DNA methylation-based biomarkers and prediction models for the survival of patients with colorectal cancer: systematic review and external validation study

Objectives To identify existing DNA methylation-based prognostic biomarkers and prediction models for colorectal cancer (CRC) prognosis and to validate them in a large external cohort. Design Systematic review and external validation study. Data source Systematic search in PubMed and Web of Science until October 2022 to identify epigenome-wide studies reporting methylation at CpG sites (CpGs) associated with survival among CRC patients. Validation data were drawn from the 2310 CRC patients of the DACHS study recruited from 22 hospitals in the Rhine-Neckar region in the southwest of Germany. Main outcome measures Overall survival (OS) in CRC patients. Results We identified 200 unique CpGs and 10 CpG-based prognostic models derived from 15 studies. In the external validation analysis, 1252 of 2310 patients died during follow-up (median 10.4 years). Thirty-nine CpGs (20%) and five prognostic models (50%) were independently associated with overall survival after adjustment for clinical variables. The five models had unsatisfactory discrimination ability, with area under the receiver operating characteristic curves at five years ranging from 0.54 to 0.60. The calibration accuracy of the five models using recalibrated baseline survival was also poor, and no relevant added prognostic value to traditional clinical variables was observed. Based on the Prediction Model Risk of Bias Assessment Tool, all models were rated as high risk of bias. Conclusions Only 20% of published CpGs associated with survival in CRC patients could be externally validated. So far derived published CpG-based prognostic models for CRC do not seem to be useful for clinical practice. What is already known on this topic What this study adds ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HO 5117/2-2, HE 5998/2-1, HE 5998/2-2, KL 2354/3-1, KL 2354 3-2, RO 2270/8-1, RO 2270/8-2, BR 1704/17-1, BR 1704/17-2); the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany; and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A, and 01ER1505B). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval: The study was approved by the ethics committees of the Medical Faculty of the University of Heidelberg and of the Medical Chambers of Baden-Wurttemberg and Rhineland-Palatinate. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors