Glioblastomas harboring gene fusions detected by next-generation sequencing


Oncogenic gene fusions have been reported in diffuse gliomas and may serve as potential therapeutic targets. Here, using next-generation sequencing analysis (Illumina TruSight Tumor 170 panel), we analyzed a total of 356 diffuse gliomas collected from 2017 to 2019 to evaluate clinical, pathological, and genetic features of gene fusion. We found 53 cases of glioblastomas harboring the following oncogenic gene fusions: MET (n = 18), EGFR (n = 14), FGFR (n = 12), NTRK (n = 5), RET (n = 2), AKT3 (n = 1), and PDGFRA fusions (n = 1). Gene fusions were consistently observed in both IDH-wildtype and IDH-mutant glioblastomas (8.8% and 9.4%, p = 1.000). PTPRZ1–MET fusion was the only fusion that genetically resembled secondary glioblastomas (i.e., high frequency of IDH mutation, ATRX loss, TP53 mutation, and absence of EGFR amplification), whereas other gene fusion types were similar to primary glioblastomas (i.e., high frequency of IDH-wildtype, TERT mutation, EGFR amplification, and PTEN mutation). In IDH-wildtype glioblastoma patients, multivariable analysis revealed that the PTPRZ1MET fusion was associated with poor progression-free survival (HR [95% CI]: 5.42 (1.72–17.05), p = 0.004). Additionally, we described two novel cases of CCDC6RET fusion in glioma. Collectively, our findings indicate that targetable gene fusions are associated with aggressive biological behavior and can aid the clinical treatment strategy for glioma patients.

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  1. 1.

    Gao Q, Liang WW, Foltz SM, Mutharasu G, Jayasinghe RG, Cao S, Liao WW, Reynolds SM, Wyczalkowski MA, Yao L, Yu L, Sun SQ, Chen K, Lazar AJ, Fields RC, Wendl MC, Van Tine BA, Vij R, Chen F, Nykter M, Shmulevich I, Ding L (2018) Driver fusions and their implications in the development and treatment of human cancers. Cell Rep 23(1):227–238.e223.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Mitelman F, Johansson B, Mertens F (2007) The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 7(4):233–245.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Mertens F, Johansson B, Fioretos T, Mitelman F (2015) The emerging complexity of gene fusions in cancer. Nat Rev Cancer 15(6):371–381.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Yoshihara K, Wang Q, Torres-Garcia W, Zheng S, Vegesna R, Kim H, Verhaak RG (2015) The landscape and therapeutic relevance of cancer-associated transcript fusions. Oncogene 34(37):4845–4854.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Lobato MN, Metzler M, Drynan L, Forster A, Pannell R, Rabbitts TH (2008) Modeling chromosomal translocations using conditional alleles to recapitulate initiating events in human leukemias. J Natl Cancer Inst Monogr 39:58–63.

    CAS  Article  Google Scholar 

  6. 6.

    Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448(7153):561–566.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Druker BJ (2004) Imatinib as a paradigm of targeted therapies. Adv Cancer Res 91:1–30.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA, Shapiro GI, Costa DB, Ou SH, Butaney M, Salgia R, Maki RG, Varella-Garcia M, Doebele RC, Bang YJ, Kulig K, Selaru P, Tang Y, Wilner KD, Kwak EL, Clark JW, Iafrate AJ, Camidge DR (2011) Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 12(11):1004–1012.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, Stroup NE, Kruchko C, Barnholtz-Sloan JS (2013) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro Oncol 15(Suppl 2):ii1–56.

  10. 10.

    (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068.

  11. 11.

    Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black KL, Eschbacher J, Finocchiaro G, Friedman W, Andrews DW, Guha A, Iacocca M, O'Neill BP, Foltz G, Myers J, Weisenberger DJ, Penny R, Kucherlapati R, Perou CM, Hayes DN, Gibbs R, Marra M, Mills GB, Lander E, Spellman P, Wilson R, Sander C, Weinstein J, Meyerson M, Gabriel S, Laird PW, Haussler D, Getz G, Chin L (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Louis DNOH, Wiestler OD, Cavenee WK (2016) WHO classification of tumours of the central nervous system, revised. 4th edn. International Agency for Research on Cancer, Lyon

  13. 13.

