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CDK4, CDK6, cyclin D1, p16(INK4a) and EGFR expression in glioblastoma with a primitive neuronal component

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Abstract

Glioblastoma with primitive neuroectodermal tumor-like component (GBM-PNET) is a rare variant of glioblastoma, which was renamed as glioblastoma with a primitive neuronal component (GBM-PN) in new WHO classification of tumours of the central nervous system in 2016. There are few publications on the investigation of GBM-PN. In this study, PCR mRNA arrays on 6 cases of conventional GBM and 10 cases of GBM-PN showed high mRNA level of CDK4 in GBM-PN and low mRNA level of EGFR in GBM-PN. Immunohistochemical stains on tissue microarrays with 28 cases of conventional GBM and 13 cases of GBM-PN demonstrated that CDK4 was selectively expressed in the primitive neuronal component of all GBM-PN cases while EGFR was positive in conventional GBM and glial component of GBM-PN, but was negative in the primitive neuronal component of all GBM-PN cases. Immunohistochemical stains with antibodies against proteins that interact with CDK4 in cell cycle regulation, such as CDK6, cyclin D1 and p16(INK4a), were performed on these GBM-PN and GBM cases. CDK6 was patchily positive in rare cases of GBM-PN and cyclin D1 was negative in GBM-PN cases. p16(INK4a) is traditionally known as an inhibitor of CDK4 and CDK6. p16(INK4a) might not be the inhibitor of CDK4 in GBM-PN cases because seven GBM-PN cases were positive for both CDK4 and p16(INK4a). It indicates that CDK4 and p16(INK4a) might play a crucial role in GBM-PN pathogenesis. Since CDK4 and EGFR are highly expressed in the primitive neuronal component and in the glial component of GBM-PN respectively, the combination of CDK4/6 inhibitor and targeted therapy against EGFR might be potential effective therapeutic regimen for GBM-PN. CDK4 and EGFR immuohistochemical stain patterns make the diagnosis of GBM-PN much easier.

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References

  1. Perry A, Miller CR, Gujrati M, Scheithauer BW, Zambrano SC, Jost SC, Raghavan R, Qian J, Cochran EJ, Huse JT, Holland EC, Burger PC, Rosenblum MK (2009) Malignant gliomas with primitive neuroectodermal tumor-like components: a clinicopathologic and genetic study of 53 cases. Brain Pathol 19(1):81–90

    Article  PubMed  Google Scholar 

  2. Song X, Andrew AR, Terence DS, Fung KM, Farmer P, Gandhi S, Ranjan T, Demopoulos A, Symons M, Schulder M, Li JY (2011) Glioblastoma with PNET-like components has a higher frequency of isocitrate dehydrogenase 1 (IDH1) mutation and likely a better prognosis than primary glioblastoma. Int J Clin Exp Pathol 4(7):651–660

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Ali S, Joseph NM, Perry A, Barajas RF Jr, Cha S (2014) Apparent diffusion coefficient in glioblastoma with PNET-like components, a GBM variant. J Neurooncol 119(2):353–360

    Article  CAS  PubMed  Google Scholar 

  4. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131(6):803–820

    Article  PubMed  Google Scholar 

  5. Andersson U, Schwartzbaum J, Wiklund F, Sjostrom S, Liu Y, Tsavachidis S, Ahlbom A, Auvinen A, Collatz-Laier H, Feychting M, Johansen C, Kiuru A, Lonn S, Schoemaker MJ, Swerdlow AJ, Henriksson R, Bondy M, Melin B (2010) A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk. Acta Oncol 49(6):767–775

    Article  CAS  PubMed  Google Scholar 

  6. Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068

    Article  Google Scholar 

  7. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4(7):844–847

    Article  CAS  PubMed  Google Scholar 

  9. Crespo I, Vital AL, Gonzalez-Tablas M, Patino MC, Otero A, Lopes MC, de Domingues OC, Orfao PA, Tabernero MD (2015) Molecular and genomic alterations in glioblastoma multiforme. Am J Pathol 185(7):1820–1833

    Article  CAS  PubMed  Google Scholar 

  10. Heimberger AB, Suki D, Yang D, Shi W, Aldape K (2005) The natural history of EGFR and EGFRvIII in glioblastoma patients. J Transl Med 3:38

