Skip to main content
Log in

A Comparison of Three Different Deep Learning-Based Models to Predict the MGMT Promoter Methylation Status in Glioblastoma Using Brain MRI

  • Published:
Journal of Digital Imaging Aims and scope Submit manuscript

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. The standard treatment for GBM consists of surgical resection followed by concurrent chemoradiotherapy and adjuvant temozolomide. O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status is an important prognostic biomarker that predicts the response to temozolomide and guides treatment decisions. At present, the only reliable way to determine MGMT promoter methylation status is through the analysis of tumor tissues. Considering the complications of the tissue-based methods, an imaging-based approach is preferred. This study aimed to compare three different deep learning-based approaches for predicting MGMT promoter methylation status. We obtained 576 T2WI with their corresponding tumor masks, and MGMT promoter methylation status from, The Brain Tumor Segmentation (BraTS) 2021 datasets. We developed three different models: voxel-wise, slice-wise, and whole-brain. For voxel-wise classification, methylated and unmethylated MGMT tumor masks were made into 1 and 2 with 0 background, respectively. We converted each T2WI into 32 × 32 × 32 patches. We trained a 3D-Vnet model for tumor segmentation. After inference, we constructed the whole brain volume based on the patch’s coordinates. The final prediction of MGMT methylation status was made by majority voting between the predicted voxel values of the biggest connected component. For slice-wise classification, we trained an object detection model for tumor detection and MGMT methylation status prediction, then for final prediction, we used majority voting. For the whole-brain approach, we trained a 3D Densenet121 for prediction. Whole-brain, slice-wise, and voxel-wise, accuracy was 65.42% (SD 3.97%), 61.37% (SD 1.48%), and 56.84% (SD 4.38%), respectively.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Code Availability

A link to the code will be shared after peer review.

Data Availability

The raw data required to reproduce the above findings are available to download from http://braintumorsegmentation.org/.

Abbreviations

BraTS:

Brain Tumor Segmentation

CCR:

Concurrent chemoradiation therapy

TMZ:

Temozolomide

GBM:

Glioblastoma

MGMT:

O-6-methylguanine-DNA methyltransferase

AUCROC:

Area under the receiver operating characteristic curve

TCIA:

The Cancer Imaging Archive

TCGA:

The Cancer Genome Atlas

References

  1. Tamimi AF, Juweid M. Epidemiology and outcome of glioblastoma. In: De Vleeschouwer S, editor. Glioblastoma. Brisbane (AU): Codon Publications; 2017.

  2. Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015. Neuro Oncol. 2018;20: iv1–iv86.

  3. Egaña L, Auzmendi-Iriarte J, Andermatten J, Villanua J, Ruiz I, Elua-Pinin A, et al. Methylation of MGMT promoter does not predict response to temozolomide in patients with glioblastoma in Donostia Hospital. Sci Rep. 2020;10: 18445.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Tesileanu CMS, Dirven L, Wijnenga MMJ, Koekkoek JAF, Vincent AJPE, Dubbink HJ, et al. Survival of diffuse astrocytic glioma, IDH1/2 wildtype, with molecular features of glioblastoma, WHO grade IV: a confirmation of the cIMPACT-NOW criteria. Neuro Oncol. 2020;22: 515–523.

    Article  CAS  PubMed  Google Scholar 

  5. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJB, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10: 459–466.

    Article  CAS  PubMed  Google Scholar 

  6. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352: 987–996.

    Article  CAS  PubMed  Google Scholar 

  7. Hombach-Klonisch S, Mehrpour M, Shojaei S, Harlos C, Pitz M, Hamai A, et al. Glioblastoma and chemoresistance to alkylating agents: involvement of apoptosis, autophagy, and unfolded protein response. Pharmacol Ther. 2018;184: 13–41.

    Article  CAS  PubMed  Google Scholar 

  8. Vlachostergios PJ, Hatzidaki E, Befani CD, Liakos P, Papandreou CN. Bortezomib overcomes MGMT-related resistance of glioblastoma cell lines to temozolomide in a schedule-dependent manner. Invest New Drugs. 2013;31: 1169–1181.

