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HIN-1: a New Epigenetic Biomarker Crucial for Therapy Selection in Glioblastoma Multiforme

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Abstract

Glioblastoma multiforme (GBM) is the most common brain tumor in adults. The role of high in normal-1 (HIN-1) as a potential biomarker in combating this disease is being described for the first time in this study. A combination of O6-methylguanine DNA methyltransferase (MGMT) and HIN-1 methylation could be a possible biomarker in therapy choice. Interestingly, survival data shows a similar trend for the methylation of MGMT and for unmethylation of HIN-1 and vice versa. Eighty-eight paraffin-embedded brain tumors were analyzed to screen methylation rates of different genes and evaluate the association between genes methylation and clinicopathologic variables. Our study is the first of its kind to indicate that MGMT and HIN-1 methylation status are inverted (97.7 % of methylated ones) and could be new markers in the study of GBM prognosis, especially in the therapy selection.

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References

  1. Herman JG et al (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054

    Article  CAS  PubMed  Google Scholar 

  2. Das PM, Singal R (2004) DNA methylation and cancer. J Clin Oncol 22:4632–4642

    Article  CAS  PubMed  Google Scholar 

  3. Jirtle RL et al (1999) Genomic imprinting and cancer. Exp Cell Res 248:18–24

    Article  CAS  PubMed  Google Scholar 

  4. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003. doi:10.1056/NEJMoa043331

    Article  CAS  PubMed  Google Scholar 

  5. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J et al (2009) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27:5874–5880. doi:10.1200/JCO.2009.23.6497

    Article  CAS  PubMed  Google Scholar 

  6. Hegi ME et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  Google Scholar 

  7. Krop IE, Sgroi D, Porter DA, Lunetta KL, LeVangie R, Seth P, Kaelin CM, Rhei E et al (2001) HIN-1, a putative cytokine highly expressed in normal but not cancerous mammary epithelial cells. Proc Natl Acad Sci USA 98:9796–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Krop I, Parker MT, Bloushtain-Qimron N, Porter D, Gelman R, Sasaki H, Maurer M, Terry MB et al (2005) HIN-1, an inhibitor of cell growth, invasion, and AKT activation. Cancer Res 65(21):9659–9669

    Article  CAS  PubMed  Google Scholar 

  9. Krop I, Player A, Tablante A, Taylor-Parker M, Lahti-Domenici J, Fukuoka J, Batra SK, Papadopoulos N et al (2004) Frequent HIN-1 promoter methylation and lack of expression in multiple human tumor types. Mol Cancer Res 2:489–494

    CAS  PubMed  Google Scholar 

  10. Wong TS, Kwong DL, Sham JS, Tsao SW, Wei WI, Kwong YL, Yuen AP (2003) Promoter hypermethylation of high-in-normal 1 gene in primary nasopharyngeal carcinoma. Clin Cancer Res 9:3042–3046

    CAS  PubMed  Google Scholar 

  11. Lehmann U, Berg-Ribbe I, Wingen LU, Brakensiek K, Becker T, Klempnauer J, Schlegelberger B, Kreipe H et al (2005) Distinct methylation patterns of benign and malignant liver tumors revealed by quantitative methylation profiling. Clin Cancer Res 11:3654–3660

    Article  CAS  PubMed  Google Scholar 

  12. Guo M, Ren J, Brock MV, Herman JG, Carraway HE (2008) Promoter methylation of HIN-1 in the progression to esophageal squamous cancer. Epigenetics 3:336–341, 13

    Article  PubMed  Google Scholar 

  13. Yutaka K, LanLan S, Jean-Pierre J (2003) Issa Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol Cell Biol 23(1):206–215

    Article  Google Scholar 

  14. Esteller M et al (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59:793–797

    CAS  PubMed  Google Scholar 

  15. Herman JG et al (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 96:9821–9826

    Article  Google Scholar 

  16. Ho CM et al (2012) Promoter Methylation status of HIN-1 associated with outcomes of ovarian clear cell adenocarcinoma. Mol Cancer 11:53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shigematsu H, Suzuki M, Takahashi T, Shivapurkar N, Echebiri C, Nomura M, Stastny V, Augustus M et al (2005) Aberrant methylation of HIN-1 (high in normal-1) is a frequent event in many human malignancies. Int J Cancer 113:600–604

    Article  CAS  PubMed  Google Scholar 

  18. Marchetti A, Barassi F, Martella C, Chella A, Salvatore S, Castrataro A, Mucilli F, Sacco R et al (2004) Down regulation of high in normal-1 (HIN-1) is a frequent event in stage I non-small cell lung cancer and correlates with poor clinical outcome. Clin Cancer Res 10:1338–1343

    Article  CAS  PubMed  Google Scholar 

  19. Qiwei Y, Kiernan CM, Yufeng T, Salwen HR, Chlenski A, Brumback BA, London WB, Cohn SL (2007) Methylation of CASP8, DCR2, and HIN-1 in neuroblastoma is associated with poor outcome. Clin Cancer Res 13:3191

    Article  Google Scholar 

  20. Harada K, Toyooka S, Shivapurkar N, Maitra A, Reddy JL, Matta H, Miyajima K, Timmons CF et al (2002) Deregulation of caspase 8 and 10 expression in pediatric tumors and cell lines. Cancer Res 62:5897–5901

    CAS  PubMed  Google Scholar 

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Acknowledgments

Pathology Department, especially Molecular BiologyArea: Elena Couso, T. Yolanda Rico and Raquel Perez-Becerra; Biobank of the Complejo Hospitalario Universitario de Santiago de Compostela, and Paula Vieiro Balo.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author Contributions

H.M. and PI.M. designed and performed the experiments and analyzed the data. ML.N. performed the clinical follow-up. AL.S., RD.P., and BV.E performed the clinical oncology analysis. C.JJ. and A.JR. performed the pathological studies, and R.A. and LL.R. wrote the paper and supervised the project.

Ethical Statement

The study complied with the Declaration of Helsinki Principles and was approved by Clinical Research Ethics Committee of Galicia (Spanish region where the study was done and name of the hospital is attached, code 2011/153). Written informed consent was obtained from all subjects.

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    Authors and Affiliations

    1. Nuclear Medicine Department, Molecular Imaging Program, IDIS, USC, Hospital Clínico Universitario. Fundación Tejerina, Santiago de Compostela, Spain

      M. Herranz & A. Ruibal

    2. Department of Functional Biology and Health Sciences, Human Anatomy and Embryology Section, University of Vigo, Vigo, Pontevedra, Spain

      M. E. Padín-Iruegas

    3. Medical Oncology Department, Hospital Clínico Universitario, Santiago de Compostela, Spain

      Nieves Martínez-Lago, S. Aguín Losada, P. Raña-Díez, E. Brozos Vázquez & R. López-López

    4. Pathology Department, Hospital Clínico Universitario, Santiago de Compostela, Spain

      J. J. Carrera & J. R. Antúnez

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    1. M. Herranz
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    3. Nieves Martínez-Lago
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    Correspondence to M. Herranz.

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    M. Herranz and M. E. Padín-Iruegas contributed equally to this work.

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    Herranz, M., Padín-Iruegas, M.E., Martínez-Lago, N. et al. HIN-1: a New Epigenetic Biomarker Crucial for Therapy Selection in Glioblastoma Multiforme. Mol Neurobiol 53, 1802–1807 (2016). https://doi.org/10.1007/s12035-015-9127-0

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    • DOI: https://doi.org/10.1007/s12035-015-9127-0

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