DNA methylation profile in CpG-depleted regions uncovers a high-risk subtype of early-stage colorectal cancer

Huichuan Yu, Xiaolin Wang, Liangliang Bai, Guannan Tang, Kelly T. Carter, Ji Cui, Pinzhu Huang, Li Liang, Yanqing Ding, Muyan Cai, Meijin Huang, Huanliang Liu, Guangwen Cao, Steven Gallinger, Rish K. Pai, Daniel D. Buchanan, Aung Ko Win, Polly A. Newcomb, Jianping Wang, William M. GradyYanxin Luo

Research output: Contribution to journalArticlepeer-review


Background: The current risk stratification system defined by clinicopathological features does not identify the risk of recurrence in early-stage (stage I-II) colorectal cancer (CRC) with sufficient accuracy. We aimed to investigate whether DNA methylation could serve as a novel biomarker for predicting prognosis in early-stage CRC patients. Methods: We analyzed the genome-wide methylation status of CpG loci using Infinium MethylationEPIC array run on primary tumor tissues and normal mucosa of early-stage CRC patients to identify potential methylation markers for prognosis. The machine-learning approach was applied to construct a DNA methylation-based prognostic classifier for early-stage CRC (MePEC) using the 4 gene methylation markers FAT3, KAZN, TLE4, and DUSP3. The prognostic value of the classifier was evaluated in 2 independent cohorts (n = 438 and 359, respectively). Results: The comprehensive analysis identified an epigenetic subtype with high risk of recurrence based on a group of CpG loci in the CpG-depleted region. In multivariable analysis, the MePEC classifier was independently and statistically significantly associated with time to recurrence in validation cohort 1 (hazard ratio = 2.35, 95% confidence interval = 1.47 to 3.76, P <. 001) and cohort 2 (hazard ratio = 3.20, 95% confidence interval = 1.92 to 5.33, P <. 001). All results were further confirmed after each cohort was stratified by clinicopathological variables and molecular subtypes. Conclusions: We demonstrated the prognostic statistical significance of a DNA methylation profile in the CpG-depleted region, which may serve as a valuable source for tumor biomarkers. MePEC could identify an epigenetic subtype with high risk of recurrence and improve the prognostic accuracy of current clinical variables in early-stage CRC.

Original languageEnglish (US)
Pages (from-to)52-61
Number of pages10
JournalJournal of the National Cancer Institute
Issue number1
StatePublished - Jan 1 2023

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'DNA methylation profile in CpG-depleted regions uncovers a high-risk subtype of early-stage colorectal cancer'. Together they form a unique fingerprint.

Cite this