gms | German Medical Science

Objective: Multifocal glioblastoma, i.e. multiple synchronous lesions in one patient, are considered to be a good model to elucidate the pathogenesis and progression of malignant gliomas. Our aim was to perform a molecular characterization of a small set of this tumor entity.

Methods: Tumor tissue and primary cell cultures from 12 GBM foci from 6 patients were used for array-CGH, spectral karyotyping, gene expression arrays and next-generation sequencing.

Results: Comparison of the different tumor foci from the same patient proved their monoclonal origin and elucidated their clonal evolution. Alterations in the p53, RB, and RTK/PI3K regulatory pathways, which are the core pathways in glioma pathogenesis, were found in all tumors. Most abundant were aberrations of EGFR and CDKN2A/B, which were found in all patients. This unexpected high frequency reflects a distinct genetic signature of multifocal GBMs in comparison to a single lesion and might account for their highly malignant and invasive phenotype. The types of mutations in the PTEN, TP53, EGFR, and CDKN2A/B genes were different in tumor foci from the same patients, which therefore must have occurred independently and late during tumor development. Only a single copy loss of PTEN and TERT promoter point mutations were found to be early in all patients.

Conclusion: The comprehensive analysis of a set of multifocal GBMs identifies the monoclonal origin of these tumors as well as the uniqueness in terms of genetic aberrations and their frequency when compared with unifocal glioblastomas. The high frequency and late occurrence of alterations in three major pathways suggest that these are no founder events but nevertheless essential steps in further GBM evolution. These data should be considered when looking for molecular targets for new therapeutically approaches.