Comprehensive molecular characterization of multifocal glioblastoma proves its monoclonal origin and reveals novel insights into clonal evolution and heterogeneity of glioblastomas
| Autor: | Karl Hackmann, Barbara Klink, Beatriz Carvalho, Dietmar Krex, Matthias Lehmann, Michael Seifert, Evelin Schröck, Kerstin Becker, Achim Temme, Gabriele Schackert, Sophie Eisenreich, Andreas Rump, Khalil Abou-El-Ardat, Gerrit A. Meijer |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Gene Expression medicine.disease_cause Somatic evolution in cancer Clonal Evolution Evolution Molecular 03 medical and health sciences 0302 clinical medicine CDKN2A medicine PTEN Humans Letters to the Editor neoplasms Genetics Mutation Chromothripsis biology Genetic heterogeneity Brain Neoplasms Point mutation nervous system diseases 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Neurology (clinical) Multifocal Glioblastomas Glioblastoma Signal Transduction |
| Zdroj: | Neuro-oncology. 19(4) |
| ISSN: | 1523-5866 |
| Popis: | Background The evolution of primary glioblastoma (GBM) is poorly understood. Multifocal GBM (ie, multiple synchronous lesions in one patient) could elucidate GBM development. Methods We present the first comprehensive study of 12 GBM foci from 6 patients using array-CGH, spectral karyotyping, gene expression arrays, and next-generation sequencing. Results Multifocal GBMs genetically resemble primary GBMs. Comparing foci from the same patient proved their monoclonal origin. All tumors harbored alterations in the 3 GBM core pathways: RTK/PI3K, p53, and RB regulatory pathways with aberrations of EGFR and CDKN2A/B in all (100%) patients. This unexpected high frequency reflects a distinct genetic signature of multifocal GBMs and might account for their highly malignant and invasive phenotype. Surprisingly, the types of mutations in these genes/pathways were different in tumor foci from the same patients. For example, we found distinct mutations/aberrations in PTEN, TP53, EGFR, and CDKN2A/B, which therefore must have occurred independently and late during tumor development. We also identified chromothripsis as a late event and in tumors with wild-type TP53. Only 2 events were found to be early in all patients: single copy loss of PTEN and TERT promoter point mutations. Conclusions Multifocal GBMs develop through parallel genetic evolution. The high frequency of alterations in 3 main pathways suggests that these are essential steps in GBM evolution; however, their late occurrence indicates that they are not founder events but rather subclonal drivers. This might account for the marked genetic heterogeneity seen in primary GBM and therefore has important implications for GBM therapy. |
| Databáze: | OpenAIRE |
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