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Genetic, epigenetic, and molecular landscapes of multifocal and multicentric glioblastoma

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Abstract

Ten to twenty percent of newly diagnosed glioblastoma (GBM) patients initially present with multiple lesions, termed multifocal or multicentric GBM (M-GBM). The prognosis of these patients is poorer than that of solitary GBM (S-GBM) patients. However, it is unknown whether multifocality has a genetic, epigenetic, or molecular basis. Here, we identified the genetic and epigenetic characteristics of M-GBM by performing a comprehensive analysis of multidimensional data, including imaging, genetic, epigenetic, and gene expression profiles, from 30 M-GBM cases in The Cancer Genome Atlas database and comparing the results with those of 173 S-GBM cases. We found that M-GBMs had no IDH1, ATRX, or PDGFRA mutations and were significantly associated with the mesenchymal subtype. We also identified the CYB5R2 gene to be hypo-methylated and overexpressed in M-GBMs. The expression level of CYB5R2 was significantly associated with patient survival in two major independent GBM cohorts, totaling 758 cases. The IDH1 mutation was markedly associated with CYB5R2 promoter methylation, but the survival influence of CYB5R2 was independent of IDH1 mutation status. CYB5R2 expression was significantly associated with collagen maturation and the catabolic process and immunoregulation pathways. These results reveal that M-GBMs have some underlying genetic and epigenetic characteristics that are associated with poor prognosis and that CYB5R2 is a new epigenetic marker for GBM prognosis.

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Acknowledgments

We thank Ms. Ann M. Sutton of the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for editing this manuscript. This work was partially supported by NIH Grants CA141432, CA09850305, and U24CA143835 to WZ and an MD Anderson core grant from the National Cancer Institute (CA16672), grants from the Cancer Systems Informatics Center from the National Foundation for Cancer Research to WZ, and grants from the Program for Changjiang Scholars and Innovative Research Team in University in China (IRT_14R40) to KC. QL was supported by a grant from Tianjin Medical University Cancer Institute and Hospital.

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Authors and Affiliations

  1. Department of Pathology, Unit 85, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Qun Liu, Yuexin Liu, Gregory N. Fuller & Wei Zhang

  2. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Raymond Sawaya & Frederick F. Lang

  3. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    W. K. Alfred Yung

  4. Department of Neurosurgery, Key Laboratory of Cancer Prevention and Therapy of Tianjin, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Hospital and Institute, Tianjin, People’s Republic of China

    Qun Liu, Wenliang Li & Xiaoguang Wang

  5. Department of Epidemiology and Biostatistics, Key Laboratory of Cancer Prevention and Therapy of Tianjin, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Hospital and Institute, Tianjin, People’s Republic of China

    Kexin Chen

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  1. Qun Liu
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Liu, Q., Liu, Y., Li, W. et al. Genetic, epigenetic, and molecular landscapes of multifocal and multicentric glioblastoma. Acta Neuropathol 130, 587–597 (2015). https://doi.org/10.1007/s00401-015-1470-8

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  • DOI: https://doi.org/10.1007/s00401-015-1470-8

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