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Predictive markers for MGMT promoter methylation in glioblastomas

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Abstract

The promoter methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene has been described as the most important predictor of chemotherapeutic response and patients’ survival in glioblastomas (GBs). Therefore, prediction of the MGMT promoter methylation status by imaging would help to preoperatively decide the overall treatment strategy as well as surgical strategy. This study aimed to detect imaging parameters to predict MGMT promoter methylation in GBs by using a commercially available software. We investigated three imaging features (ring enhancement, tumor location, and laterality) and apparent diffusion coefficient (ADC) parameters in 48 newly diagnosed GBs treated at Keio University Hospital in 2006 or later. For ADC, texture analyses were performed. Regions of interest (ROIs) were drawn manually with reference to contrast-enhanced areas, excluding necrotic and cystic regions. Mean ADC value and ADC histogram parameters, including kurtosis, skewness, and entropy, were compared with MGMT promoter methylation. Each parameter was evaluated to determine correlation with MGMT promoter methylation, and the parameters with significant associations with the methylation status were correlated with the MGMT-positive cell ratio determined by immunohistochemistry (IHC) analysis. The mean ADC value and ADC entropy were significantly associated with MGMT promoter methylation. The combination of mean ADC value and ADC entropy predicted MGMT promoter methylation, with a PPV of 81.2% and specificity of 88.9%. The mean ADC value and ADC entropy were negatively correlated with the MGMT-positive cell ratio in the IHC analysis. This study demonstrated that texture analyses of ADC histograms in GBs were predictive of MGMT promoter methylation.

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References

  1. Alvarez-Linera J (2008) 3T MRI: advances in brain imaging. Eur J Radiol 67:415–426. https://doi.org/10.1016/j.ejrad.2008.02.045

    Article  PubMed  Google Scholar 

  2. Ashby LS, Smith KA, Stea B (2016) Gliadel wafer implantation combined with standard radiotherapy and concurrent followed by adjuvant temozolomide for treatment of newly diagnosed high-grade glioma: a systematic literature review. World J Surg Oncol 14:225. https://doi.org/10.1186/s12957-016-0975-5

    Article  PubMed  PubMed Central  Google Scholar 

  3. Barajas RF Jr, Hodgson JG, Chang JS, Vandenberg SR, Yeh RF, Parsa AT, McDermott MW, Berger MS, Dillon WP, Cha S (2010) Glioblastoma multiforme regional genetic and cellular expression patterns: influence on anatomic and physiologic MR imaging. Radiology 254:564–576. https://doi.org/10.1148/radiol.09090663

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chang P, Grinband J et al (2018) Deep-learning convolutional neural networks accurately classify genetic mutations in gliomas. AJNR Am J Neuroradiol 39:1201–1207. https://doi.org/10.3174/ajnr.A5667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Choi YS, Ahn SS, Kim DW, Chang JH, Kang SG, Kim EH, Kim SH, Rim TH, Lee SK (2016) Incremental prognostic value of ADC histogram analysis over MGMT promoter methylation status in patients with glioblastoma. Radiology 281:175–184. https://doi.org/10.1148/radiol.2016151913

    Article  PubMed  Google Scholar 

  6. Coons SW, Johnson PC, Scheithauer BW, Yates AJ, Pearl DK (1997) Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas. Cancer 79:1381–1393

    Article  CAS  Google Scholar 

  7. 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 49:1398–1405. https://doi.org/10.1016/j.neuroimage.2009.09.049

    Article  CAS  PubMed  Google Scholar 

  8. Dunn J, Baborie A, Alam F, Joyce K, Moxham M, Sibson R, Crooks D, Husband D, Shenoy A, Brodbelt A, Wong H, Liloglou T, Haylock B, Walker C (2009) Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer 101:124–131. https://doi.org/10.1038/sj.bjc.6605127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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 59:908–916. https://doi.org/10.1016/j.neuroimage.2011.09.076

    Article  CAS  PubMed  Google Scholar 

  10. 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 13:2606–2613. https://doi.org/10.1158/1078-0432.CCR-06-2184

    Article  CAS  PubMed  Google Scholar 

  11. Firbank MJ, Coulthard A, Harrison RM, Williams ED (1999) Partial volume effects in MRI studies of multiple sclerosis. Magn Reson Imaging 17:593–601

