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Background: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Early detection of CRC can significantly reduce its mortality rate. Current method of CRC diagnosis relies on the invasive endoscopy. Non-invasive assays including fecal occult blood testing (FOBT) and fecal immunological test (FIT) are compromised by low sensitivity and specificity, especially at early stages. Thus, a non-invasive and accurate approach for CRC screening would be highly desirable. Results: A new qPCR-based assay combining the simultaneous detection of the DNA methylation status of ten candidate genes was used to examine plasma samples from 56 normal controls, 6 hyperplastic polys, 9 non-advanced adenomas (NAAs), 22 advanced adenomas (AAs) and 175 CRC patients, using 10 ng of cfDNA. We further built a logistic regression model for CRC diagnosis. We tested ten candidate methylation markers including twist1, vav3-as1, fbn1, c9orf50, sfmbt2, kcnq5, fam72c, itga4, kcnj12 and znf132. All markers showed moderate diagnostic performance with AUCs ranging from 0.726 to 0.815. Moreover, a 4-marker model, comprised of two previously reported markers (c9orf50 and twist1) and two novel ones (kcnj12 and znf132), demonstrated high performance for detecting colorectal cancer in an independent validation set (N = 69) with an overall AUC of 0.911 [95% confidence interval (CI) 0.834–0.988], sensitivity of 0.800 [95% CI 0.667–0.933] and specificity of 0.971 [95% CI 0.914–1.000]. The stage-stratified sensitivity of the model was 0.455 [95% CI 0.227–0.682], 0.667 [95% CI 0.289–1.000], 0.800 [95% CI 0.449–1.000], 0.800 [95% CI 0.449–1.000] and 0.842 [95% CI 0.678–1.000] for advanced adenoma and CRC stage I-IV, respectively. Conclusion: kcnj12 and znf132 are two novel methylation biomarkers for CRC diagnosis. The 4-marker methylation model provides a new non-invasive choice for CRC screening and interception. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Early detection of CRC can significantly reduce its mortality rate. Current method of CRC diagnosis relies on the invasive endoscopy. Non-invasive assays including fecal occult blood testing (FOBT) and fecal immunological test (FIT) are compromised by low sensitivity and specificity, especially at early stages. Thus, a non-invasive and accurate approach for CRC screening would be highly desirable. Results: A new qPCR-based assay combining the simultaneous detection of the DNA methylation status of ten candidate genes was used to examine plasma samples from 56 normal controls, 6 hyperplastic polys, 9 non-advanced adenomas (NAAs), 22 advanced adenomas (AAs) and 175 CRC patients, using 10 ng of cfDNA. We further built a logistic regression model for CRC diagnosis. We tested ten candidate methylation markers including twist1, vav3-as1, fbn1, c9orf50, sfmbt2, kcnq5, fam72c, itga4, kcnj12 and znf132. All markers showed moderate diagnostic performance with AUCs ranging from 0.726 to 0.815. Moreover, a 4-marker model, comprised of two previously reported markers (c9orf50 and twist1) and two novel ones (kcnj12 and znf132), demonstrated high performance for detecting colorectal cancer in an independent validation set (N = 69) with an overall AUC of 0.911 [95% confidence interval (CI) 0.834–0.988], sensitivity of 0.800 [95% CI 0.667–0.933] and specificity of 0.971 [95% CI 0.914–1.000]. The stage-stratified sensitivity of the model was 0.455 [95% CI 0.227–0.682], 0.667 [95% CI 0.289–1.000], 0.800 [95% CI 0.449–1.000], 0.800 [95% CI 0.449–1.000] and 0.842 [95% CI 0.678–1.000] for advanced adenoma and CRC stage I-IV, respectively. Conclusion: kcnj12 and znf132 are two novel methylation biomarkers for CRC diagnosis. The 4-marker methylation model provides a new non-invasive choice for CRC screening and interception. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the second leading malignancy worldwide. Accurate screening is pivotal to early CRC detection, yet current screening modality involves invasive colonoscopy while non-invasive FIT tests have limited sensitivity. We applied a DNA methylation assay to identify biomarkers for early-stage CRC detection, risk stratification and precancerous lesion screening at tissue level. A model of biomarkers SFMBT2, ITGA4, THBD and ZNF304 showed 96.1% sensitivity and 87.0% specificity in CRC detection, with 100.0% sensitivity for advanced precancerous lesion and stage I CRC. Performances were further validated with TCGA data set, which showed a consistent AUC of 0.99 and exhibited specificity against other cancer types. KCNJ12, VAV3-AS1 and EVC were further identified for stage stratification (stage 0-I versus stage II-IV), with AUC of 0.87, 83.0% sensitivity and 71.2% specificity. Additionally, dual markers of NEUROD1 and FAM72C showed 83.2% sensitivity and 77.4% specificity in differing non-advanced precancerous lesions from inflammatory bowel diseases. • Three sets of methylation markers for CRC management were identified at tissue level. • SFMBT2, ITGA4, THBD and ZNF304 were markers for early-stage CRC detection. • Methylation of KCNJ12, VAV3-AS1 and EVC were identified for CRC stage stratification. • NEUROD1 and FAM72C differentiated non-advanced precancerous lesions from IBD. [ABSTRACT FROM AUTHOR]