A noninvasive test for methylated cell-free DNA markers identified colorectal cancer.

  • Major Finding: A noninvasive test for methylated cell-free DNA markers identified colorectal cancer.

  • Concept: The test's sensitivity was 89.7% and specificity was 86.8%, superior to other noninvasive tests.

  • Impact: A randomized trial to determine the utility of the test in diagnosis and prognosis is justified.


Multiple screening methods for colorectal cancer are available, but their use is limited by factors such as invasiveness, as with colonoscopy, or low sensitivity, as with serum carcinoembryonic antigen (CEA) quantification. Recently, evaluating cell-free DNA (cfDNA) has shown promise as a method of diagnostic and prognostic use in several cancers. Luo, Zhao, Wei, Zheng, Yi, and colleagues compared DNA-methylation markers specific to colorectal cancer by comparing data from colorectal cancer tissue with data from normal leukocytes and used a machine-learning algorithm to identify several markers of potential diagnostic and prognostic significance. They then selected 1,493 people at high risk for colorectal cancer for a prospective screening cohort study in which participants underwent colonoscopy and tests for methylation of cfDNA. Twenty-nine patients (1.9%) were discovered to have colorectal cancer, and 78 (5.2%) had advanced precancerous lesions. Used alone, testing for a single cfDNA methylation marker correctly identified 19 of 21 patients (90.5%) with colorectal cancer and 7 of 8 patients (87.5%) with colorectal cancer in situ with a sensitivity of 89.7% and a specificity of 86.8%, surpassing the sensitivity and specificity of the serum CEA test. Additionally, testing using a separate five-marker cfDNA methylation panel was able to distinguish patient prognoses better than testing for other prognostic markers, such as serum CEA status, TNM stage, or primary tumor location, and combining these other prognostic markers with the cfDNA-methylation test produced even more accurate results. However, it is important to note that the follow-up period was relatively brief (median 26.6 months), meaning that additional, longer-term study will be needed to validate the usefulness of this test for making clinical decisions; further, this was not a randomized controlled study, so selection bias cannot be excluded. Nonetheless, the promising results of this study as well as the noninvasive nature of the test—which may improve patient adherence to screening recommendations—indicate that a large-scale randomized clinical trial is warranted.

Luo H, Zhao Q, Wei W, Zheng L, Yi S, Li G, et al. Circulating tumor DNA methylation profiles enable early diagnosis, prognosis prediction, and screening for colorectal cancer. Sci Transl Med 2020;12:eaax7533.

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