    Article  CAS  PubMed  Google Scholar 

  9. Hegi ME, Diserens A-C, Gorlia T, Hamou M-F, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352: 997–1003.

    Article  CAS  PubMed  Google Scholar 

  10. Tierling S, Jürgens-Wemheuer WM, Leismann A, Becker-Kettern J, Scherer M, Wrede A, et al. Bisulfite profiling of the MGMT promoter and comparison with routine testing in glioblastoma diagnostics. Clin Epigenetics. 2022;14: 26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brigliadori G, Goffredo G, Bartolini D, Tosatto L, Gurrieri L, Mercatali L, et al. Influence of intratumor heterogeneity on the predictivity of MGMT gene promoter methylation status in glioblastoma. Front Oncol. 2020;10: 533000.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hamilton MG, Roldán G, Magliocco A, McIntyre JB, Parney I, Easaw JC. Determination of the methylation status of MGMT in different regions within glioblastoma multiforme. J Neurooncol. 2011;102: 255–260.

    Article  CAS  PubMed  Google Scholar 

  13. Grasbon-Frodl EM, Kreth FW, Ruiter M, Schnell O, Bise K, Felsberg J, et al. Intratumoral homogeneity of MGMT promoter hypermethylation as demonstrated in serial stereotactic specimens from anaplastic astrocytomas and glioblastomas. Int J Cancer. 2007;121: 2458–2464.

    Article  CAS  PubMed  Google Scholar 

  14. Singh G, Manjila S, Sakla N, True A, Wardeh AH, Beig N, et al. Radiomics and radiogenomics in gliomas: a contemporary update. Br J Cancer. 2021; 1–17.

  15. Kickingereder P, Bonekamp D, Nowosielski M, Kratz A, Sill M, Burth S, et al. Radiogenomics of glioblastoma: machine learning-based classification of molecular characteristics by using multiparametric and multiregional MR imaging features. Radiology. 2016;281: 907–918.

    Article  PubMed  Google Scholar 

  16. Drabycz S, Roldán G, de Robles P, Adler D, McIntyre JB, Magliocco AM, et al. An analysis of image texture, tumor location, and MGMT promoter methylation in glioblastoma using magnetic resonance imaging. Neuroimage. 2010;49: 1398–1405.

    Article  CAS  PubMed  Google Scholar 

  17. Ellingson BM, Cloughesy TF, Pope WB, Zaw TM, Phillips H, Lalezari S, et al. Anatomic localization of O6-methylguanine DNA methyltransferase (MGMT) promoter methylated and unmethylated tumors: a radiographic study in 358 de novo human glioblastomas. Neuroimage. 2012;59: 908–916.

    Article  CAS  PubMed  Google Scholar 

  18. Fathi Kazerooni A, Bakas S, Saligheh Rad H, Davatzikos C. Imaging signatures of glioblastoma molecular characteristics: a radiogenomics review. J Magn Reson Imaging. 2020;52: 54–69.

    Article  PubMed  Google Scholar 

  19. Xi Y-B, Guo F, Xu Z-L, Li C, Wei W, Tian P, et al. Radiomics signature: a potential biomarker for the prediction of MGMT promoter methylation in glioblastoma. J Magn Reson Imaging. 2018;47: 1380–1387.

    Article  PubMed  Google Scholar 

  20. Han L, Kamdar MR. MRI to MGMT: predicting methylation status in glioblastoma patients using convolutional recurrent neural networks. Biocomputing 2018. WORLD SCIENTIFIC; 2017. pp. 331–342.

  21. Yogananda CGB, Shah BR, Nalawade SS, Murugesan GK, Yu FF, Pinho MC, et al. MRI-based deep-learning method for determining glioma MGMT promoter methylation status. AJNR Am J Neuroradiol. 2021;42: 845–852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Korfiatis P, Kline TL, Coufalova L, Lachance DH, Parney IF, Carter RE, et al. MRI texture features as biomarkers to predict MGMT methylation status in glioblastomas. Med Phys. 2016;43: 2835–2844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chang P, Grinband J, Weinberg BD, Bardis M, Khy M, Cadena G, et al. Deep-learning convolutional neural networks accurately classify genetic mutations in gliomas. AJNR Am J Neuroradiol. 2018;39: 1201–1207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Korfiatis P, Kline TL, Lachance DH, Parney IF, Buckner JC, Erickson BJ. Residual deep convolutional neural network predicts MGMT methylation status. J Digit Imaging. 2017;30: 622–628.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kihira S, Tsankova NM, Bauer A, Sakai Y, Mahmoudi K, Zubizarreta N, et al. Multiparametric MRI texture analysis in prediction of glioma biomarker status: added value of MR diffusion. Neurooncol Adv. 2021;3: vdab051.

