Diagnosis using methylation

Early diagnosis enables substantially better outcomes among patients with colorectal cancer (CRC). Several methods of screening for early stage CRC exist, although these are either invasive (colonoscopy) or lack sufficient sensitivity (serum carcinoembryonic antigen (CEA)). Now, data from a large-cohort study reveal the potential of methylation of cell-free DNA (cfDNA) in the detection of CRC.

Credit: Simon Bradbrook/Springer Nature Limited

Researchers compared methylation data from 459 CRC samples analysed as part of The Cancer Genome Atlas with methylation profiles from 754 individuals without CRC.

The diagnostic performance of classification based on methylation profile was investigated in the training and validation sets (comprising 1,202 and 620 patients, respectively), and revealed sensitivities and specificities for CRC detection of 87.5% and 89.9% in the training set, and 87.9% and 89.6% in the validation set, respectively. Comparisons of methylation-based CRC detection with CEA testing revealed the superiority of the methylation-based approach (AUC 0.96 versus 0.67). A composite (cd)-score, based on nine different methylation markers, was then constructed.

cd-score was then combined with other prognostic features to develop a combined prognostic (cp) score. Application of cp-score revealed significant differences in overall survival durations between patients with CRCs classified as high-risk versus low-risk in the training set (P < 0.001) and validation set (P = 0.0012): cd-score was independently predictive of survival in both sets.

Owing to the challenges associated with implementation of complex biomarkers, researchers selected the most promising single marker (methylation of site CpG cg10673833) for prospective testing. A total of 19 of 21 CRCs were identified using this test (sensitivity 89.7%, specificity 86.8%) in a cohort of 1,493 individuals with a high risk of CRC undergoing colonoscopy.

Lead author Rui-Hua Xu summarizes: “Our most important finding is that accurate early diagnosis of CRC is feasible by detecting cfDNA methylation markers in just a few mls of blood”. When asked about future directions, Xu adds: “we need to design a randomized, population-based study to compare this non-invasive screening strategy with other tests”.


Original article

  1. Luo, H. et al. Sci. Transl Med. 524, eaax7533 (2020)

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Correspondence to Peter Sidaway.

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Sidaway, P. Diagnosis using methylation. Nat Rev Clin Oncol 17, 196 (2020).

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