    Touat M, Idbaih A, Sanson M, Ligon KL (2017) Glioblastoma targeted therapy: updated approaches from recent biological insights. Ann Oncol 28(7):1457–1472.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Aldape K, Zadeh G, Mansouri S, Reifenberger G, von Deimling A (2015) Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol 129(6):829–848.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Charest A, Lane K, McMahon K, Park J, Preisinger E, Conroy H, Housman D (2003) Fusion of FIG to the receptor tyrosine kinase ROS in a glioblastoma with an interstitial del(6)(q21q21). Genes Chromosomes Cancer 37(1):58–71.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Kim J, Lee Y, Cho HJ, Lee YE, An J, Cho GH, Ko YH, Joo KM, Nam DH (2014) NTRK1 fusion in glioblastoma multiforme. PLoS ONE 9(3):e91940.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Ozawa T, Brennan CW, Wang L, Squatrito M, Sasayama T, Nakada M, Huse JT, Pedraza A, Utsuki S, Yasui Y, Tandon A, Fomchenko EI, Oka H, Levine RL, Fujii K, Ladanyi M, Holland EC (2010) PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas. Genes Dev 24(19):2205–2218.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Parker BC, Annala MJ, Cogdell DE, Granberg KJ, Sun Y, Ji P, Li X, Gumin J, Zheng H, Hu L, Yli-Harja O, Haapasalo H, Visakorpi T, Liu X, Liu CG, Sawaya R, Fuller GN, Chen K, Lang FF, Nykter M, Zhang W (2013) The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma. J Clin Invest 123(2):855–865.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, Liu EM, Reichel J, Porrati P, Pellegatta S, Qiu K, Gao Z, Ceccarelli M, Riccardi R, Brat DJ, Guha A, Aldape K, Golfinos JG, Zagzag D, Mikkelsen T, Finocchiaro G, Lasorella A, Rabadan R, Iavarone A (2012) Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337(6099):1231–1235.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Fisher KE, Zhang L, Wang J, Smith GH, Newman S, Schneider TM, Pillai RN, Kudchadkar RR, Owonikoko TK, Ramalingam SS, Lawson DH, Delman KA, El-Rayes BF, Wilson MM, Sullivan HC, Morrison AS, Balci S, Adsay NV, Gal AA, Sica GL, Saxe DF, Mann KP, Hill CE, Khuri FR, Rossi MR (2016) Clinical validation and implementation of a targeted next-generation sequencing assay to detect somatic variants in non-small cell lung, melanoma, and gastrointestinal malignancies. J Mol Diagn 18(2):299–315.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Di Stefano AL, Fucci A, Frattini V, Labussiere M, Mokhtari K, Zoppoli P, Marie Y, Bruno A, Boisselier B, Giry M, Savatovsky J, Touat M, Belaid H, Kamoun A, Idbaih A, Houillier C, Luo FR, Soria J-C, Tabernero J, Eoli M, Paterra R, Yip S, Petrecca K, Chan JA, Finocchiaro G, Lasorella A, Sanson M, Iavarone A (2015) Detection, characterization, and inhibition of FGFR-TACC fusions in IDH wild-type glioma. Clin Cancer Res 21(14):3307–3317.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Heyer EE, Deveson IW, Wooi D, Selinger CI, Lyons RJ, Hayes VM, O'Toole SA, Ballinger ML, Gill D, Thomas DM, Mercer TR, Blackburn J (2019) Diagnosis of fusion genes using targeted RNA sequencing. Nat Commun 10(1):1388.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Ferguson SD, Zhou S, Huse JT, de Groot JF, Xiu J, Subramaniam DS, Mehta S, Gatalica Z, Swensen J, Sanai N, Spetzler D, Heimberger AB (2018) Targetable gene fusions associate with the IDH wild-type astrocytic lineage in adult gliomas. J Neuropathol Exp Neurol 77(6):437–442.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Bao ZS, Chen HM, Yang MY, Zhang CB, Yu K, Ye WL, Hu BQ, Yan W, Zhang W, Akers J, Ramakrishnan V, Li J, Carter B, Liu YW, Hu HM, Wang Z, Li MY, Yao K, Qiu XG, Kang CS, You YP, Fan XL, Song WS, Li RQ, Su XD, Chen CC, Jiang T (2014) RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas. Genome Res 24(11):1765–1773.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Hu H, Mu Q, Bao Z, Chen Y, Liu Y, Chen J, Wang K, Wang Z, Nam Y, Jiang B, Sa JK, Cho HJ, Her NG, Zhang C, Zhao Z, Zhang Y, Zeng F, Wu F, Kang X, Liu Y, Qian Z, Wang Z, Huang R, Wang Q, Zhang W, Qiu X, Li W, Nam DH, Fan X, Wang J, Jiang T (2018) Mutational landscape of secondary glioblastoma guides MET-targeted trial in brain tumor. Cell 175(6):1665–1678.e1618.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Cheng F, Guo D (2019) MET in glioma: signaling pathways and targeted therapies. J Exp Clin Cancer Res 38(1):270.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Maire CL, Ligon KL (2014) Molecular pathologic diagnosis of epidermal growth factor receptor. Neuro Oncol 16(Suppl 8):viii1–6.

  28. 28.

    Frattini V, Trifonov V, Chan JM, Castano A, Lia M, Abate F, Keir ST, Ji AX, Zoppoli P, Niola F, Danussi C, Dolgalev I, Porrati P, Pellegatta S, Heguy A, Gupta G, Pisapia DJ, Canoll P, Bruce JN, McLendon RE, Yan H, Aldape K, Finocchiaro G, Mikkelsen T, Privé GG, Bigner DD, Lasorella A, Rabadan R, Iavarone A (2013) The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet 45(10):1141–1149.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Li AY, McCusker MG, Russo A, Scilla KA, Gittens A, Arensmeyer K, Mehra R, Adamo V, Rolfo C (2019) RET fusions in solid tumors. Cancer Treat Rev 81:101911.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Spina R, Voss DM, Asnaghi L, Sloan A, Bar EE (2016) Atracurium Besylate and other neuromuscular blocking agents promote astroglial differentiation and deplete glioblastoma stem cells. Oncotarget 7(1):459–472.

  31. 31.

    Kumar-Sinha C, Kalyana-Sundaram S, Chinnaiyan AM (2015) Landscape of gene fusions in epithelial cancers: seq and ye shall find. Genome Med 7:129.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C (2014) The landscape of kinase fusions in cancer. Nat Commun 5(1):4846.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Davare MA, Tognon CE (2015) Detecting and targetting oncogenic fusion proteins in the genomic era. Biol Cell 107(5):111–129.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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S.H.K. was supported by grants from the Brain Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (Grant No. 2016M3C7A1913844). The funding source had no role in the design, practice, or analysis of this study. The authors would like to gratefully thank Won Young Park and Yi Rang Kim for their dedicated effort in NGS testing.

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Correspondence to Se Hoon Kim.

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Woo, H.Y., Na, K., Yoo, J. et al. Glioblastomas harboring gene fusions detected by next-generation sequencing. Brain Tumor Pathol 37, 136–144 (2020).

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  • Next-generation sequencing
  • Glioma
  • Fusion
  • Glioblastoma
  • MET