Identification of a Metastasis-Specific MicroRNA Signature in Human Colorectal Cancer
Authors: Keun Hur, Yuji Toiyama, Aaron J. Schetter, Yoshinaga Okugawa, Curtis C. Harris, C. Richard Boland, Ajay Goel
Journal: JNCI Journal of the National Cancer Institute (2015)

Background: Distant metastasis is the major cause of mortality in colorectal cancer (CRC).We performed a systemic, comprehensive discovery for expression patterns of metastasis-specific microRNAs (miRNAs) by directly comparing primary CRCs (pCRCs) and matched liver metastases (LMs) and evaluated the feasibility of their clinical application as metastasis-specific biomarkers.Methods: CRC metastasis-specific miRNA profiles were generated by analyzing nine pairs of pCRC and LM tissues, followed by quantitative validation in an independent cohort of 58 pairs of matched pCRC and LM tissues.We evaluated associations between miRNA expression and patient survival and ability to predict metastasis in another 84 patients with CRC.Subsequently, associations were quantitatively validated in 175 CRC tissues and 169 serum samples.Kaplan-Meier, Cox regression, and logistic regression analyses were used.All statistical tests were twosided.Results: Twenty-three miRNAs were identified that were differentially expressed between pCRC and LM (P < .001;FDR < .5).Four miRNAs downregulated in LM (let-7i, miR-10b, miR-221, and miR-320a) and one upregulated miR (miR-885-5p) were quantitatively validated in pCRC (P < .0001).Low let-7i expression in pCRC tissue predicted worsened prognosis (hazard ratio [HR] = 5.0, 95% confidence interval [CI] = 1.0 to 24.4,P = .0479)as well as distant metastasis (odds ratio [OR] = 5.5, 95% CI = 1.1 to 26.8, P = .0334).High miR-10b expression in pCRC tissue independently predicted distant metastasis (OR = 4.9, 95% CI = 1.2 to 19.7, P = .0248).High serum miR-885-5p expression independently predicted prognosis (HR = 2.9, 95% CI = 1.1 to 7.5, P = .0323),LN metastasis (OR = 3.0, 95% CI = 1.3 to 7.2, P = .0116),and distant metastasis (OR = 3.1, 95% CI = 1.0 to 10.0, P = .0456),whereas tissue miR-885-5p expression did not.Expression patterns of miRNAs were confirmed by in situ hybridization. Conclusions:We discovered a metastasis-specific miRNA signature in pCRCs and discovered novel tissue-and serum-based CRC metastasis-specific miRNA biomarkers through intensive validation.These unique miRNAs may be clinically applicable to predict prognosis and distant metastasis in CRC.article * P values are paired t tests on the log2-transformed values of the NanoString expression data.FDR, Benjamini, and Hochberg False discovery rate based on the 219 miRNAs that passed the filtering criteria.CRC = colorectal cancer; FDR = false discovery rate; LM = liver metastasis; pCRC = primary CRC.article * All statistical tests were two-sided.CI = confidence interval; CRC = colorectal cancer; HR = hazard ratio; M stage = distant metastasis in Union for International Cancer Control classification; miRNA = microRNA; N stage = lymph node metastasis; OR = odds ratio; pCRC = primary CRC; T stage = tumor depth.article * All statistical tests were two-sided.CI = confidence interval; CRC = colorectal cancer; HR = hazard ratio; miRNA = microRNA; N stage = lymph node metastasis in Union for International Cancer Control classification; OR = odds ratio; T stage = tumor depth.