Discovery and validation of methylation signatures in blood-based circulating tumor cell-free DNA in early detection of colorectal carcinoma: a case–control study

BACKGROUND: Early 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. RESULTS: In 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%]). CONCLUSIONS: Together 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.