Feasibility of Methylated CLIP4 in Stool for Early Detection of Colorectal Cancer: A Training Study in Chinese Population

Abstract

BackgroundEarly detection of colorectal cancer (CRC) and precancerous lesion is vitally important for mitigating CRC morbidity and mortality. Aberrant DNA methylations in certain promoter regions have been identified to be closely associated with CRC development and progression, suggesting their potential as diagnostic biomarkers for early detection. In this study, we evaluated the performance of methylated CLIP4 in stool specimens as a potential biomarker for CRC detection.MethodsA total of 321 subjects out of 365 enrolled participants were included in the final analysis, including 154 CRC patients, 23 advanced adenoma (AA) patients, 49 small polyp (SP) patients, and 95 healthy controls. CLIP4 methylation level was examined by qPCR with bisulfite converted DNA purified from approximately 5 g stool specimen.ResultsMethylated CLIP4 test showed high sensitivities of 78.3% (95% CI: 55.8%–91.7%) and 90.3% (95% CI: 84.2%–94.3%) for detecting AA and CRC, respectively, with a specificity of 88.4% (95% CI: 79.8%–93.8%). CLIP4 methylation level discriminated AA and CRC patients from control subjects with area under the curve values of 0.892 (95% CI: 0.795–0.988) and 0.961 (95% CI: 0.938–0.983). Further analysis indicated no significant difference in sensitivities among different ages, genders, stages, locations, sides, tumor sizes and differentiation statuses.ConclusionsMethylated CLIP4 showed a strong potential as a noninvasive biomarker for early CRC detection.

Promising Epigenetic Biomarkers for the Early Detection of Colorectal Cancer: A Systematic Review

“…Recent studies have shown that methylated CAP-Gly domain containing linker protein family member 4—CLIP4, may be a potential biomarker for early detection of CRC. An mCLIP4 assay was carried out on stool and tissue samples, showing a sensitivity of 90.3% and specificity of 88.4% ( Figure 4 ) [ 72 , 78 ].…”

“… Sensitivities of stool mCLIP4 test in detecting different CRC stages (after Cao et al, 2021) [ 72 ]. …”

“…Several studies investigated potential new biomarkers in the early screening of colorectal cancer. As single biomarkers, CLIP4 was evaluated in one study [72], TWIST1 in three articles [73][74][75], and LINE-1 in two [76,77]. A panel of methylated biomarkers was also employed-C9orf50 was assessed together with CLIP4 and KCNQ5 [78], with TWIST1 [79] or just with KCNQ5 [80].…”

A Novel Plasma-Based Methylation Panel for Upper Gastrointestinal Cancer Early Detection

“…Although numerous non-invasive methods based on liquid biopsy biomarkers have been developed, most of these methods only targeted one cancer type [ 32 , 33 ]. As we all know, the cost of the current liquid biopsy method is still significantly higher than that of traditional serum tumor markers [ 34 ]; thus, it is difficult to apply those new methods in clinical practice in developing countries such as China. In this study, we detected three UGC types together for the first time and reacted the markers simultaneously in a single tube.…”

Coupling of serum CK20 and hyper-methylated CLIP4 as promising biomarker for colorectal cancer diagnosis: from bioinformatics screening to clinical validation

“…With systematic bioinformatics screening and clinical verification, our study showed that a combination of serum CK20 and hyper-methylated CLIP4 was a novel and effective biomarker for CRC diagnosis with 91.67% sensitivity and 82.54% specificity in the training cohort; and 95% sensitivity and 81.7% specificity in the validation cohort. It was more sensitive than CLIP4 hyper-methylated alone in stool specimens (90.3% sensitive, 88.4% specificity) [ 33 ]. Comparing with previous serum CRC biomarkers, CK20/hyper-methylated CLIP4 was more effective than CEA/MMP-7/TIMP-1 (sensitivity: 70.3%, specificity: 91.3%) [ 34 ], RUNX3/SFRP1/CEA (sensitivity 84.71%) [ 35 ], LRG1/EGFR/ITIH4/ HPX/SOD3 (sensitivity: over 70%, specificity: 89%) [ 36 ], anti-SLP2/-p53/-SEC61B/-PLSCR1 (sensitivity: 64.1%, specificity: 80%) [ 37 ], miR-203a-3p/miR-145-5p/miR-375-3p/miR-200c-3p (sensitivity: 81.52%, specificity: 73.33%) [ 38 ], miR-144-3p/miR-425-5p/miR-1260b (sensitivity: 93.8%, specificity: 91.3%) [ 39 ], and less than CCL20/IL-17A (sensitivity: 96.1%, specificity: 96.5%) [ 40 ].…”