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CDKN2A (p16) mRNA decreased expression is a marker of poor prognosis in malignant high-grade glioma

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Tumor Biology

Abstract

Human high-grade glioma is heterogeneous in nature based on pathological and genetic profiling. Various tumour suppressor gene alterations are considered as prognostic markers in high-grade glioma. Gene expression of CDKN2A (p16) is used in various cancers as a prognostic biomarker along with methylation and deletion status of this gene. Expression levels of p16 mRNA were not studied as a biomarker in gliomas before. In this study, we have performed mRNA quantification analysis on 48 high-grade glioma tissues and checked for a possible prognostic role. The decreased expression of p16 mRNA in majority of the tumour tissues (57.1 %) was observed when compared to control tissues (P = 0.02). mRNA expression level was correlated with clinical variables also. p16 deletion status and BMI1 mRNA expression were also considered for comparison. p16 mRNA was negatively correlated with the BMI1 mRNA (P = <0.0001) but not with p16 deletion. p16 mRNA expression, midline shift in MRI and tumour type were able to predict patient survival in overall survival (OS) and progression-free survival (PFS). p16 mRNA could independently predict prognosis of OS (P = 0.0146) and PFS (P = 0.0305) in multivariate analysis. We have shown that p16 mRNA expression can act as an independent prognostic biomarker in high-grade glioma.

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References

  1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114(2):97–109.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro-Oncology. 2013;15 suppl 2:ii1–56.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63(18):5821–8.

    CAS  PubMed  Google Scholar 

  4. Yuan X, Curtin J, Xiong Y, Liu G, Waschsmann-Hogiu S, Farkas DL, et al. Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene. 2004;23(58):9392–400.

    Article  CAS  PubMed  Google Scholar 

  5. Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, et al. A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci U S A. 2004;101(39):14228–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cruceru ML, Neagu M, Demoulin JB, Constantinescu SN. Therapy targets in glioblastoma and cancer stem cells: lessons from haematopoietic neoplasms. J Cell Mol Med. 2013;17(10):1218–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81(3):323–30.

    Article  CAS  PubMed  Google Scholar 

  8. Agarwal P, Kabir FML, DeInnocentes P, Bird RC. Tumor suppressor gene p16/INK4A/P16 and its role in cell cycle exit, differentiation, and determination of cell fate. Tumor suppressor genes. Rijeka, Croatia: InTech Open Access Pub, 1–34; 2012.

  9. Park IK, Morrison SJ, Clarke MF. BMI1, stem cells, and senescence regulation. J Clin Investig. 2004;113(2):175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jiang L, Song L, Wu J, Yang Y, Zhu X, Hu B, et al. Bmi-1 promotes glioma angiogenesis by activating NF-κB signaling. PLoS One. 2013;8(1), e55527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jiang L, Wu J, Yang Y, Liu L, Song L, Li J, et al. Bmi-1 promotes the aggressiveness of glioma via activating the NF-kappaB/MMP-9 signaling pathway. BMC Cancer. 2012;12(1):406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 1999;13(20):2678–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Arima Y, Hayashi N, Hayashi H, Sasaki M, Kai K, Sugihara E, et al. Loss of p16 expression is associated with the stem cell characteristics of surface markers and therapeutic resistance in estrogen receptor‐negative breast cancer. Int J Cancer. 2012;130(11):2568–79.

    Article  CAS  PubMed  Google Scholar 

  14. Sibin MK, Bhat DI, Lavanya C, Manoj MJ, Aakershita S, Chetan GK. P16 exon-wise deletion status and novel somatic mutations in Indian glioma patients. Tumor Biol. 2014;35(2):1467–72.

    Article  CAS  Google Scholar 

  15. Sibin MK, Bhat DI, Lavanya C, Arati S, Chetan GK. Over-expression and lack of copy number variation in BMI-1 gene in human glioma from Indian population. Oncology Letters. 2015;(In Press).

  16. Alves TR, Lima FRS, Kahn SA, Lobo D, Dubois LGF, Soletti R, et al. Glioblastoma cells: a heterogeneous and fatal tumor interacting with the parenchyma. Life Sci. 2011;89(15):532–9.