    Article  CAS  Google Scholar 

  12. Fukushima T, Takeshima H, Kataoka H (2009) Anti-glioma therapy with temozolomide and status of the DNA-repair gene MGMT. Anticancer Res 29:4845–4854

    CAS  PubMed  Google Scholar 

  13. Glickman ME, Rao SR, Schultz MR (2014) False discovery rate control is a recommended alternative to Bonferroni-type adjustments in health studies. J Clin Epidemiol 67:850–857. https://doi.org/10.1016/j.jclinepi.2014.03.012

    Article  PubMed  Google Scholar 

  14. Guo AC, Cummings TJ, Dash RC, Provenzale JM (2002) Lymphomas and high-grade astrocytomas: comparison of water diffusibility and histologic characteristics. Radiology 224:177–183. https://doi.org/10.1148/radiol.2241010637

    Article  PubMed  Google Scholar 

  15. Gupta A, Omuro AM, Shah AD, Graber JJ, Shi W, Zhang Z, Young RJ (2012) Continuing the search for MR imaging biomarkers for MGMT promoter methylation status: conventional and perfusion MRI revisited. Neuroradiology 54:641–643. https://doi.org/10.1007/s00234-011-0970-z

    Article  PubMed  Google Scholar 

  16. Gupta A, Prager A, Young RJ, Shi W, Omuro AM, Graber JJ (2013) Diffusion-weighted MR imaging and MGMT methylation status in glioblastoma: a reappraisal of the role of preoperative quantitative ADC measurements. AJNR Am J Neuroradiol 34:E10–E11. https://doi.org/10.3174/ajnr.A3467

    Article  CAS  PubMed  Google Scholar 

  17. Han Y, Yan LF, Wang XB, Sun YZ, Zhang X, Liu ZC, Nan HY, Hu YC, Yang Y, Zhang J, Yu Y, Sun Q, Tian Q, Hu B, Xiao G, Wang W, Cui GB (2018) Structural and advanced imaging in predicting MGMT promoter methylation of primary glioblastoma: a region of interest based analysis. BMC Cancer 18:215. https://doi.org/10.1186/s12885-018-4114-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hegi ME, Diserens AC, Godard S, Dietrich PY, Regli L, Ostermann S, Otten P, Van Melle G, de Tribolet N, Stupp R (2004) Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 10:1871–1874

    Article  CAS  Google Scholar 

  19. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003. https://doi.org/10.1056/NEJMoa043331

    Article  CAS  PubMed  Google Scholar 

  20. Hsu CY, Lin SC, Ho HL, Chang-Chien YC, Hsu SP, Yen YS, Chen MH, Guo WY, Ho DM (2013) Exclusion of histiocytes/endothelial cells and using endothelial cells as internal reference are crucial for interpretation of MGMT immunohistochemistry in glioblastoma. Am J Surg Pathol 37:264–271. https://doi.org/10.1097/PAS.0b013e318267b061

    Article  PubMed  Google Scholar 

  21. Kanas VG, Zacharaki EI, Thomas GA, Zinn PO, Megalooikonomou V, Colen RR (2017) Learning MRI-based classification models for MGMT methylation status prediction in glioblastoma. Comput Methods Prog Biomed 140:249–257. https://doi.org/10.1016/j.cmpb.2016.12.018

    Article  Google Scholar 

  22. Kanazawa T, Fujiwara H, Takahashi H, Nishiyama Y, Hirose Y, Tanaka S, Yoshida K, Sasaki H (2018) Imaging scoring systems for preoperative molecular diagnoses of lower-grade gliomas. Neurosurg Rev. https://doi.org/10.1007/s10143-018-0981-x

  23. Kickingereder P, Bonekamp D, Nowosielski M, Kratz A, Sill M, Burth S, Wick A, Eidel O, Schlemmer HP, Radbruch A, Debus J, Herold-Mende C, Unterberg A, Jones D, Pfister S, Wick W, von Deimling A, Bendszus M, Capper D (2016) Radiogenomics of glioblastoma: machine learning-based classification of molecular characteristics by using multiparametric and multiregional MR imaging features. Radiology 281:907–918. https://doi.org/10.1148/radiol.2016161382

