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Anatomical specificity of O6-methylguanine DNA methyltransferase protein expression in glioblastomas

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Abstract

O6-methylguanine DNA methyltransferase (MGMT) is one of the important tumor-related biomarkers and is considered to be a prognostic factor for glioblastoma. This study aimed to investigate the anatomical location of tumor-related MGMT protein expression in histologically confirmed de novo glioblastoma multiforme (GBM). Preoperative magnetic resonance images were retrospectively examined from GBM patients. Tumor tissues were manually segmented based on the structural image of each patient and subsequently registered to a standard brain atlas. Superimposition of the tumor tissues was carried out in patients with and without epigenetic changes. We used voxel-based lesion symptom mapping (VLSM) to identify the specific brain regions that were associated with level of MGMT protein expression. The tumors with low expression of MGMT protein and those with high expression of MGMT protein showed not significant differences in tumor size on T2 imaging. The VLSM analysis demonstrated that tumors with low expression of MGMT protein were more likely to occur in the right temporal-parietal lobe, while tumors with high expression of MGMT protein occurred more often in the left frontal lobe. Based upon VLSM data, our results suggest that the epigenetic changes, which occur during tumorigenesis, may have anatomical specificity. The identified correlation between molecular biomarkers and anatomical distribution underscores the current understanding of the biological characteristics of glioblastoma.

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References

  1. DeAngelis LM (2001) Brain tumors. N Engl J Med 344(2):114–123

    Article  PubMed  CAS  Google Scholar 

  2. Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. JAMA 310(17):1842–1850

    Article  PubMed  CAS  Google Scholar 

  3. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507

    Article  PubMed  CAS  Google Scholar 

  4. Ohgaki H (2009) Epidemiology of brain tumors. Methods Mol Biol 472:323–342

    Article  PubMed  CAS  Google Scholar 

  5. Ohgaki H, Kleihues P (2005) Epidemiology and etiology of gliomas. Acta Neuropathol 109(1):93–108

    Article  PubMed  Google Scholar 

  6. Labussiere M, Wang XW, Idbaih A, Ducray F, Sanson M (2010) Prognostic markers in gliomas. Future Oncol 6(5):733–739

    Article  PubMed  CAS  Google Scholar 

  7. Felsberg J, Rapp M, Loeser S, Fimmers R, Stummer W, Goeppert M, Steiger HJ, Friedensdorf B, Reifenberger G, Sabel MC (2009) Prognostic significance of molecular markers and extent of resection in primary glioblastoma patients. Clin Cancer Res 15(21):6683–6693

    Article  PubMed  CAS  Google Scholar 

  8. Polivka J Jr, Polivka J, Rohan V, Topolcan O, Ferda J (2012) New molecularly targeted therapies for glioblastoma multiforme. Anticancer Res 32(7):2935–2946

    PubMed  CAS  Google Scholar 

  9. McNamara MG, Sahebjam S, Mason WP (2013) Emerging biomarkers in glioblastoma. Cancers (Basel) 5(3):1103–1119

    Article  CAS  Google Scholar 

  10. Kaina B (2003) DNA damage-triggered apoptosis: critical role of DNA repair, double-strand breaks, cell proliferation and signaling. Biochem Pharmacol 66(8):1547–1554

    Article  PubMed  CAS  Google Scholar 

  11. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for R, Treatment of Cancer Brain T, Radiotherapy G, National Cancer Institute of Canada Clinical Trials G (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996

    Article  PubMed  CAS  Google Scholar 

  12. Brandes AA, Franceschi E, Tosoni A, Benevento F, Scopece L, Mazzocchi V, Bacci A, Agati R, Calbucci F, Ermani M (2009) Temozolomide concomitant and adjuvant to radiotherapy in elderly patients with glioblastoma: correlation with MGMT promoter methylation status. Cancer 115(15):3512–3518

    Article  PubMed  CAS  Google Scholar 

  13. Thon N, Kreth S, Kreth FW (2013) Personalized treatment strategies in glioblastoma: promoter methylation status. Onco Targets Ther 6:1363–1372

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Fouse SD, Nakamura JL, James CD, Chang S, Costello JF (2014) Response of primary glioblastoma cells to therapy is patient specific and independent of cancer stem cell phenotype. Neuro Oncol 16(3):361–371

    Article  PubMed  CAS  Google Scholar 

  15. Ellingson BM, Cloughesy TF, Pope WB, Zaw TM, Phillips H, Lalezari S, Nghiemphu PL, Ibrahim H, Naeini KM, Harris RJ, Lai A (2012) Anatomic localization of O6-methylguanine DNA methyltransferase (MGMT) promoter methylated and unmethylated tumors: a radiographic study in 358 de novo human glioblastomas. Neuroimage 59(2):908–916

    Article  PubMed  CAS  Google Scholar 

  16. Eoli M, Menghi F, Bruzzone MG, De Simone T, Valletta L, Pollo B, Bissola L, Silvani A, Bianchessi D, D’Incerti L, Filippini G, Broggi G, Boiardi A, Finocchiaro G (2007) Methylation of O6-methylguanine DNA methyltransferase and loss of heterozygosity on 19q and/or 17p are overlapping features of secondary glioblastomas with prolonged survival. Clin Cancer Res 13(9):2606–2613

    Article  PubMed  CAS  Google Scholar 

  17. Drabycz S, Roldan G, de Robles P, Adler D, McIntyre JB, Magliocco AM, Cairncross JG, Mitchell JR (2010) An analysis of image texture, tumor location, and MGMT promoter methylation in glioblastoma using magnetic resonance imaging. Neuroimage 49(2):1398–1405

    Article  PubMed  CAS  Google Scholar 

  18. Lalezari S, Chou AP, Tran A, Solis OE, Khanlou N, Chen W, Li S, Carrillo JA, Chowdhury R, Selfridge J, Sanchez DE, Wilson RW, Zurayk M, Lalezari J, Lou JJ, Ormiston L, Ancheta K, Hanna R, Miller P, Piccioni D, Ellingson BM, Buchanan C, Mischel PS, Nghiemphu PL, Green R, Wang HJ, Pope WB, Liau LM, Elashoff RM, Cloughesy TF, Yong WH, Lai A (2013) Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome. Neuro Oncol 15(3):370–381

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Bates E, Wilson SM, Saygin AP, Dick F, Sereno MI, Knight RT, Dronkers NF (2003) Voxel-based lesion-symptom mapping. Nat Neurosci 6(5):448–450

    PubMed  CAS  Google Scholar 

  20. Glascher J, Adolphs R, Damasio H, Bechara A, Rudrauf D, Calamia M, Paul LK, Tranel D (2012) Lesion mapping of cognitive control and value-based decision making in the prefrontal cortex. Proc Natl Acad Sci USA 109(36):14681–14686

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Rousseaux M, Honore J, Vuilleumier P, Saj A (2013) Neuroanatomy of space, body, and posture perception in patients with right hemisphere stroke. Neurology 81(15):1291–1297

    Article  PubMed  Google Scholar 

  22. Verdon V, Schwartz S, Lovblad KO, Hauert CA, Vuilleumier P (2010) Neuroanatomy of hemispatial neglect and its functional components: a study using voxel-based lesion-symptom mapping. Brain 133(Pt 3):880–894

    Article  PubMed  Google Scholar 

  23. Zhang W, Qiu XG, Chen BS, Li SW, Cui Y, Ren H, Jiang T (2009) Antiangiogenic therapy with bevacizumab in recurrent malignant gliomas: analysis of the response and core pathway aberrations. Chin Med J (Engl) 122(11):1250–1254

    CAS  Google Scholar 

  24. Kimberg DY, Coslett HB, Schwartz MF (2007) Power in voxel-based lesion-symptom mapping. J Cogn Neurosci 19(7):1067–1080

    Article  PubMed  Google Scholar 

  25. Medina J, Kimberg DY, Chatterjee A, Coslett HB (2010) Inappropriate usage of the Brunner-Munzel test in recent voxel-based lesion-symptom mapping studies. Neuropsychologia 48(1):341–343

    Article  PubMed  PubMed Central  Google Scholar 

  26. Bleeker FE, Molenaar RJ, Leenstra S (2012) Recent advances in the molecular understanding of glioblastoma. J Neurooncol 108(1):11–27

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Weller M, Stupp R, Reifenberger G, Brandes AA, van den Bent MJ, Wick W, Hegi ME (2010) MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 6(1):39–51

