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Genomic analysis reveals secondary glioblastoma after radiotherapy in a subset of recurrent medulloblastomas

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Abstract

Despite great advances in understanding of molecular pathogenesis and achievement of a high cure rate in medulloblastoma, recurrent medulloblastomas are still dismal. Additionally, misidentification of secondary malignancies due to histological ambiguity leads to misdiagnosis and eventually to inappropriate treatment. Nevertheless, the genomic characteristics of recurrent medulloblastomas are poorly understood, largely due to a lack of matched primary and recurrent tumor tissues. We performed a genomic analysis of recurrent tumors from 17 pediatric medulloblastoma patients. Whole transcriptome sequencing revealed that a subset of recurrent tumors initially diagnosed as locally recurrent medulloblastomas are secondary glioblastomas after radiotherapy, showing high similarity to the non-G-CIMP proneural subtype of glioblastoma. Further analysis, including whole exome sequencing, revealed missense mutations or complex gene fusion events in PDGFRA with augmented expression in the secondary glioblastomas after radiotherapy, implicating PDGFRA as a putative driver in the development of secondary glioblastomas after treatment exposure. This result provides insight into the possible application of PDGFRA-targeted therapy in these second malignancies. Furthermore, genomic alterations of TP53 including 17p loss or germline/somatic mutations were also found in most of the secondary glioblastomas after radiotherapy, indicating a crucial role of TP53 alteration in the process. On the other hand, analysis of recurrent medulloblastomas revealed that the most prevalent alterations are the loss of 17p region including TP53 and gain of 7q region containing EZH2 which already exist in primary tumors. The 7q gain events are frequently accompanied by high expression levels of EZH2 in both primary and recurrent medulloblastomas, which provides a clue to a new therapeutic target to prevent recurrence. Considering the fact that it is often challenging to differentiate between recurrent medulloblastomas and secondary glioblastomas after radiotherapy, our findings have major clinical implications both for correct diagnosis and for potential therapeutic interventions in these devastating diseases.

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Acknowledgements

This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1420020). This work was also supported by the 2016 Research Fund (1.160052.01) of Ulsan National Institute of Science and Technology (UNIST) and the Collaborative Genome Program for Fostering New Post-Genome Industry of the National Research Foundation (NRF) funded by the Ministry of Science and ICT (MSIT) (NRF-2017M3C9A5031004).

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  1. Ji Hoon Phi, Ae Kyung Park and Semin Lee contributed equally to this article.

Authors and Affiliations

  1. Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul, 03080, Republic of Korea

    Ji Hoon Phi, Seung Ah Choi, Ji Yeoun Lee, Kyu-Chang Wang & Seung-Ki Kim

  2. Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea

    Ji Hoon Phi, Seung Ah Choi, Ji Yeoun Lee, Kyu-Chang Wang & Seung-Ki Kim

  3. College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon, 57922, Republic of Korea

    Ae Kyung Park

  4. Department of Biomedical Engineering, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea

    Semin Lee & Jong Bhak

  5. Korean Genomics Industrialization and Commercialization Center (KOGIC), Ulsan, 44919, Republic of Korea

    Semin Lee & Jong Bhak

  6. TheragenEtex Bio Institute, Suwon, 16229, Republic of Korea

    In-Pyo Baek

  7. School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    Pora Kim

  8. Gerotech Inc., Ulsan, 44919, Republic of Korea

    Eun-Hye Kim

  9. Clinomics Inc., Ulsan, 44919, Republic of Korea

    Hee Chul Park & Byung Chul Kim

  10. Department of Pathology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea

    Sung-Hye Park

  11. Department of Anatomy, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea

    Ji Yeoun Lee

  12. Department of Pediatric Neurosurgery, Severance Children’s Hospital, Yonsei University College of Medicine, Brain Korea 21 Project for Medical Science, Seoul, 03722, Republic of Korea

    Dong-Seok Kim & Kyu Won Shim

  13. Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea

    Se Hoon Kim

  14. Department of Neurosurgery, Seoul National University Bundang Hospital, Seongnam, 13620, Republic of Korea

    Chae-Yong Kim

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  1. Ji Hoon Phi
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Phi, J.H., Park, A.K., Lee, S. et al. Genomic analysis reveals secondary glioblastoma after radiotherapy in a subset of recurrent medulloblastomas. Acta Neuropathol 135, 939–953 (2018). https://doi.org/10.1007/s00401-018-1845-8

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