    Article  PubMed  Google Scholar 

  24. Kleihues P, Burger PC, Scheithauer BW (1993) Histological typing of tumors of the central nervous system, 2nd edn. Springer, Berlin

    Book  Google Scholar 

  25. Kleihues P, Cavanee W (2000) Pathology and genetics of tumors of the nervous system. International Agency for Research on Cancer Press, Lyon

    Google Scholar 

  26. Korfiatis P, Kline TL, Coufalova L, Lachance DH, Parney IF, Carter RE, Buckner JC, Erickson BJ (2016) MRI texture features as biomarkers to predict MGMT methylation status in glioblastomas. Med Phys 43:2835–2844. https://doi.org/10.1118/1.4948668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lechapt-Zalcman E, Levallet G, Dugue AE, Vital A, Diebold MD, Menei P, Colin P, Peruzzy P, Emery E, Bernaudin M, Chapon F, Guillamo JS (2012) O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation and low MGMT-encoded protein expression as prognostic markers in glioblastoma patients treated with biodegradable carmustine wafer implants after initial surgery followed by radiotherapy with concomitant and adjuvant temozolomide. Cancer 118:4545–4554. https://doi.org/10.1002/cncr.27441

    Article  CAS  PubMed  Google Scholar 

  28. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2007) WHO classification of tumours of the central nervous system, 4th edn. International Agency for Research on Cancer, Lyon

    Google Scholar 

  29. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Ellison DW, Figarella-Branger D, Perry A, Reifenberger G, von Deimling A (2016) WHO classification of tumours of the central nervous system. In: Revised 4th edn. International Agency for Research on Cancer, Lyon

    Google Scholar 

  30. Miwa T, Hirose Y, Sasaki H, Ikeda E, Yoshida K, Kawase T (2009) Genetic characterization of adult infratentorial gliomas. J Neuro-Oncol 91:251–255. https://doi.org/10.1007/s11060-008-9714-2

    Article  Google Scholar 

  31. Moon WJ, Choi JW, Roh HG, Lim SD, Koh YC (2012) Imaging parameters of high grade gliomas in relation to the MGMT promoter methylation status: the CT, diffusion tensor imaging, and perfusion MR imaging. Neuroradiology 54:555–563. https://doi.org/10.1007/s00234-011-0947-y

    Article  PubMed  Google Scholar 

  32. Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. Jama 310:1842–1850. https://doi.org/10.1001/jama.2013.280319

    Article  CAS  PubMed  Google Scholar 

  33. Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS (2015) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro-Oncology 17(Suppl 4):iv1–iv62. https://doi.org/10.1093/neuonc/nov189

    Article  PubMed  PubMed Central  Google Scholar 

  34. Pope WB, Lai A, Mehta R, Kim HJ, Qiao J, Young JR, Xue X, Goldin J, Brown MS, Nghiemphu PL, Tran A, Cloughesy TF (2011) Apparent diffusion coefficient histogram analysis stratifies progression-free survival in newly diagnosed bevacizumab-treated glioblastoma. AJNR Am J Neuroradiol 32:882–889. https://doi.org/10.3174/ajnr.A2385

    Article  CAS  PubMed  Google Scholar 

  35. Prayson RA, Agamanolis DP, Cohen ML, Estes ML, Kleinschmidt-DeMasters BK, Abdul-Karim F, McClure SP, Sebek BA, Vinay R (2000) Interobserver reproducibility among neuropathologists and surgical pathologists in fibrillary astrocytoma grading. J Neurol Sci 175:33–39

    Article  CAS  Google Scholar 

  36. Riemenschneider MJ, Hegi ME, Reifenberger G (2010) MGMT promoter methylation in malignant gliomas. Target Oncol 5:161–165. https://doi.org/10.1007/s11523-010-0153-6

    Article  PubMed  Google Scholar 

  37. Romano A, Calabria LF, Tavanti F, Minniti G, Rossi-Espagnet MC, Coppola V, Pugliese S, Guida D, Francione G, Colonnese C, Fantozzi LM, Bozzao A (2013) Apparent diffusion coefficient obtained by magnetic resonance imaging as a prognostic marker in glioblastomas: correlation with MGMT promoter methylation status. Eur Radiol 23:513–520. https://doi.org/10.1007/s00330-012-2601-4