    Article  PubMed  CAS  Google Scholar 

  28. Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La Cruz C, Sulman EP, Bekele BN, Aldape KD (2010) MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol 12(2):116–121

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Carlson MR, Pope WB, Horvath S, Braunstein JG, Nghiemphu P, Tso CL, Mellinghoff I, Lai A, Liau LM, Mischel PS, Dong J, Nelson SF, Cloughesy TF (2007) Relationship between survival and edema in malignant gliomas: role of vascular endothelial growth factor and neuronal pentraxin 2. Clin Cancer Res 13(9):2592–2598

    Article  PubMed  CAS  Google Scholar 

  30. Lim DA, Cha S, Mayo MC, Chen MH, Keles E, VandenBerg S, Berger MS (2007) Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro Oncol 9(4):424–429

    Article  PubMed  PubMed Central  Google Scholar 

  31. Pope WB, Chen JH, Dong J, Carlson MR, Perlina A, Cloughesy TF, Liau LM, Mischel PS, Nghiemphu P, Lai A, Nelson SF (2008) Relationship between gene expression and enhancement in glioblastoma multiforme: exploratory DNA microarray analysis. Radiology 249(1):268–277

    Article  PubMed  PubMed Central  Google Scholar 

  32. Carrillo JA, Lai A, Nghiemphu PL, Kim HJ, Phillips HS, Kharbanda S, Moftakhar P, Lalaezari S, Yong W, Ellingson BM, Cloughesy TF, Pope WB (2012) Relationship between tumor enhancement, edema, IDH1 mutational status, MGMT promoter methylation, and survival in glioblastoma. Am J Neuroradiol 33(7):1349–1355

    Article  PubMed  CAS  Google Scholar 

  33. Kumar N, Kumar P, Angurana SL, Khosla D, Mukherjee KK, Aggarwal R, Kumar R, Bera A, Sharma SC (2013) Evaluation of outcome and prognostic factors in patients of glioblastoma multiforme: a single institution experience. J Neurosci Rural Pract 4(Suppl 1):S46–S55

    Article  PubMed  PubMed Central  Google Scholar 

  34. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN, Cancer Genome Atlas Research N (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Sun T, Patoine C, Abu-Khalil A, Visvader J, Sum E, Cherry TJ, Orkin SH, Geschwind DH, Walsh CA (2005) Early asymmetry of gene transcription in embryonic human left and right cerebral cortex. Science 308(5729):1794–1798

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Sun T, Walsh CA (2006) Molecular approaches to brain asymmetry and handedness. Nat Rev Neurosci 7(8):655–662

    Article  PubMed  CAS  Google Scholar 

  37. Zlatescu MC, TehraniYazdi A, Sasaki H, Megyesi JF, Betensky RA, Louis DN, Cairncross JG (2001) Tumor location and growth pattern correlate with genetic signature in oligodendroglial neoplasms. Cancer Res 61(18):6713–6715

    PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Yuling Yang for tissue sample collection and clinical data retrieval. This work was supported by funding from the National 973 Program (No. 2011CB707804) and the National High Technology Research and Development Program (No. 2012AA02A508).

Conflict of interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Authors and Affiliations

  1. Beijing Neurosurgical Institute, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing, 100050, People’s Republic of China

    Yinyan Wang & Tao Jiang

  2. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing, 100050, People’s Republic of China

    Yinyan Wang, Xing Fan, Chuanbao Zhang, Tan Zhang, Lei Wang & Tao Jiang

  3. Department of Epidemiology and Biostatistics, School of Public Health and Family Medicine, Capital Medical University, Beijing, 100069, People’s Republic of China

    Xiaoxia Peng

  4. Department of Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China

    Shaowu Li & Jun Ma

  5. Beijing Institute for Brain Disorders Brain Tumor Center, Beijing, 100069, People’s Republic of China

    Tao Jiang

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  1. Yinyan Wang
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Correspondence to Tao Jiang.

Additional information

Yinyan Wang and Xing Fan contributed equally to this study.

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Wang, Y., Fan, X., Zhang, C. et al. Anatomical specificity of O6-methylguanine DNA methyltransferase protein expression in glioblastomas. J Neurooncol 120, 331–337 (2014). https://doi.org/10.1007/s11060-014-1555-6

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  • DOI: https://doi.org/10.1007/s11060-014-1555-6

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