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

Abstract

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 the 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.