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Next Generation Molecular Classification of Glioblastomas using the Heidelberg-Dresden Brain Tumor Panel to uncover mechanisms of radioresistance

Summary of the Project

Within the Core Unit for Molecular Tumor Diagnostics (CMTD) at the NCT Dresden, we aim to establish and validate the "next generation" of molecular diagnostic approaches in patients with brain tumors, in particular gliomas. Therefore, a comprehensive panel that includes more than 130 genes and for the first time regions involved in copy number changes in brain tumor was designed at the Department of Neuropathology in Heidelberg (Prof. Dr. med. Andreas von Deimling and Dr. med. Felix Sahm) together with Dr. med. Barbara Klink, Dresden.

This project aims to implement this panel at the NCT Dresden and apply it to FFPE glioblastoma tissue samples from a unique and clinically well-characterized study cohort consisting of non-responders and responders to treatment with radiotherapy in combination with temozolomide. We will establish a stratification algorithm to predict radio-resistance in glioblastoma and to identify patients suitable for innovative targeted therapies. The findings will directly translate into clinical practice. It is planned to implement the panel into routine diagnostic of brain tumors in Dresden to enable for a molecular-based treatment decision-making and initiation of future clinical trials.

Scientific Goals

  • Development and clinical implementation of next generation sequencing based molecular diagnostics for patients with gliomas.
  • Comprehensive characterization of brain tumors with one single experiment, an approach we will apply to other cancers as well in the future.
  • Development of novel and innovative algorithms for the robust identification of CNVs from NGS-data, which can be used in many applications.

Abou-El-Ardat K, Seifert M, Becker K, Eisenreich S, Lehmann M, Hackmann K, Rump A, Meijer G, Carvalho B, Temme A, Schackert G, Schröck E, Krex D, Klink B. Comprehensive molecular characterization of multifocal glioblastoma proves its monoclonal origin and reveals novel insights into clonal evolution and heterogeneity of glioblastomas. Neuro Oncol. 2017 Apr 1;19(4):546-557

Ronellenfitsch MW, Oh JE, Satomi K, Sumi K, Harter PN, Steinbach JP, Felsberg J, Capper D, Voegele C, Durand G, McKay J, Le Calvez-Kelm F, Schittenhelm J, Klink B, Mittelbronn M, Ohgaki H. CASP9 germline mutation in a family with multiple brain tumors. Brain Pathol. 2016; Epub ahead of print

Rump A, Benet-Pages A, Schubert S, Kuhlmann JD, Janavičius R, Macháčková E, Foretová L, Kleibl Z, Lhota F, Zemankova P, Betcheva-Krajcir E, Mackenroth L, Hackmann K, Lehmann J, Nissen A, DiDonato N, Opitz R, Thiele H, Kast K, Wimberger P, Holinski-Feder E, Emmert S, Schröck E, Klink B. Identification and Functional Testing of ERCC2 Mutations in a Multi-national Cohort of Patients with Familial Breast- and Ovarian Cancer. PLoS Genet. 2016;12(8):e1006248.

Schroeder C, Faust U, Sturm M, Hackmann K, Grundmann K, Harmuth F, Bosse K, Kehrer M, Benkert T, Klink B, Mackenroth L, Betcheva-Krajcir E, Wimberger P, Kast K, Heilig M, Nguyen HP, Riess O, Schröck E, Bauer P, Rump A. HBOC multi-gene panel testing: comparison of two sequencing centers. Breast Cancer Res Treat. 2015 Jul;152(1):129-36.

Seifert M, Garbe M, Friedrich B, Mittelbronn M, Klink B. Comparative Transcriptomics Reveals Similarities and Differences between Astrocytoma Grades. BMC Cancer 2015;15:952.

Buder T, Deutsch A, Klink B, Voss-Böhme A. Model-Based Evaluation of Spontaneous Tumor Regression in Pilocytic Astrocytoma. PLoS Comput Biol. 2015 Dec 10;11(12):e1004662.

Contact

Dr. med. Barbara Klink
Department for Clinical Genetics, Medical Faculty and University Hospital Carl Gustav Carus Dresden
Phone: +49 (0)351 458 2894
Email: barbara.klink(at)uniklinikum-dresden.de