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Aaron J. Schetter, PhD, MPH; Suet Yi Leung, MD; Jane J. Sohn, PhD; Krista A. Zanetti, PhD, MPH; Elise D. Bowman, MS; Nozomu Yanaihara, MD, PhD; Siu Tsan Yuen, MD; Tsun Leung Chan, MD; Dora L. W. Kwong, MD; Gordon K. H. Au, MD; Chang-Gong Liu, PhD; George A. Calin, MD, PhD; Carlo M. Croce, MD; Curtis C. Harris, MD

JAMA. 2008;299(4):425-436.

Context  MicroRNAs have potential as diagnostic biomarkers and therapeutic targets in cancer. No study has evaluated the association between microRNA expression patterns and colon cancer prognosis or therapeutic outcome.

Objective  To identify microRNA expression patterns associated with colon adenocarcinomas, prognosis, or therapeutic outcome.

Design, Setting, and Patients  MicroRNA microarray expression profiling of tumors and paired nontumorous tissues was performed on a US test cohort of 84 patients with incident colon adenocarcinoma, recruited between 1993 and 2002. We evaluated associations with tumor status, TNM staging, survival prognosis, and response to adjuvant chemotherapy. Associations were validated in a second, independent Chinese cohort of 113 patients recruited between 1991 and 2000, using quantitative reverse transcription polymerase chain reaction assays. The final date of follow-up was December 31, 2004, for the Maryland cohort and August 16, 2004, for the Hong Kong cohort.

Main Outcome Measures  MicroRNAs that were differentially expressed in tumors and microRNA expression patterns associated with survival using cancer-specific death as the end point.

RESULTS  Thirty-seven microRNAs were differentially expressed in tumors from the test cohort. Selected for validation were miR-20a, miR-21, miR-106a, miR-181b, and miR-203, and all 5 were enriched in tumors from the validation cohort (P < .001). Higher miR-21 expression was present in adenomas (P = .006) and in tumors with more advanced TNM staging (P < .001). In situ hybridization demonstrated miR-21 to be expressed at high levels in colonic carcinoma cells. The 5-year cancer-specific survival rate was 57.5% for the Maryland cohort and was 49.5% for the Hong Kong cohort. High miR-21 expression was associated with poor survival in both the training (hazard ratio, 2.5; 95% confidence interval, 1.2-5.2) and validation cohorts (hazard ratio, 2.4; 95% confidence interval, 1.4-3.9), independent of clinical covariates, including TNM staging, and was associated with a poor therapeutic outcome.

Conclusions  Expression patterns of microRNAs are systematically altered in colon adenocarcinomas. High miR-21 expression is associated with poor survival and poor therapeutic outcome.

Author Affiliations: Laboratory of Human Carcinogenesis, Center for Cancer Research (Drs Schetter, Sohn, Zanetti, Yanaihara, and Harris and Ms Bowman) and Cancer Prevention Fellowship Program, Office of Preventive Oncology (Drs Schetter and Zanetti), National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Departments of Pathology (Drs Leung, Yuen, and Chan) and Clinical Oncology (Drs Kwong and Au), University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong; Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Comprehensive Cancer Center, Columbus, Ohio (Drs Liu and Croce); and Department of Experimental Therapeutics, M. D. Anderson Cancer Center, Houston, Texas (Dr Calin).

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