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A novel cell-free DNA methylation-based model improves the early detection of colorectal cancer.

ABSTRACT: Screening for early-stage disease is vital for reducing colorectal cancer (CRC)-related mortality. Methylation of circulating tumor DNA has been previously used for various types of cancer screening. A novel cell-free DNA (cfDNA) methylation-based model which can improve the early detection of CRC is warranted. For our study, we collected 313 tissue and 577 plasma samples from patients with CRC, advanced adenoma (AA), non-AA and healthy controls. After quality control, 187 tissue DNA samples (91 non-malignant tissue from CRC patients, 26 AA and 70 CRC) and 489 plasma cfDNA samples were selected for targeted DNA methylation sequencing. We further developed a cfDNA methylation model based on 11 methylation biomarkers for CRC detection in the training cohort (area under curve [AUC] = 0.90 (0.85-0.94]) and verified the model in the validation cohort (AUC = 0.92 [0.88-0.96]). The cfDNA methylation model robustly detected patients pre-diagnosed with early-stage CRC (AUC = 0.90 [0.86-0.95]) or AA (AUC = 0.85 [0.78-0.91]). Here we established and validated a non-invasive cfDNA methylation model based on 11 DNA methylation biomarkers for the detection of early-stage CRC and AA. The utilization of the model in clinical practice may contribute to the early diagnosis of CRC.

SUBMITTER: Wu X

PROVIDER: S-EPMC8486566 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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A novel cell-free DNA methylation-based model improves the early detection of colorectal cancer.

Wu Xianrui X Zhang Yunfeng Y Hu Tuo T He Xiaowen X Zou Yifeng Y Deng Qiling Q Ke Jia J Lian Lei L He Xiaosheng X Zhao Dezhi D Cai Xuyu X Chen Zhiwei Z Wu Xiaojian X Fan Jian-Bing JB Gao Feng F Lan Ping P

Molecular oncology 20210325 10

Screening for early-stage disease is vital for reducing colorectal cancer (CRC)-related mortality. Methylation of circulating tumor DNA has been previously used for various types of cancer screening. A novel cell-free DNA (cfDNA) methylation-based model which can improve the early detection of CRC is warranted. For our study, we collected 313 tissue and 577 plasma samples from patients with CRC, advanced adenoma (AA), non-AA and healthy controls. After quality control, 187 tissue DNA samples (91 ...[more]

PMID: 33694305

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Project description:BackgroundMethylated SDC2 has been proved as a diagnostic marker for human colorectal cancer (CRC), noninvasive stool DNA-based methylation testing also emerges as a novel approach for detecting CRC. The aim of this study was to evaluate the clinical performance of stool DNA-based SDC2 methylation test by a new qPCR detection reagent for early detection of CRC.MethodsA new qPCR detection reagent contained two differentially methylated regions in SDC2 CpG islands for the detection of CRC was used in this study. Performance of the SDC2 methylation detection reagent was evaluated by analyzing limit of detection, precision, and specificity. The effect of interfering substances on assay performance was also tested. 339 subjects (102 CRC patients, 50 patients with advanced adenomas, 39 patients with non-advanced adenomas, 18 colitis patients and 130 normal individuals) from the China-Japan Friendship Hospital were evaluated. Approximately 2.5 g of stool sample was collected from each participant. Stool DNA was extracted and bisulfite-converted, followed by qPCR assay, which contained two pairs of primers for the methylation detection of two fragments of the SDC2 gene (named SDC2-A and SDC2-B). The diagnostic value of this test in CRC was evaluated by calculating receiver operating characteristic (ROC) curve, and value of the area under the curve (AUC).ResultsThe test kit was able to detect methylated SDC2 in stool DNA samples with concentrations as low as 90 copies/μL in 100% of replicates. The sensitivity for detecting CRC by methylated SDC2-A alone was 85.29% (95% CI 77.03-91.00%) with a specificity of 96.15% (95% CI 91.08-98.58%). The sensitivity by methylated SDC2-B alone was 83.33% (95% CI 74.82-89.42%) with a specificity of 97.69% (95% CI 93.14-99.51%). However, when methylated SDC2-A and methylated SDC2-B were combined, the sensitivity for CRC detection improved to 87.25% (95% CI 79.27-92.53%) with a specificity of 94.62% (95% CI 89.11-97.56%). Further, the detection reagent achieved ROC-AUC 0.874 (95% CI 0.822-0.927) for SDC2-A, 0.906 (95% CI 0.859-0.952) for SDC2-B, and 0.939 (95% CI 0.902-0.977) for SDC2-Combine A&B.ConclusionsThis study validated the capability of stool DNA-based SDC2 methylation test for early screening of CRC, and combined detection of two fragments of SDC2 gene could improve detection sensitivity.

