MicroRNA biomarkers predicting risk, initiation and progression of colorectal cancer

Table 1 Summary of experiments relevant to microRNA detection of colorectal cancer

miRNA	Sample size		Findings	Specimen type	Ref.
	Cases (n)	Controls (n)
miR-21 miR-106a miR-17 miR-143 miR-622 miR-654-3p	9 non-advanced adenomas and AA 10 CRC	10 controls (normal colonoscopy)	miR-21, miR-106a: Colorectal neoplasia (adenoma, CRC) patients had higher stool expression of these two miRNA compared to normal colonoscopy subjects (P < 0.05). Adenoma patients had higher stool miR-21 and miR-106a expression compared to CRC patients miR-17, miR-143, miR-622, miR-654-3p: No differences between groups	Stool	Link et al[23]
miR-21 miR-92a miR-31 miR-18a miR-106a	50 AA 200 CRC	80 controls (do not have a current or previous malignancy or inflammatory condition)	miR-21, miR-92a: miR-21 and miR-92a levels in CRC patients and AA patients were significantly higher compared to controls (all P < 0.05). miR-21 yielded an AUC of 0.709 in differentiating AA from controls. miR-92a yielded an AUC of 0.701 in differentiating AA from controls. Both miRNA together yielded an AUC of 0.722 in differentiating AA from controls miR-18a, miR-31, and miR-106a: No significant differences between groups	Serum	Liu et al[24]
miR-21 miR-31	43 AA 60 postoperative patients 186 CRC	53 controls (negative colonoscopic examination, no prior diagnosis of any other malignancy)	miR-21: Serum levels were increased in adenomatous polyp patients compared with controls (P < 0.001). Serum miR-21 levels yielded an AUC of 0.803 (95%CI: 0.669-0.869) in differentiating AA from controls. The sensitivity, specificity, positive predictive value and negative predictive values were 76.8 % and 81.1%, 76.7%, and 81.1%, respectively, at a cut-off value of 0.0013	Serum	Toiyama et al[25]
miR-92a miR-21	44 patients with minor polyp (defined as hyperplastic polyp or adenoma less than 1 cm in diameter) 13 AA 88 CRC	101 controls (asymptomatic individuals)	miR-92a: Stool miR-92a was significantly increased in polyp patients compared with controls (P < 0.0001). Sensitivity of 56.1% for polyp, specificity of 73.3%. Higher sensitivity for AA than minor polyps (P < 0.05). The removal of AA led to a decrease in stool miR-92a level (P < 0.05). miR-21: No difference between polyps and controls	Stool	Wu et al[26]
miR-29a, miR -106b, miR -133a, miR -342-3p, miR -532-3p miR-18a, miR -20a, miR -21, miR -92a, miR -143, miR -145, miR -181b	Marker validation phase 50 AA	Marker validation phase 50 controls (free of colorectal neoplasms)	No statistically significant differences between AA patients and controls for any of the investigated miRNA	Plasma	Luo et al[27]
miR-10a, miR-29a, miR-31, miR-92a, miR-100, miR-125b, miR-184, miR-187, miR-196a, miR-200b, miR-203, miR-17-3p	73 non-advanced adenoma 43 AA 8 CRC	48 controls (polyp-free)	No statistically significant associations with non-advanced adenoma or AA for any of the investigated miRNA	Plasma	Adams et al[28]
miR-34a miR-150 miR-923	Discovery set 8 polyp 16 adenoma 8 CRC (stage I/II) 8 CRC (stage III/IV)	Discovery set 8 controls	miR-34a: Validation cohort: Significantly higher in adenoma group compared to controls (FC 2.09, P = 0.028). Significantly higher in adenoma group compared to the polyp group (FC 2.71, P = 0.002). miR-923: Validation cohort: No significantly different levels	Plasma	Aherne et al[29]
	Validation set 20 polyp 20 adenoma 23 CRC (stage I/II) 14 CRC (stage III/IV)	Validation set 20 controls
miR-18a miR-15b miR-19a miR-19b miR-29a miR-335	Set 1 20 AA 21 CRC Set 2 40 AA 42 CRC	Set 1 20 controls Set 2 53 controls	miR-18a: Set 1 and Set 2: Significantly overexpressed in AA patients compared to controls in both sets. Set 1: Good discriminative capacity in AA patients (AUROC, 0.84; 95%CI: 0.72-0.96; sensitivity [S], 80%; specificity [Sp], 80%). Set 2: Lower discriminative capacity in AA patients (AUROC, 0.64; 95%CI: 0.52- 0.75; S, 72%; Sp, 57%)	Plasma	Giráldez et al[30]
