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

Authors
 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 
Citation
 Acta Neuropathologica, Vol.135(6) : 939-953, 2018 
Journal Title
 Acta Neuropathologica 
ISSN
 0001-6322 
Issue Date
2018
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.
Full Text
https://link.springer.com/article/10.1007%2Fs00401-018-1845-8
DOI
10.1007/s00401-018-1845-8
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
김동석(Kim, Dong Seok)
김세훈(Kim, Se Hoon) ORCID logo https://orcid.org/0000-0001-7516-7372
심규원(Shim, Kyu Won) ORCID logo https://orcid.org/0000-0002-9441-7354
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/165051
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