Genetic Analysis Of Multifocal Glioblastoma Multiforme Foci Points To Their Monoclonal Evolution And Highlights Early And Late Events In Their Development

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Glioblastoma (GBM) is the most common and malignant type of brain tumor in adults with an average survival time of less than a year. A hallmark of GBM is its infiltrating growth hampering successful surgical treatment and precluding curative therapy. Multifocal GBMs - multiple synchronous lesions in the same patient - represent approximately 8-10% of all gliomas and generally have a poor prognosis. There are two theories as to the nature of these multifocal GBMs: they could either have originated from one main GBM or they can be independent tumors. Genetic studies of multifocal GBMs are very rare and such studies could elucidate the nature of these tumors. We have analyzed eleven tumor foci of six patients with multifocal GBMs using array comparative genome hybridization (aCGH), spectral karyotyping (SKY), and Sanger sequencing of PTEN, TP53, and IDH1/2. Array CGH analysis of ten of the tumors revealed multiple genetic aberrations. The most frequent were gain of chromosome 7 (9/10), amplification of EGFR (10/10), loss of chromosome 10 (10/10), and partial loss of chromosome 9 (7/10). SKY analysis identified multiple translocations including complex rearrangements. None of the tumors carried a mutation in IDH1/2 and they were genetically similar to primary GBMs although they exhibited unique characteristics; e.g. all carried an EGFR amplification, indicating that it is important for the multifocal phenotype. Tumor foci derived from the same patient always shared identical aberrations, proving monoclonal origin of these tumors but also exhibited additional aberrations, which were specific for each focus and therefore must have occurred later in tumor development. Moreover, our results show that events important for gliomagenesis could occur at different time points in tumor evolution: for example, the region involved in the EGFR amplification was different in both foci from three patients and identical in two foci from one patient. The same can be said of point mutations in TP53 and PTEN; TP53 mutations were identical in the different foci from one patient and different in another patient while PTEN mutations were different in the foci from two patients and similar in those of one. Interestingly, in each patient one focus always contained more aberrations than the other, highlighting the possibility that one derived from the other; this would further support the hypothesis that multifocal GBMs are of monoclonal origin and then develop independently of each other by clonal evolution. Taken together, multifocal GBM provide an excellent model for investigating tumor progression and invasion and might help to distinguish between driver and passenger alterations in GBM. Acknowledgements: This work was partially supported by a grant (MeDDrive program) of the Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden. Citation Format: Khalil Abou-El-Ardat, Dietmar Krex, Michael Seifert, Kerstin Becker, Morten Hillmer, Sophie Eisenreich, Arleta Kasner-Frensel, Petra Freitag, Eva-Maria Gerlach, Karl Hackmann, Andreas Rump, Gabriele Schackert, Evelin Schrock, Barbara Klink. Genetic analysis of multifocal glioblastoma multiforme foci points to their monoclonal evolution and highlights early and late events in their development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3415. doi:10.1158/1538-7445.AM2014-3415