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Updated: Jun 25, 2025
Evaluation of Colorectal Cancer Risk and Prevalence by Stool DNA Integrity Detection
Published on: June 8, 2020
A 5-Hydroxymethylcytosine-Based Noninvasive Model for Early Detection of Colorectal Carcinomas and Advanced Adenomas:
Wenju Chang1,2,3, Zhou Zhang4, Baoqing Jia5
1Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Purpose:
Detection of colorectal carcinomas at a time when there are more treatment options is associated with better outcomes. This prospective case-control study assessed the 5-hydroxymethylcytosine (5hmC) biomarkers in circulating cell-free DNA (cfDNA) for early detection of colorectal carcinoma and advanced adenomas (AA).
Experimental Design:
Plasma cfDNA samples from 2,576 study participants from the multicenter METHOD-2 study (NCT03676075) were collected, comprising patients with newly diagnosed colorectal carcinoma (n = 1,074), AA (n = 356), other solid tumors (n = 80), and non-colorectal carcinoma/AA controls (n = 1,066), followed by genome-wide 5hmC profiling using the 5hmC-Seal technique and the next-generation sequencing. A weighted diagnostic model for colorectal carcinoma (stage I-III) and AA was developed using the elastic net regularization in a discovery set and validated in independent samples.
Results:
Distribution of 5hmC in cfDNA reflected gene regulatory relevance and tissue of origin. Besides being confirmed in internal validation, a 96-gene model achieved an area under the curve (AUC) of 90.7% for distinguishing stage I-III colorectal carcinoma from controls in 321 samples from multiple centers for external validation, regardless of primary location or mutation status. This model also showed cancer-type specificity as well as high capacity for distinguishing AA from controls with an AUC of 78.6%. Functionally, differential 5hmC features associated with colorectal carcinoma and AA demonstrated relevance to colorectal carcinoma biology, including pathways such as calcium and MAPK signaling.
Conclusions:
Genome-wide mapping of 5hmC in cfDNA shows promise as a highly sensitive and specific noninvasive blood test to be integrated into screening programs for improving early detection of colorectal carcinoma and high-risk AA.
