SEPT9 gene methylation was validated as a biomarker for colorectal cancer (CRC) for >10 years and available as the Epi proColon test as an aid in CRC detection for >6 years. It was proven to be an accurate, reliable, fast, and convenient molecular test. In this opportunistic screening study, we validated a further simplified SEPT9 gene methylation assay in 1031 subjects in Chinese hospitals. The sensitivity for CRC detection was 76.6% at a specificity of 95.9%, and the results showed a satisfactory detection rate for each CRC stage, including early stages. The new SEPT9 assay, with enhanced technical simplicity, convenience, and lower cost, did not differ in performance compared with Epi proColon 2.0, the commercialized SEPT9 assay. The CRC detection sensitivity was further enhanced when the assay was combined with carcinoembryonic antigen (sensitivity, 86.4%) or fecal immunochemical test (sensitivity, 94.4%), suggesting that the combined tests may be an effective option for future opportunistic screening. In brief, our study has validated a new SEPT9 assay and combined testing as an aid in cancer detection, providing a new approach for opportunistic CRC screening.
Algorithm, cancer stage and age are factors affecting the detection rate of the SEPT9 assay, while sex and cancer location appeared to have no influence on its performance.
Epigenetic markers based on differential methylation of DNA sequences are used in cancer screening and diagnostics. Detection of abnormal methylation at specific loci by real-time quantitative polymerase chain reaction (RT-qPCR) has been developed to enable high-throughput cancer screening. For tests that combine the results of multiple PCR replicates into a single reportable result, both individual PCR cutoff and weighting of the individual PCR result are essential to test outcome. In this opportunistic screening study, we tested samples from 1133 patients using the triplicate Epi proColon assay with various algorithms and compared it with the newly developed single replicate SensiColon assay that measures methylation status of the same SEPT9 gene sequence. The Epi proColon test approved by the US FDA (1/3 algorithm) showed the highest sensitivity (82.4%) at a lower specificity (82.0%) compared with the Epi proColon 2.0 CE version with 2/3 algorithm (75.1% sensitivity, 97.1% specificity) or 1/1 algorithm (71.3% sensitivity, 92.7% specificity). No significant difference in performance was found between the Epi proColon 2.0 CE and the SensiColon assays. The choice of algorithm must depend on specific test usage, including screening and early detection. These considerations allow one to choose the optimal algorithm to maximize the test performance. We hope this study can help to optimize the methylation detection in cancer screening and early detection.
The SEPT9 assay detected 38.7% of all types of adenoma, including 27.8% of serrated adenoma, 28.7% of tubular adenoma, 53.7% of tubulovillous adenoma and 83.3% of villous adenoma. It also detected 27.5% of nonadvanced adenoma (NAA), 47.0% of advanced adenoma (AA) without high-grade dysplasia and 62.5% of AA with high-grade dysplasia. The average adenoma detection rate was 31.8% (95% CI: 28.3-35.4%) with the Boston Bowel Preparation Scale score at 7.6 ± 1.2 (mean ± SD). Our study provided strong evidence for the application of the SEPT9 assay in AA detection in opportunistic screening.
Background and Aim:Methylated SEPT9 is a novel circulating tumor DNA marker for colorectal cancer, while the effects of various colorectal cancer clinicopathological factors on its detection performance have not been fully evaluated. This study aims to investigate the significance of the clinicopathological factors on methylated SEPT9 performance in a symptomatic endoscopy cohort, with a specific focus on colorectal cancer.Methods:A total of 1160 participants were recruited in this study, including 300 patients with colorectal cancer, 122 patients with adenoma, 103 patients with hyperplastic polyps, 568 normal participants (no evidence of disease), and 67 patients with other gastrointestinal diseases. Peripheral blood samples of these participants were collected from 3 Chinese hospitals, and the methylated SEPT9 level was measured using the Epi proColon 2.0 assay.Results:Cancer stage, size, and invasion depth were positively correlated with the detection sensitivity, while no difference in sensitivity was identified among cancers at various locations. Infiltrative colorectal cancer exhibited higher sensitivity than ulcerative and protrude colorectal cancer, while no difference in sensitivity was observed among assessed histological types. The colorectal cancer differentiation showed a clear correlation with the cancer stage, and moderate and poorly differentiated colorectal cancer exhibited higher sensitivity than well-differentiated colorectal cancer. Furthermore, colorectal cancer with distal metastasis (M1) showed higher sensitivity than those without any metastasis, while colorectal cancer with lymph node metastasis (N1 and N2) did not show statistical significance compared to those without it. Finally, local vessel or nerve invasion did not affect the sensitivity.Conclusion:Factors that reflect the colorectal cancer intrinsic properties, including cancer stage, size, invasion depth, classification, differentiation, and metastasis, exhibited significant effect on the mSEPT9 detection performance.
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