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Acta Neuropathologica

, Volume 135, Issue 6, pp 939–953 | Cite as

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

  • Ji Hoon Phi
  • Ae Kyung Park
  • Semin Lee
  • Seung Ah Choi
  • In-Pyo Baek
  • Pora Kim
  • Eun-Hye Kim
  • Hee Chul Park
  • Byung Chul Kim
  • Jong Bhak
  • Sung-Hye Park
  • Ji Yeoun Lee
  • Kyu-Chang Wang
  • Dong-Seok Kim
  • Kyu Won Shim
  • Se Hoon Kim
  • Chae-Yong Kim
  • Seung-Ki Kim
Original Paper

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.

Keywords

Medulloblastoma Recurrence Secondary glioblastoma after radiotherapy Genomic analysis 

Notes

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).

Compliance with ethical standards

Conflict of interest

The authors declare no potential conflicts of interest.

Supplementary material

401_2018_1845_MOESM1_ESM.xlsx (1.1 mb)
Supplementary material 1 (XLSX 1092 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ji Hoon Phi
    • 1
    • 2
  • Ae Kyung Park
    • 3
  • Semin Lee
    • 4
    • 5
  • Seung Ah Choi
    • 1
    • 2
  • In-Pyo Baek
    • 6
  • Pora Kim
    • 7
  • Eun-Hye Kim
    • 8
  • Hee Chul Park
    • 9
  • Byung Chul Kim
    • 9
  • Jong Bhak
    • 4
    • 5
  • Sung-Hye Park
    • 10
  • Ji Yeoun Lee
    • 1
    • 2
    • 11
  • Kyu-Chang Wang
    • 1
    • 2
  • Dong-Seok Kim
    • 12
  • Kyu Won Shim
    • 12
  • Se Hoon Kim
    • 13
  • Chae-Yong Kim
    • 14
  • Seung-Ki Kim
    • 1
    • 2
  1. 1.Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience CenterSeoul National University Children’s HospitalSeoulRepublic of Korea
  2. 2.Department of Neurosurgery, Seoul National University HospitalSeoul National University College of MedicineSeoulRepublic of Korea
  3. 3.College of Pharmacy and Research Institute of Life and Pharmaceutical SciencesSunchon National UniversitySuncheonRepublic of Korea
  4. 4.Department of Biomedical Engineering, School of Life SciencesUlsan National Institute of Science and Technology (UNIST)UlsanRepublic of Korea
  5. 5.Korean Genomics Industrialization and Commercialization Center (KOGIC)UlsanRepublic of Korea
  6. 6.TheragenEtex Bio InstituteSuwonRepublic of Korea
  7. 7.School of Biomedical InformaticsThe University of Texas Health Science Center at HoustonHoustonUSA
  8. 8.Gerotech Inc.UlsanRepublic of Korea
  9. 9.Clinomics Inc.UlsanRepublic of Korea
  10. 10.Department of PathologySeoul National University College of MedicineSeoulRepublic of Korea
  11. 11.Department of AnatomySeoul National University College of MedicineSeoulRepublic of Korea
  12. 12.Department of Pediatric Neurosurgery, Severance Children’s HospitalYonsei University College of Medicine, Brain Korea 21 Project for Medical ScienceSeoulRepublic of Korea
  13. 13.Department of Pathology, Severance HospitalYonsei University College of MedicineSeoulRepublic of Korea
  14. 14.Department of NeurosurgerySeoul National University Bundang HospitalSeongnamRepublic of Korea

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