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Genome-wide DNA methylation analysis reveals a prognostic classifier for non-metastatic colorectal cancer (ProMCol classifier)
  1. Melanie Gündert1,2,
  2. Dominic Edelmann3,
  3. Axel Benner3,
  4. Lina Jansen4,
  5. Min Jia4,
  6. Viola Walter4,
  7. Phillip Knebel5,
  8. Esther Herpel6,7,
  9. Jenny Chang-Claude8,9,
  10. Michael Hoffmeister4,
  11. Hermann Brenner4,10,11,
  12. Barbara Burwinkel1,2
  1. 1 Division of Molecular Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  2. 2 Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany
  3. 3 Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
  4. 4 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  5. 5 Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
  6. 6 Department of General Pathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
  7. 7 NCT Tissue Bank, National Center for Tumor Diseases (NCT), Heidelberg, Germany
  8. 8 Division of Cancer Epidemiology, Unit of Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  9. 9 Genetic Tumour Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  10. 10 Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
  11. 11 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
  1. Correspondence to Dr. Melanie Gündert, Molecular Epidemiology, Im Neuenheimer Feld 581, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; m.guendert{at}


Objective Pathological staging used for the prediction of patient survival in colorectal cancer (CRC) provides only limited information.

Design Here, a genome-wide study of DNA methylation was conducted for two cohorts of patients with non-metastatic CRC (screening cohort (n=572) and validation cohort (n=274)). A variable screening for prognostic CpG sites was performed in the screening cohort using marginal testing based on a Cox model and subsequent adjustment of the p-values via independent hypothesis weighting using the methylation difference between 34 pairs of tumour and normal mucosa tissue as auxiliary covariate. From the 1000 CpG sites with the smallest adjusted p-value, 20 CpG sites with the smallest Brier score for overall survival (OS) were selected. Applying principal component analysis, we derived a prognostic methylation-based classifier for patients with non-metastatic CRC (ProMCol classifier).

Results This classifier was associated with OS in the screening (HR 0.51, 95% CI 0.41 to 0.63, p=6.2E−10) and the validation cohort (HR 0.61, 95% CI 0.45 to 0.82, p=0.001). The independent validation of the ProMCol classifier revealed a reduction of the prediction error for 3-year OS from 0.127, calculated only with standard clinical variables, to 0.120 combining the clinical variables with the classifier and for 4-year OS from 0.153 to 0.140. All results were confirmed for disease-specific survival.

Conclusion The ProMCol classifier could improve the prognostic accuracy for patients with non-metastatic CRC.

  • cancer epidemiology
  • colorectal cancer
  • methylation

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  • Contributors Substantial contributions to the conception and design (MG, DE, BB), development of methodology (MG, DE, BB), acquisition of data (MG, MH, PK, EH, JC-C, HB, BB), analysis and interpretation of data (MG, DE, BB), draft of the article (MG, DE, BB), critical revision of the article (all authors), final approval of the version (all authors).

  • Funding This project was supported by grants from the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1, BR 1704/17-1), the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A, 01ER1505B) and the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany.

  • Disclaimer The sponsors had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data and preparation, review or approval of the manuscript.

  • Competing interests None declared.

  • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

  • Ethics approval Ethical committees of the Medical Faculty of the University of Heidelberg and of the Medical Chambers of Baden-Württemberg and Rhineland-Palatinate.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The data that support the findings of this study are available on reasonable request from the corresponding author (MG). The data are not publicly available due to restrictions of informed consent.

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