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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)939-953
Number of pages15
JournalActa Neuropathologica
Volume135
Issue number6
DOIs
Publication statusPublished - 2018 Jun 1

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Medulloblastoma
Glioblastoma
Radiotherapy
Neoplasms
Exome
Therapeutics
Second Primary Neoplasms
Germ-Line Mutation
Gene Fusion
Missense Mutation
Diagnostic Errors
Transcriptome
Pediatrics
Recurrence

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Phi, Ji Hoon ; Park, Ae Kyung ; Lee, Semin ; Choi, Seung Ah ; Baek, In Pyo ; Kim, Pora ; Kim, Eun Hye ; Park, Hee Chul ; Kim, Byung Chul ; Bhak, Jong ; Park, Sung Hye ; Lee, Ji Yeoun ; Wang, Kyu Chang ; Kim, Dong Seok ; Shim, Kyu Won ; Kim, Se Hoon ; Kim, Chae Yong ; Kim, Seung Ki. / Genomic analysis reveals secondary glioblastoma after radiotherapy in a subset of recurrent medulloblastomas. In: Acta Neuropathologica. 2018 ; Vol. 135, No. 6. pp. 939-953.
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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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Phi, JH, Park, AK, Lee, S, Choi, SA, Baek, IP, Kim, P, Kim, EH, Park, HC, Kim, BC, Bhak, J, Park, SH, Lee, JY, Wang, KC, Kim, DS, Shim, KW, Kim, SH, Kim, CY & Kim, SK 2018, 'Genomic analysis reveals secondary glioblastoma after radiotherapy in a subset of recurrent medulloblastomas', Acta Neuropathologica, vol. 135, no. 6, pp. 939-953. https://doi.org/10.1007/s00401-018-1845-8

Genomic analysis reveals secondary glioblastoma after radiotherapy in a subset of recurrent medulloblastomas. / Phi, Ji Hoon; Park, Ae Kyung; Lee, Semin; Choi, Seung Ah; Baek, In Pyo; Kim, Pora; Kim, Eun Hye; Park, Hee Chul; Kim, Byung Chul; Bhak, Jong; Park, Sung Hye; Lee, Ji Yeoun; Wang, Kyu Chang; Kim, Dong Seok; Shim, Kyu Won; Kim, Se Hoon; Kim, Chae Yong; Kim, Seung Ki.

In: Acta Neuropathologica, Vol. 135, No. 6, 01.06.2018, p. 939-953.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genomic analysis reveals secondary glioblastoma after radiotherapy in a subset of recurrent medulloblastomas

AU - Phi, Ji Hoon

AU - Park, Ae Kyung

AU - Lee, Semin

AU - Choi, Seung Ah

AU - Baek, In Pyo

AU - Kim, Pora

AU - Kim, Eun Hye

AU - Park, Hee Chul

AU - Kim, Byung Chul

AU - Bhak, Jong

AU - Park, Sung Hye

AU - Lee, Ji Yeoun

AU - Wang, Kyu Chang

AU - Kim, Dong Seok

AU - Shim, Kyu Won

AU - Kim, Se Hoon

AU - Kim, Chae Yong

AU - Kim, Seung Ki

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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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