    Article  CAS  PubMed  Google Scholar 

  17. Juratli TA, Kirsch M, Geiger K, Klink B, Leipnitz E, Pinzer T, et al. The prognostic value of IDH mutations and MGMT promoter status in secondary high-grade gliomas. J Neuro-Oncol. 2012;110(3):325–33.

    Article  CAS  Google Scholar 

  18. McLendon R, Friedman A, Bigner D, Van Meir EG, Brat DJ, Mastrogianakis GM, et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8.

    Article  CAS  Google Scholar 

  19. Liu W, Lv G, Li Y, Wang B. Down regulation of P16 and suppression of cyclin D1 gene expressions in malignant gliomas. J Exp Clin Cancer Res. 2011;30(1):1–7.

    Article  Google Scholar 

  20. Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M, Malmer B, et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet. 2009;41(8):899–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Costello JF, Berger MS, Huang HS, Cavenee WK. Silencing of p16/CDKN2 expression in human gliomas by methylation and chromatin condensation. Cancer Res. 1996;56(10):2405–10.

    CAS  PubMed  Google Scholar 

  22. Fueyo J, Gomez-Manzano C, Bruner JM, Saito Y, Zhang B, Zhang W, et al. Hypermethylation of the CpG island of p16/CDKN2 correlates with gene inactivation in gliomas. Oncogene. 1996;13(8):1615–9.

    CAS  PubMed  Google Scholar 

  23. Hui R, Macmillan RD, Kenny FS, Musgrove EA, Blamey RW, Nicholson RI, et al. INK4a gene expression and methylation in primary breast cancer: overexpression of p16INK4a messenger RNA is a marker of poor prognosis. Clin Cancer Res. 2000;6(7):2777–87.

    CAS  PubMed  Google Scholar 

  24. Oshima M, Okano K, Muraki S, Haba R, Maeba T, Suzuki Y, et al. Immunohistochemically detected expression of 3 major genes (P16/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer. Ann Surg. 2013;258(2):336–46.

    Article  PubMed  Google Scholar 

  25. Mihic‐Probst D, Mnich CD, Oberholzer PA, Seifert B, Sasse B, Moch H, et al. p16 expression in primary malignant melanoma is associated with prognosis and lymph node status. Int J Cancer. 2006;118(9):2262–8.

    Article  PubMed  Google Scholar 

  26. Dalle JH, Fournier M, Nelken B, Mazingue F, Laı̈ JL, Bauters F, et al. p16INK4a immunocytochemical analysis is an independent prognostic factor in childhood acute lymphoblastic leukemia. Blood. 2002;99(7):2620–3.

    Article  CAS  PubMed  Google Scholar 

  27. Geisler SA, Olshan AF, Weissler MC, Cai J, Funkhouser WK, Smith J, et al. p16 and p53 protein expression as prognostic indicators of survival and disease recurrence from head and neck cancer. Clin Cancer Res. 2002;8(11):3445–53.

    CAS  PubMed  Google Scholar 

  28. González-Quevedo R, Iniesta P, Morán A, de Juan C, Sánchez-Pernaute A, Fernández C, et al. Cooperative role of telomerase activity and p16 expression in the prognosis of non-small-cell lung cancer. J Clin Oncol. 2002;20(1):254–62.

    PubMed  Google Scholar 

  29. Puduvalli VK, Kyritsis AP, Hess KR, Bondy ML, Fuller GN, Kouraklis GP, et al. Patterns of expression of Rb and p16 in astrocytic gliomas, and correlation with survival. Int J Oncol. 2000;17(5):963–72.

    CAS  PubMed  Google Scholar 

  30. Lee CT, Capodieci P, Osman I, Fazzari M, Ferrara J, Scher HI, et al. Overexpression of the cyclin-dependent kinase inhibitor p16 is associated with tumor recurrence in human prostate cancer. Clin Cancer Res. 1999;5(5):977–83.