  26. Wei J, Yang G, Hao X, Gu D, Tan Y, Wang X, et al. A multi-sequence and habitat-based MRI radiomics signature for preoperative prediction of MGMT promoter methylation in astrocytomas with prognostic implication. Eur Radiol. 2019;29: 877–888.

    Article  PubMed  Google Scholar 

  27. Mikkelsen VE, Dai HY, Stensjøen AL, Berntsen EM, Salvesen Ø, Solheim O, et al. MGMT promoter methylation status is not related to histological or radiological features in IDH wild-type glioblastomas. J Neuropathol Exp Neurol. 2020;79: 855–862.

    Article  CAS  PubMed  Google Scholar 

  28. Li Z-C, Bai H, Sun Q, Li Q, Liu L, Zou Y, et al. Multiregional radiomics features from multiparametric MRI for prediction of MGMT methylation status in glioblastoma multiforme: a multicentre study. Eur Radiol. 2018;28: 3640–3650.

    Article  PubMed  Google Scholar 

  29. Clark K, Vendt B, Smith K, Freymann J, Kirby J, Koppel P, et al. The Cancer Imaging Archive (TCIA): maintaining and operating a public information repository. J Digit Imaging. 2013;26: 1045–1057.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Cancer Genome Atlas Research Network, Weinstein JN, Collisson EA, Mills GB, Shaw KRM, Ozenberger BA, et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. 2013;45: 1113–1120.

  31. Baid U, Ghodasara S, Mohan S, Bilello M, Calabrese E, Colak E, et al. The RSNA-ASNR-MICCAI BraTS 2021 Benchmark on Brain Tumor Segmentation and Radiogenomic Classification. arXiv [cs.CV]. 2021. Available: http://arxiv.org/abs/2107.02314

  32. Menze BH, Jakab A, Bauer S, Kalpathy-Cramer J, Farahani K, Kirby J, et al. The Multimodal Brain Tumor Image Segmentation Benchmark (BRATS). IEEE Trans Med Imaging. 2015;34: 1993–2024.

    Article  PubMed  Google Scholar 

  33. Bakas S, Akbari H, Sotiras A, Bilello M, Rozycki M, Kirby JS, et al. Advancing The Cancer Genome Atlas glioma MRI collections with expert segmentation labels and radiomic features. Sci Data. 2017;4: 170117.

    Article  PubMed  PubMed Central  Google Scholar 

  34. RSNA-MICCAI Brain Tumor Radiogenomic Classification. [cited 8 Apr 2022]. Available: https://www.kaggle.com/competitions/rsna-miccai-brain-tumor-radiogenomic-classification/overview

  35. Pedregosa F, Varoquaux G, Gramfort A, Michel V, Thirion B, Grisel O, et al. Scikit-learn: Machine Learning in Python. J Mach Learn Res. 2011;12: 2825–2830.

    Google Scholar 

  36. Rouzrokh P, Khosravi B, Faghani S, Moassefi M, Vera Garcia DV, Singh Y, et al. Mitigating bias in radiology machine learning: 1. Data handling. Radiology: Artificial Intelligence. 2022;4: e210290.

    PubMed  PubMed Central  Google Scholar 

  37. MONAI Consortium. MONAI: Medical Open Network for AI. Zenodo; 2022.

  38. Zhang K, Khosravi B, Vahdati S, Faghani S, Nugen F, Rassoulinejad-Mousavi SM, et al. Mitigating bias in radiology machine learning: 2. Model development. Radiology: Artificial Intelligence. 2022;4: e220010.

    PubMed  PubMed Central  Google Scholar 

  39. Jocher G, Stoken A, Borovec J, NanoCode, ChristopherSTAN, Changyu L, et al. ultralytics/yolov5: v3.1 - Bug Fixes and Performance Improvements. 2020.

  40. Faghani S, Khosravi B, Zhang K, Moassefi M, Jagtap JM, Nugen F, et al. Mitigating bias in radiology machine learning: 3. Performance metrics. Radiology: Artificial Intelligence. 2022; e220061.