    Article  PubMed  Google Scholar 

  38. Ronning PA, Helseth E, Meling TR, Johannesen TB (2012) A population-based study on the effect of temozolomide in the treatment of glioblastoma multiforme. Neuro-Oncology 14:1178–1184. https://doi.org/10.1093/neuonc/nos153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sasaki H, Hirose Y, Yazaki T, Kitamura Y, Katayama M, Kimura T, Fujiwara H, Toda M, Ohira T, Yoshida K (2015) Upfront chemotherapy and subsequent resection for molecularly defined gliomas. J Neuro-Oncol 124:127–135. https://doi.org/10.1007/s11060-015-1817-y

    Article  CAS  Google Scholar 

  40. Sasaki H, Zlatescu MC, Betensky RA, Ino Y, Cairncross JG, Louis DN (2001) PTEN is a target of chromosome 10q loss in anaplastic oligodendrogliomas and PTEN alterations are associated with poor prognosis. Am J Pathol 159:359–367. https://doi.org/10.1016/s0002-9440(10)61702-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Squillaci E, Manenti G, Cova M, Di Roma M, Miano R, Palmieri G, Simonetti G (2004) Correlation of diffusion-weighted MR imaging with cellularity of renal tumours. Anticancer Res 24:4175–4179

    PubMed  Google Scholar 

  42. 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 (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. https://doi.org/10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  43. Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z (2015) Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. Jama 314:2535–2543. https://doi.org/10.1001/jama.2015.16669

    Article  CAS  PubMed  Google Scholar 

  44. Sunwoo L, Choi SH, Park CK, Kim JW, Yi KS, Lee WJ, Yoon TJ, Song SW, Kim JE, Kim JY, Kim TM, Lee SH, Kim JH, Sohn CH, Park SH, Kim IH, Chang KH (2013) Correlation of apparent diffusion coefficient values measured by diffusion MRI and MGMT promoter methylation semiquantitatively analyzed with MS-MLPA in patients with glioblastoma multiforme. J Magn Reson Imaging 37:351–358. https://doi.org/10.1002/jmri.23838

    Article  PubMed  Google Scholar 

  45. Urbschat S, Sippl C, Engelhardt J, Kammers K, Oertel J, Ketter R (2017) Importance of biomarkers in glioblastomas patients receiving local BCNU wafer chemotherapy. Mol Cytogenet 10:16. https://doi.org/10.1186/s13039-017-0317-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Clement PM, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S, Griffin M, Brachman DG, Taal W, Ruda R, Weller M, McBain C, Reijneveld J, Enting RH, Weber DC, Lesimple T, Clenton S, Gijtenbeek A, Pascoe S, Herrlinger U, Hau P, Dhermain F, van Heuvel I, Stupp R, Aldape K, Jenkins RB, Dubbink HJ, Dinjens WNM, Wesseling P, Nuyens S, Golfinopoulos V, Gorlia T, Wick W, Kros JM (2017) Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 390:1645–1653. https://doi.org/10.1016/s0140-6736(17)31442-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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 6:39–51. https://doi.org/10.1038/nrneurol.2009.197

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We greatly thank Ms. Naoko Tsuzaki at the Department of Neurosurgery, Keio University School of Medicine for technical assistance of laboratory works. The authors also greatly thank Dr. Takayuki Abe at the Center for Clinical Research, Department of Preventive Medicine and Public Health, Keio University School of Medicine for statistical advice.

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  1. Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Tokunori Kanazawa, Masahiro Toda, Kazunari Yoshida & Hikaru Sasaki

  2. Department of Diagnostic Radiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Yasuhiro Minami & Masahiro Jinzaki

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  1. Tokunori Kanazawa
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Correspondence to Tokunori Kanazawa.

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This study was approved by the Institutional Review Board of Keio University. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Fig. S2

ROC curve for MGMT promoter methylation status correlated with the mean ADC value (PNG 84 kb)

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Fig. S3

ROC curve for MGMT promoter methylation status correlated with ADC entropy (PNG 105 kb)

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Kanazawa, T., Minami, Y., Jinzaki, M. et al. Predictive markers for MGMT promoter methylation in glioblastomas. Neurosurg Rev 42, 867–876 (2019). https://doi.org/10.1007/s10143-018-01061-5

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