    CAS  PubMed  Google Scholar 

  31. Dong Y, Walsh MD, McGuckin MA, Gabrielli BG, Cummings MC, Wright RG, et al. Increased expression of cyclin-dependent kinase inhibitor 2 (P16) gene product P16INK4A in ovarian cancer is associated with progression and unfavourable prognosis. Int J Cancer. 1997;74(1):57–63.

    Article  CAS  PubMed  Google Scholar 

  32. Dublin EA, Patel NK, Gillett CE, Smith P, Peters G, Barnes DM. Retinoblastoma and p16 proteins in mammary carcinoma: their relationship to cyclin D1 and histopathological parameters. Int J Cancer. 1998;79(1):71–5.

    Article  CAS  PubMed  Google Scholar 

  33. Simon M, Simon C, Köster G, Hans VH, Schramm J. Conditional expression of the tumor suppressor p16 in a heterotopic glioblastoma model results in loss of pRB expression. J Neuro-Oncol. 2002;60(1):1–12.

    Article  Google Scholar 

  34. Zolota V, Tsamandas AC, Aroukatos P, Panagiotopoulos V, Maraziotis T, Poulos C, et al. Expression of cell cycle inhibitors p21, p27, p14 and p16 in gliomas. Correlation with classic prognostic factors and patients’ outcome. Neuropathology. 2008;28(1):35–42.

    Article  PubMed  Google Scholar 

  35. Chakravarti A, Delaney MA, Noll E, Black PM, Loeffler JS, Muzikansky A, et al. Prognostic and pathologic significance of quantitative protein expression profiling in human gliomas. Clin Cancer Res. 2001;7(8):2387–95.

    CAS  PubMed  Google Scholar 

  36. Kamiryo T, Tada K, Shiraishi S, Shinojima N, Nakamura H, Kochi M, et al. Analysis of homozygous deletion of the p16 gene and correlation with survival in patients with glioblastoma multiforme. J Neurosurg. 2002;96(5):815–22.

    Article  CAS  PubMed  Google Scholar 

  37. Nakamura M, Konishi N, Hiasa Y, Tsunoda S, Fukushima Y, Tsuzuki T, et al. Immunohistochemical detection of CDKN2, retinoblastoma and p53 gene products in primary astrocytic tumors. Int J Oncol. 1996;8(5):889–93.

    CAS  PubMed  Google Scholar 

  38. Cenci T, Martini M, Montano N, D’Alessandris QG, Falchetti ML, Annibali D, et al. Prognostic relevance of c-Myc and BMI1 expression in patients with glioblastoma. Am J Clin Pathol. 2012;138(3):390–6.

    Article  CAS  PubMed  Google Scholar 

  39. Farivar S, Zati Keikha R, Shiari R, Jadali F. Expression of bmi-1 in pediatric brain tumors as a new independent prognostic marker of patient survival. BioMed Research International, 2013; 2013.

  40. Wu Z, Wang Q, Wang L, Li G, Liu H, Fan F, et al. Combined aberrant expression of BMI1 and EZH2 is predictive of poor prognosis in glioma patients. J Neurol Sci. 2013;335(1):191–6.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Mr. Sibin M K is a CSIR-Senior Research Fellow; thus, financial support provided by CSIR, New Delhi, is kindly acknowledged. This study was financially supported by DST-SERB, Government of India. Histopathological diagnosis was done by the neuropathology department, NIMHANS duly acknowledged.

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Authors and Affiliations

  1. Department of Human Genetics, National Institute of Mental Health and Neuro Sciences, Bangalore, India, 560029

    M. K. Sibin, Ch. Lavanya & G. K. Chetan

  2. Department of Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore, India, 560029

    Dhananjaya I. Bhat & K. V. L. Narasingarao

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  1. M. K. Sibin
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  2. Dhananjaya I. Bhat
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  3. K. V. L. Narasingarao
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Correspondence to G. K. Chetan.

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Sibin, M.K., Bhat, D.I., Narasingarao, K.V.L. et al. CDKN2A (p16) mRNA decreased expression is a marker of poor prognosis in malignant high-grade glioma. Tumor Biol. 36, 7607–7614 (2015). https://doi.org/10.1007/s13277-015-3480-5

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  • DOI: https://doi.org/10.1007/s13277-015-3480-5

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