  41. The MONAI Consortium. Project MONAI. 2020. https://doi.org/10.5281/zenodo.4323059

  42. Milletari F, Navab N, Ahmadi S-A. V-Net: Fully Convolutional Neural Networks for Volumetric Medical Image Segmentation. arXiv [cs.CV]. 2016. Available: http://arxiv.org/abs/1606.04797

  43. Kingma DP, Ba J. Adam: A Method for Stochastic Optimization. arXiv [cs.LG]. 2014. Available: http://arxiv.org/abs/1412.6980

  44. Bakas S, Reyes M, Jakab A, Bauer S, Rempfler M, Crimi A, et al. Identifying the Best Machine Learning Algorithms for Brain Tumor Segmentation, Progression Assessment, and Overall Survival Prediction in the BRATS Challenge. arXiv [cs.CV]. 2018. Available: http://arxiv.org/abs/1811.02629

  45. Saeed N, Hardan S, Abutalip K, Yaqub M. Is it Possible to Predict MGMT Promoter Methylation from Brain Tumor MRI Scans Using Deep Learning Models? arXiv [eess.IV]. 2022. Available: http://arxiv.org/abs/2201.06086

  46. Pálsson S, Cerri S, Van Leemput K. Prediction of MGMT Methylation Status of Glioblastoma Using Radiomics and Latent Space Shape Features. arXiv [eess.IV]. 2021. Available: http://arxiv.org/abs/2109.12339

  47. Kanas VG, Zacharaki EI, Thomas GA, Zinn PO, Megalooikonomou V, Colen RR. Learning MRI-based classification models for MGMT methylation status prediction in glioblastoma. Comput Methods Programs Biomed. 2017;140: 249–257.

    Article  PubMed  Google Scholar 

  48. Le NQK, Do DT, Chiu F-Y, Yapp EKY, Yeh H-Y, Chen C-Y. XGBoost improves classification of MGMT promoter methylation status in IDH1 wildtype glioblastoma. J Pers Med. 2020;10. https://doi.org/10.3390/jpm10030128

  49. Crisi G, Filice S. Predicting MGMT promoter methylation of glioblastoma from dynamic susceptibility contrast perfusion: a radiomic approach. J Neuroimaging. 2020;30: 458–462.

    Article  PubMed  Google Scholar 

  50. Jiang C, Kong Z, Liu S, Feng S, Zhang Y, Zhu R, et al. Fusion radiomics features from conventional MRI predict MGMT promoter methylation status in lower grade gliomas. Eur J Radiol. 2019;121: 108714.

    Article  PubMed  Google Scholar 

  51. Hajianfar G, Shiri I, Maleki H, Oveisi N, Haghparast A, Abdollahi H, et al. Noninvasive O6 methylguanine-DNA methyltransferase status prediction in glioblastoma multiforme cancer using magnetic resonance imaging radiomics features: univariate and multivariate radiogenomics analysis. World Neurosurg. 2019;132: e140–e161.

    Article  PubMed  Google Scholar 

  52. Lu Y, Patel M, Natarajan K, Ughratdar I, Sanghera P, Jena R, et al. Machine learning-based radiomic, clinical and semantic feature analysis for predicting overall survival and MGMT promoter methylation status in patients with glioblastoma. Magn Reson Imaging. 2020;74: 161–170.

    Article  CAS  PubMed  Google Scholar 

  53. Calabrese E, Villanueva-Meyer JE, Cha S. A fully automated artificial intelligence method for non-invasive, imaging-based identification of genetic alterations in glioblastomas. Sci Rep. 2020;10: 11852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Malmström A, Łysiak M, Kristensen BW, Hovey E, Henriksson R, Söderkvist P. Do we really know who has an MGMT methylated glioma? Results of an international survey regarding use of MGMT analyses for glioma. Neurooncol Pract. 2020;7: 68–76.

    PubMed  Google Scholar 

  55. Calabrese E, Rudie JD, Rauschecker AM, Villanueva-Meyer JE, Clarke JL, Solomon DA, et al. Combining radiomics and deep convolutional neural network features from preoperative MRI for predicting clinically relevant genetic biomarkers in glioblastoma. Neurooncol Adv. 2022;4: vdac060.

Download references

Acknowledgements

This project was supported in part by funding from the Mayo Clinic Center for Individualized Medicine (CIM).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bradley J. Erickson.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Gian Marco Conte and Bradley J. Erickson are co-senior authors.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Faghani, S., Khosravi, B., Moassefi, M. et al. A Comparison of Three Different Deep Learning-Based Models to Predict the MGMT Promoter Methylation Status in Glioblastoma Using Brain MRI. J Digit Imaging 36, 837–846 (2023). https://doi.org/10.1007/s10278-022-00757-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10278-022-00757-x

Keywords

Navigation