title: Identification of a metastasis-specific MicroRNA signature in human colorectal cancer.
abstract: 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 two-sided.
  
  
  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.
authors: Center for Gastrointestinal Research and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, TX (KH, YT, YO, CRB, AG); National Cancer Institute, National Institutes of Health, Bethesda, MD (AJS, CCH).
authors: Keun
authors: K
authors: Hur
authors: Center for Gastrointestinal Research and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, TX (KH, YT, YO, CRB, AG); National Cancer Institute, National Institutes of Health, Bethesda, MD (AJS, CCH).
authors: Yuji
authors: Y
authors: Toiyama
authors: Center for Gastrointestinal Research and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, TX (KH, YT, YO, CRB, AG); National Cancer Institute, National Institutes of Health, Bethesda, MD (AJS, CCH).
authors: Aaron J
authors: AJ
authors: Schetter
authors: Center for Gastrointestinal Research and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, TX (KH, YT, YO, CRB, AG); National Cancer Institute, National Institutes of Health, Bethesda, MD (AJS, CCH).
authors: Yoshinaga
authors: Y
authors: Okugawa
authors: Center for Gastrointestinal Research and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, TX (KH, YT, YO, CRB, AG); National Cancer Institute, National Institutes of Health, Bethesda, MD (AJS, CCH).
authors: Curtis C
authors: CC
authors: Harris
authors: Center for Gastrointestinal Research and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, TX (KH, YT, YO, CRB, AG); National Cancer Institute, National Institutes of Health, Bethesda, MD (AJS, CCH).
authors: C Richard
authors: CR
authors: Boland
authors: Center for Gastrointestinal Research and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, TX (KH, YT, YO, CRB, AG); National Cancer Institute, National Institutes of Health, Bethesda, MD (AJS, CCH). ajay.goel@baylorhealth.edu rickbo@baylorhealth.edu.
authors: Ajay
authors: A
authors: Goel
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000097:blood*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000097:blood* / Q000737:chemistry / Q000401:mortality / Q000556:secondary*; D016015:Logistic Models; D008297:Male; D035683:MicroRNAs / Q000032:analysis / Q000097:blood*; D008875:Middle Aged; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; C547183:MIRN10 microRNA, human; C525709:MIR221, human; C572916:MIRN320 microRNA, human; C574934:MIRN885 microRNA, human; C487931:mirnlet7 microRNA, human