Project description:BackgroundEarly detection of colorectal carcinoma (CRC) would help to identify tumors when curative treatments are available and beneficial. However, current screening methods for CRC, e.g., colonoscopy, may affect patients' compliance due to the uncomfortable, invasive and time-consuming process. In recent decades, methylation profiles of blood-based circulating tumor DNA (ctDNA) have shown promising results in the early detection of multiple tumors. Here we conducted a study to investigate the performance of ctDNA methylation markers in early detection of CRC.ResultsIn total, 742 participants were enrolled in the study including CRC (n = 332), healthy control (n = 333), benign colorectal disease (n = 65) and advanced adenoma (n = 12). After age-matched and randomization, 298 participants (149 cancer and 149 healthy control) were included in training set and 141 (67 cancer and 74 healthy control) were in test set. In the training set, the specificity was 89.3% (83.2-93.7%) and the sensitivity was 88.6% (82.4-93.2%). In terms of different stages, the sensitivities were 79.4% (62.1-91.2%) in patients with stage I, 88.9% (77.3-95.8%) in patients with stage II, 91.4% (76.9-98.2%) in patients with stage III and 96.2% (80.3-99.9%) in patients with stage IV. Similar results were validated in the test set with the specificity of 91.9% (83.1-97.0%) and sensitivity of 83.6% (72.5-91.6%). Sensitivities for stage I-III were 87.0% (79.7-92.4%) in the training set and 82.5% (70.2-91.3%) in the test set, respectively. In the unmatched total population, the positive ratios were 7.8% (5.2-11.2%) in healthy control, 30.8% (19.9-43.5%) in benign colorectal disease and 58.3% (27.5-84.7%) in advanced adenoma, while the sensitivities of stage I-IV were similar with training and test sets. Compared with methylated SEPT9 model, the present model had higher sensitivity (87.0% [81.8-91.2%] versus 41.2% [34.6-48.1%], P < 0.001) under comparable specificity (90.1% [85.4-93.7%] versus 90.6% [86.0-94.1%]).ConclusionsTogether our findings showed that ctDNA methylation markers were promising in the early detection of CRC. Further validation of this model is warranted in prospective studies.

Project description:An effective blood-based method for the diagnosis of colorectal cancer has not yet been developed. Molecular alterations of immune cells occur early in tumorigenesis, providing the theoretical underpinning for early cancer diagnosis based on immune cell profiling. Therefore, we aimed to develop an effective detection method based on peripheral blood mononuclear cells (PBMC) to improve the diagnosis of colorectal cancer. Analysis of the genome-wide methylation landscape of PBMCs from patients with colorectal cancer and healthy controls by microarray, pyrosequencing, and targeted bisulfite sequencing revealed five DNA methylation markers for colorectal cancer diagnosis, especially early-stage colorectal cancer. A single-tube multiple methylation-specific quantitative PCR assay (multi-msqPCR) for simultaneous detection of five methylation markers was established, which allowed quantitative analysis of samples with as little as 0.1% PBMC DNA and had better discriminative performance than single-molecule detection. Then, a colorectal cancer diagnostic model (CDM) based on methylation markers and the multi-msqPCR method was constructed that achieved high accuracy for early-stage colorectal cancer (AUC = 0.91; sensitivity = 81.18%; specificity = 89.39%), which was improved compared with CEA (AUC = 0.79). The CDM also enabled a high degree of discrimination for advanced adenoma cases (AUC = 0.85; sensitivity = 63.04%). Follow-up data also demonstrated that the CDM could identify colorectal cancer potential up to 2 years before currently used diagnostic methods. In conclusion, the approach constructed in this study based on PBMC-derived DNA methylation markers and a multi-msqPCR method is a promising and easily implementable diagnostic method for early-stage colorectal cancer.SignificanceDevelopment of a diagnostic model for early colorectal cancer based on epigenetic analysis of PBMCs supports the utility of altered DNA methylation in immune cells for cancer diagnosis.

Dataset Information

A novel cell-free DNA methylation-based model improves the early detection of colorectal cancer.

Publications

A novel cell-free DNA methylation-based model improves the early detection of colorectal cancer.

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