Results of previous studies on the association of the CpG island methylator phenotype (CIMP) with colorectal cancer (CRC) prognosis were inconsistent and the variety of markers selected to define CIMP was widely blamed for the inconsistency. The current study was therefore aimed to comprehensively investigate the associations of DNA methylation at CIMP-related genes with CRC survival.
Patients with CRC diagnosed between 2003 and 2007 were followed up for a median of 5.2 years and divided into a screening cohort (n = 568) and a validation cohort (n = 308). DNA methylation was measured in tumor tissue using the Illumina Infinium HumanMethylation450 BeadChip. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) of survival after CRC, including adjustment for tumor stage, microsatellite instability, BRAF mutation status and other important factors.
Of 48 genes used to define CIMP in the previous studies, 43 were also covered by the methylation array. In the screening cohort, ten CpG sites were identified to be associated with CRC survival. Seven of these ten CpG sites were also associated with CRC survival in the validation cohort and were used to construct a prognostic score. CRC patients with a prognostic score in the lowest tertile (lowest methylation levels at the CpG sites) showed poorer disease-specific survival compared with patients in the highest tertile in both the study cohort and the validation cohort (HR = 3.11; 95% CI = 1.97-4.91 and HR = 3.06; 95% CI = 1.71-5.45 respectively).
A CpG panel consisting of seven CpG sites was found to be strongly associated with CRC survival, independent from important clinical factors and mutations associated with CIMP.
Clinical trial identification
Legal entity responsible for the study
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center
The German Research Council, the German Federal Ministry of Education and Research
All authors have declared no conflicts of interest.