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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Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma.Nat Mater. 2017 Nov;16(11):1155-1161. doi: 10.1038/nmat4997. Epub 2017 Oct 9. Nat Mater. 2017. PMID: 29035356 Clinical Trial.
Cell-Free DNA as a Diagnostic Blood-Based Biomarker for Colorectal Cancer: A Systematic Review.J Surg Res. 2019 Apr;236:184-197. doi: 10.1016/j.jss.2018.11.029. Epub 2018 Dec 21. J Surg Res. 2019. PMID: 30694754
Circulating tumour DNA for monitoring colorectal cancer-a prospective cohort study to assess relationship to tissue methylation, cancer characteristics and surgical resection.Clin Epigenetics. 2018 May 16;10:63. doi: 10.1186/s13148-018-0500-5. eCollection 2018. Clin Epigenetics. 2018. PMID: 29796114 Free PMC article. Clinical Trial.
The Use of Circulating Tumor DNA for Prognosis of Gastrointestinal Cancers.Front Oncol. 2018 Jul 24;8:275. doi: 10.3389/fonc.2018.00275. eCollection 2018. Front Oncol. 2018. PMID: 30087854 Free PMC article. Review.
Review of Blood-Based Colorectal Cancer Screening: How Far Are Circulating Cell-Free DNA Methylation Markers From Clinical Implementation?Clin Colorectal Cancer. 2018 Jun;17(2):e415-e433. doi: 10.1016/j.clcc.2018.02.012. Epub 2018 Mar 2. Clin Colorectal Cancer. 2018. PMID: 29678513 Review.
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