conclusion: We have generated highly precise and comprehensive gene copy number profiles in human gliomas, which allowed accurate delineation of known and new chromosomal alterations. Gliomas can be clustered into genetic subgroups based on recurrent patterns of interrelated chromosomal changes, a subset of which predicts glioma phenotype. We have identified the persistent deletion of five putative candidate tumor suppressor genes that could have a role in gliomagenesis.