Research ArticleCancer

Circulating tumor DNA methylation profiles enable early diagnosis, prognosis prediction, and screening for colorectal cancer

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Science Translational Medicine  01 Jan 2020:
Vol. 12, Issue 524, eaax7533
DOI: 10.1126/scitranslmed.aax7533

Methylation marks the spot

The detection of circulating tumor DNA in the blood is a noninvasive method that may help detect cancer at early stages if one knows the correct markers for evaluation. Luo et al. analyzed methylation patterns in blood samples from multiple large cohorts of patients, including a prospective screening cohort of people at high risk of colorectal cancer. The authors identified and validated a methylation-based diagnostic score to help distinguish patients with colorectal cancer from healthy controls, as well as a prognostic score that correlated with patients’ survival. One methylation marker in particular appeared to have high sensitivity and specificity for identifying patients with cancer.


Circulating tumor DNA (ctDNA) has emerged as a useful diagnostic and prognostic biomarker in many cancers. Here, we conducted a study to investigate the potential use of ctDNA methylation markers for the diagnosis and prognostication of colorectal cancer (CRC) and used a prospective cohort to validate their effectiveness in screening patients at high risk of CRC. We first identified CRC-specific methylation signatures by comparing CRC tissues to normal blood leukocytes. Then, we applied a machine learning algorithm to develop a predictive diagnostic and a prognostic model using cell-free DNA (cfDNA) samples from a cohort of 801 patients with CRC and 1021 normal controls. The obtained diagnostic prediction model discriminated patients with CRC from normal controls with high accuracy (area under curve = 0.96). The prognostic prediction model also effectively predicted the prognosis and survival of patients with CRC (P < 0.001). In addition, we generated a ctDNA-based molecular classification of CRC using an unsupervised clustering method and obtained two subgroups of patients with CRC with significantly different overall survival (P = 0.011 in validation cohort). Last, we found that a single ctDNA methylation marker, cg10673833, could yield high sensitivity (89.7%) and specificity (86.8%) for detection of CRC and precancerous lesions in a high-risk population of 1493 participants in a prospective cohort study. Together, our findings showed the value of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of CRC.

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