    Article  PubMed  PubMed Central  Google Scholar 

  11. Reifenberger G, Ichimura K, Reifenberger J, Elkahloun AG, Meltzer PS, Collins VP (1996) Refined mapping of 12q13-q15 amplicons in human malignant gliomas suggests CDK4/SAS and MDM2 as independent amplification targets. Cancer Res 56(22):5141–5145

    CAS  PubMed  Google Scholar 

  12. Furgason JM, Koncar RF, Michelhaugh SK, Sarkar FH, Mittal S, Sloan AE, Barnholtz-Sloan JS, eM B (2015) Whole genome sequence analysis links chromothripsis to EGFR, MDM2, MDM4, and CDK4 amplification in glioblastoma. Oncoscience 2(7):618–628

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lam PY, Di TE, Ng HK, Pang JC, Roussel MF, Hjelm NM (2000) Expression of p19INK4d, CDK4, CDK6 in glioblastoma multiforme. Br J Neurosurg 14(1):28–32

    Article  CAS  PubMed  Google Scholar 

  14. Maxwell M, Galanopoulos T, Antoniades H (1996) Cell-cycle regulator cyclin D1 mRNA and protein overexpression occurs in primary malignant gliomas. Int J Oncol 9(3):493–497

    CAS  PubMed  Google Scholar 

  15. Hartmann C, Kluwe L, Lucke M, Westphal M (1999) The rate of homozygous CDKN2A/p16 deletions in glioma cell lines and in primary tumors. Int J Oncol 15(5):975–982

    CAS  PubMed  Google Scholar 

  16. Purkait S, Jha P, Sharma MC, Suri V, Sharma M, Kale SS, Sarkar C (2013) CDKN2A deletion in pediatric versus adult glioblastomas and predictive value of p16 immunohistochemistry. Neuropathology 33(4):405–412

    Article  CAS  PubMed  Google Scholar 

  17. Hirai H, Shimomura T, Kobayashi M, Eguchi T, Taniguchi E, Fukasawa K, Machida T, Oki H, Arai T, Ichikawa K, Hasako S, Haze K, Kodera T, Kawanishi N, Takahashi-Suziki I, Nakatsuru Y, Kotani H, Iwasawa Y (2010) Biological characterization of 2-aminothiazole-derived Cdk4/6 selective inhibitor in vitro and in vivo. Cell Cycle 9(8):1590–1600

    Article  CAS  PubMed  Google Scholar 

  18. Barton KL, Misuraca K, Cordero F, Dobrikova E, Min HD, Gromeier M, Kirsch DG, Becher OJ (2013) PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma. PLoS ONE 8(10):e77639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Raub TJ, Wishart GN, Kulanthaivel P, Staton BA, Ajamie RT, Sawada GA, Gelbert LM, Shannon HE, Sanchez-Martinez C, De DA (2015) Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft. Drug Metab Dispos 43(9):1360–1371

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We give special thanks to Dr. Betty Diamond, who provided the lab space and equipments. We also appreciate help and support from all her lab members. We are thankful for Mr. Daniel Loen and Ms. Jill Wishinsky for managing the Grant. Dept. of Pathology and Lab. Medicine: We thank Dr. James Crawford for his support and encouragement, Ms. Claudine Alexis for ordering all our materials, and people in histology laboratory and immunostain laboratory for technical support. Note: Dr. Guiyan Xu currently stays at home.

Funding

This work was supported by Northwell Health Cancer Institute.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, North Shore University Hospital and Long Island Jewish Medical Center, Northwell Health, Lake Success, 11040, NY, USA

    Guiyan Xu & Jian Yi Li

  2. Cancer Institute, Northwell Health, Lake Success, USA

    Jian Yi Li

  3. Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA

    Jian Yi Li

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  1. Guiyan Xu
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Correspondence to Jian Yi Li.

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Xu, G., Li, J.Y. CDK4, CDK6, cyclin D1, p16(INK4a) and EGFR expression in glioblastoma with a primitive neuronal component. J Neurooncol 136, 445–452 (2018). https://doi.org/10.1007/s11060-017-2674-7

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  • DOI: https://doi.org/10.1007/s11060-017-2674-7

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