Development of a miR-26 companion diagnostic test for adjuvant interferon-alpha therapy in hepatocellular carcinoma

Int J Biol Sci. 2013;9(3):303-12. doi: 10.7150/ijbs.6214. Epub 2013 Mar 16.

Abstract

Background & aims: Adjuvant therapies for hepatocellular carcinoma (HCC) such as interferon-alpha are effective only in a subset of patients. Previously we found that HCC patients with low level of miR-26 have survival benefits from interferon-alpha. The purpose of this study is to develop a standardized miR-26 diagnostic test (referred as MIR26-DX) to assist identification of candidate HCC patients for adjuvant interferon-alpha therapy.

Methods: We developed a multiplex reverse-transcription quantitative polymerase-chain-reaction assay to determine the levels of two HCC-related miR-26 transcripts along with six small RNA reference transcripts. We evaluated archived paraffin-embedded tissues from three cohorts of HCC patients (n=248) who underwent radical resection at three different clinical centers. Fifty-two percent of them underwent adjuvant interferon-alpha therapy. We used Cox-Mantel log-rank test to evaluate patient survival.

Results: We found that the multiplexing assay was stable and reproducible regardless of differences in sample preparations and operators. We developed a matrix template and a scoring algorithm based on a training cohort (n=129) to assign HCC patients, and then applied the template in two test cohorts (n=119). The proportions of HCC patients assigned as low miR-26 by this algorithm were 68, 4, and 63 percent in the training cohort and two test cohorts, respectively. Consistently, HCC with low miR-26 had a favorable response to interferon-alpha with improved median overall survival (≥3 year).

Conclusions: MIR26-DX is a simple and reliable companion diagnostic test to select HCC patients for adjuvant interferon-alpha therapy.

Keywords: adjuvant therapy; companion diagnostics.; hepatocellular carcinoma; interferon-alpha; miR-26.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Chemotherapy, Adjuvant
  • Cohort Studies
  • Female
  • Humans
  • Immunologic Factors / therapeutic use*
  • Interferon-alpha / therapeutic use*
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Male
  • MicroRNAs / metabolism*
  • Middle Aged
  • Polymerase Chain Reaction / methods
  • Survival Analysis

Substances

  • Immunologic Factors
  • Interferon-alpha
  • MIRN26A microRNA, human
  • MicroRNAs