miR-29a, miR-92a,	Large-scale validation 37 AA 100 CRC	Large-scale validation 59 controls (negative results of health examination including blood test, chest X-ray, abdominal ultrasound examination, fecal occult-blood testing, rectal touch, CT scan and colonoscopy. None of these controls had previously been diagnosed with any types of malignancy previously)	miR-29a and miR-92a: Significantly higher in AA compared to controls (P < 0.0001 for miR-29a, P < 0.0001 for miR-92a). Both miRNAs together yielded an AUC of 0.773 (95%CI: 0.669-0.877), sensitivity 73.0% and specificity 79.7%, in discriminating AA. miR-29a: Yielded an AUC of 0.769 (95%CI: 0.669-0.869) for differentiating AA from controls. The sensitivity was 62.2% and specificity 84.7%, at a cut-off value of 1.210 for miR-29a. The odds ratio for cases with miR-29a > 1.210 being associated with AA was 12.20 (95%CI: 4.350-34.237). miR-92a: Yielded an AUC of 0.749 (95%CI: 0.642-0.856) for differentiating AA from controls. Sensitivity 64.9% and specificity 81.4%, at a cut-off value of 1.682 for miR-92a. The odds ratio for cases with miR-92a > 1.682 being associated with AA was 4.56 (95%CI: 1.893-10.988)	Plasma	Huang et al[31]
A panel of 8 miRNAs miR-532-3p + miR-331 + miR-195 + miR-17 + miR-142-3p + miR-15b + miR-532 + miR-652	Initial Screening 9 adenoma 20 CRC (stage III/IV) Validation 16 adenoma 15 CRC (stage I/II) 15 CRC (stage III) 15 CRC (stage IV)	Initial Screening 12 controls (without CR neoplasia) Validation 26 controls (without CR neoplasia)	Initial Screening 15 out of 380 screened miRNAs most dys-regulated in plasma of adenoma patients compared to controls (P < 0.05, FDR: 5%). Validation A panel of 8 plasma miRNAs yielded an AUC of 0.868 (95%CI: 0.76-0.98), sensitivity 88% and specificity 64% in differentiating adenoma from controls	Plasma	Kanaan et al[32]
miR-601 miR-760	Large scale validation 43 AA 90 CRC	Large scale validation 58 controls	miR-601: AUC of 0.638, sensitivity of 72.1% and specificity of 51.7% in differentiating AA from controls miR-760: AUC of 0.682, sensitivity of 69.8% and specificity of 62.1% in differentiating AA from controls miR-601 + miR-760: Significantly decreased in colorectal neoplasia (AA and CRC) compared to controls. Both miRNAs together yielded AUC of 0.683, sensitivity 72.1% and specificity 62.1% in differentiating AA from controls	Plasma	Wang et al[33]
miR-135b miR-31	110 adenomas < 1 cm in size 59 AA 42 IBD 104 CRC	109 controls (normal colonoscopy)	miR-135b: Significantly increased in adenoma subjects (median, 28.4; IQR, 0.2-79.7; P < 0.0001) compared to controls (median, 0; IQR, 0-30.8). No significant difference in IBD subjects compared to controls. AUC of 0.71 for detection of adenoma. Sensitivity of 73% for AA, 61% for adenoma < 1 cm in diameter, 65% for any adenoma and specificity of 68%, at a cut-off of 14 copies/ng of stool RNA. Sensitivity of 44% for adenoma < 1 cm, 46% for AA, and specificity of 80%, at a cut-off of 38 copies/ng of stool RNA. Removal of AA or CRC resulted in a significant reduction of stool miR-135b. miR-31: No significant differences between groups	Stool	Wu et al[34]
miR-18a miR-221	151 adenoma 48 AA 198 CRC	198 controls (normal colonoscopy)	miR-18a, miR-221: No significant up-regulation in adenoma or AA	Stool	Yau et al[35]
A panel of 4 miRNAs miR-19a-3p + miR-223-3p + miR-92a-3p + miR-422a	Validation of the diagnostic performance of the miRNA panel: 73 adenoma 117 CRC	Validation of the diagnostic performance of the miRNA panel: 102 controls (healthy individuals seeking a routine health check- up)	Validation of the miRNA panel The miRNA panel yielded an AUC of 0.765 (95%CI: 0.669-0.845) in differentiating adenoma from controls	Serum	Zheng et al[36]

CRC: Colorectal cancer; AA: Advanced adenomas; IBD: Inflammatory bowel disease.