A Highly Predictive Model for Diagnosis of Colorectal Neoplasms Using Plasma MicroRNA: Improving Specificity and Sensitivity.

OBJECTIVE: To develop a plasma-based microRNA (miRNA) diagnostic assay specific for colorectal neoplasms, building upon our prior work. BACKGROUND: Colorectal neoplasms [colorectal cancer (CRC) and colorectal advanced adenoma (CAA)] frequently develop in individuals at ages when other common cancers also occur. Current screening methods lack sensitivity, specificity, and have poor patient compliance. METHODS: Plasma was screened for 380 miRNAs using microfluidic array technology from a "Training" cohort of 60 patients, (10 each) control, CRC, CAA, breast cancer, pancreatic cancer, and lung cancer. We identified uniquely dysregulated miRNAs specific for colorectal neoplasia (P < 0.05, false discovery rate: 5%, adjusted α = 0.0038). These miRNAs were evaluated using single assays in a "Test" cohort of 120 patients. A mathematical model was developed to predict blinded sample identity in a 150 patient "Validation" cohort using repeat-sub-sampling validation of the testing dataset with 1000 iterations each to assess model detection accuracy. RESULTS: Seven miRNAs (miR-21, miR-29c, miR-122, miR-192, miR-346, miR-372, and miR-374a) were selected based upon P value, area under the curve (AUC), fold change, and biological plausibility. Area under the curve (±95% confidence interval) for "Test" cohort comparisons were 0.91 (0.85-0.96) between all neoplasia and controls, 0.79 (0.70-0.88) between colorectal neoplasia and other cancers, and 0.98 (0.96-1.0) between CRC and colorectal adenomas. In our "Validation" cohort, our mathematical model predicted blinded sample identity with 69% to 77% accuracy, 67% to 76% accuracy, and 86% to 90% accuracy for each comparison, respectively. CONCLUSIONS: Our plasma miRNA assay and prediction model differentiate colorectal neoplasia from patients with other neoplasms and from controls with higher sensitivity and specificity compared with current clinical standards.

A plasma microRNA panel for detection of colorectal adenomas: a step toward more precise screening for colorectal cancer.

OBJECTIVE: The main objective of this study was to investigate the potential use of circulating microRNAs (miRNAs) as biomarkers of colorectal (CR) adenomas. BACKGROUND: Detection of precancerous lesions such as CR adenoma is a key to reduce CR cancer (CRC) mortality. There is a great need for accurate, noninvasive biomarkers for detection of CR adenoma and CRC. MiRNAs are non-protein-coding RNAs that regulate gene expression. Our prior work investigated the dysregulation of 5 plasma miRNAs in CRC patients. As intended, we undertook a more comprehensive plasma-miRNA screening study in patients with CR adenoma and CRC. METHODS: We screened for 380 plasma-miRNAs using microfluidic array technology (Applied BioSystems) in a screening cohort of 12 healthy controls, 9 patients with CR adenomas, and 20 patients with CRC. A panel of the most dysregulated miRNAs (P < 0.05, False Discovery Rate: 5%) was then validated in a blinded cohort of 26 healthy controls, 16 patients with large adenomas, and 45 patients with CRC. RESULTS: A panel of 8 plasma miRNAs (miR-532-3p, miR-331, miR-195, miR-17, miR-142-3p, miR-15b, miR-532, and miR-652) distinguished polyps from controls with high accuracy [area under curve (AUC) = 0.868 (95% confidence interval [CI]: 0.76-0.98)]. In addition, a panel of 3 plasma miRNAs (miR-431, miR-15b, and miR-139-3p) distinguished Stage IV CRC from controls with an [AUC = 0.896 (95% CI: 0.78-1.0)]. Receiver-operating-characteristic curves of miRNA panels for all CRC versus controls and polyps versus all CRC showed AUC values of 0.829 (95% CI: 0.73-0.93) and 0.856 (95% CI: 0.75-0.97), respectively. CONCLUSIONS: Plasma miRNAs are reliable, noninvasive, and inexpensive markers for CR adenomas. This miRNA panel warrants study in larger cohorts. Plasma-based assays could provide better screening compliance compared to fecal occult blood or endoscopic screening.