TY - JOUR
T1 - Molecular characterization of astrocytoma progression towards secondary glioblastomas utilizing patient-matched tumor pairs
AU - Seifert, Michael
AU - Schackert, Gabriele
AU - Temme, Achim
AU - Schröck, Evelin
AU - Deutsch, Andreas
AU - Klink, Barbara
N1 - Funding Information:
This work was supported by the Free State of Saxony and European Social Fund of the European Union (ESF, grant GlioMath-Dresden SAB-number 100098214, coordinator: Andreas Deutsch). We acknowledge support by the German Research Foundation and the Open Access Publication Funds of the SLUB/TU Dresden to cover the article processing charge. Acknowledgments: We thank the patients and their families that have made this research possible. We are grateful to all members of our GlioMath-Dresden consortium for their support and valuable discussions. In particular, we thank Alexander Krüger (Institute for Clinical Genetics, TU Dresden) and Katja Robel (Department of Neurosurgery, TU Dresden) for technical support, Pirasteh Pahlavan (Institute for Medical Informatics and Biometry, TU Dresden/NCT Dresden) and Falk Zakrzewski (NCT Dresden) for initial support of gene copy number and gene expression data analysis, and Kathrin Geiger (Institute for Pathology, University Hospital CGC at TU Dresden) for initial histological evaluation of tumor tissues.
Funding Information:
Funding: This work was supported by the Free State of Saxony and European Social Fund of the European Union (ESF, grant GlioMath-Dresden SAB-number 100098214, coordinator: Andreas Deutsch). We acknowledge support by the German Research Foundation and the Open Access Publication Funds of the SLUB/TU Dresden to cover the article processing charge.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/6
Y1 - 2020/6
N2 - Astrocytomas are primary human brain tumors including diffuse or anaplastic astrocytomas that develop towards secondary glioblastomas over time. However, only little is known about molecular alterations that drive this progression. We measured multi-omics profiles of patient-matched astrocytoma pairs of initial and recurrent tumors from 22 patients to identify molecular alterations associated with tumor progression. Gene copy number profiles formed three major subcluters, but more than half of the patient-matched astrocytoma pairs differed in their gene copy number profiles like astrocytomas from different patients. Chromosome 10 deletions were not observed for diffuse astrocytomas, but occurred in corresponding recurrent tumors. Gene expression profiles formed three other major subclusters and patient-matched expression profiles were much more heterogeneous than their copy number profiles. Still, recurrent tumors showed a strong tendency to switch to the mesenchymal subtype. The direct progression of diffuse astrocytomas to secondary glioblastomas showed the largest number of transcriptional changes. Astrocytoma progression groups were further distinguished by signaling pathway expression signatures affecting cell division, interaction and differentiation. As expected, IDH1 was most frequently mutated closely followed by TP53, but also MUC4 involved in the regulation of apoptosis and proliferation was frequently mutated. Astrocytoma progression groups differed in their mutation frequencies of these three genes. Overall, patient-matched astrocytomas can differ substantially within and between patients, but still molecular signatures associated with the progression to secondary glioblastomas exist and should be analyzed for their potential clinical relevance in future studies.
AB - Astrocytomas are primary human brain tumors including diffuse or anaplastic astrocytomas that develop towards secondary glioblastomas over time. However, only little is known about molecular alterations that drive this progression. We measured multi-omics profiles of patient-matched astrocytoma pairs of initial and recurrent tumors from 22 patients to identify molecular alterations associated with tumor progression. Gene copy number profiles formed three major subcluters, but more than half of the patient-matched astrocytoma pairs differed in their gene copy number profiles like astrocytomas from different patients. Chromosome 10 deletions were not observed for diffuse astrocytomas, but occurred in corresponding recurrent tumors. Gene expression profiles formed three other major subclusters and patient-matched expression profiles were much more heterogeneous than their copy number profiles. Still, recurrent tumors showed a strong tendency to switch to the mesenchymal subtype. The direct progression of diffuse astrocytomas to secondary glioblastomas showed the largest number of transcriptional changes. Astrocytoma progression groups were further distinguished by signaling pathway expression signatures affecting cell division, interaction and differentiation. As expected, IDH1 was most frequently mutated closely followed by TP53, but also MUC4 involved in the regulation of apoptosis and proliferation was frequently mutated. Astrocytoma progression groups differed in their mutation frequencies of these three genes. Overall, patient-matched astrocytomas can differ substantially within and between patients, but still molecular signatures associated with the progression to secondary glioblastomas exist and should be analyzed for their potential clinical relevance in future studies.
KW - Astrocytomas
KW - Cancer genomics
KW - Patient-matched astrocytoma pairs
KW - Secondary glioblastoma
KW - Stage-wise astrocytoma development
UR - http://www.scopus.com/inward/record.url?scp=85088615644&partnerID=8YFLogxK
U2 - 10.3390/cancers12061696
DO - 10.3390/cancers12061696
M3 - Article
AN - SCOPUS:85088615644
SN - 2072-6694
VL - 12
SP - 1
EP - 27
JO - Cancers
JF - Cancers
IS - 6
M1 - 1696
ER -