title: Development of a miR-26 companion diagnostic test for adjuvant interferon-alpha therapy in hepatocellular carcinoma.
abstract: OBJECTIVE
  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.
authors.affiliation: Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. jijun@mail.nih.gov
authors.forename: Junfang
authors.initials: J
authors.lastname: Ji
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Yu
authors.forename: Marshonna
authors.initials: M
authors.lastname: Forgues
authors.forename: Takahiro
authors.initials: T
authors.lastname: Uenishi
authors.forename: Shoji
authors.initials: S
authors.lastname: Kubo
authors.forename: Kenichi
authors.initials: K
authors.lastname: Wakasa
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.forename: Zhao-You
authors.initials: ZY
authors.lastname: Tang
authors.forename: Shijun
authors.initials: S
authors.lastname: Fu
authors.forename: Hongguang
authors.initials: H
authors.lastname: Zhu
authors.forename: Jason Gang
authors.initials: JG
authors.lastname: Jin
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Sun
authors.forename: Xin Wei
authors.initials: XW
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D016019:Survival Analysis
chemical_list: D007155:Immunologic Factors; D016898:Interferon-alpha; D035683:MicroRNAs; C528163:MIRN26 microRNA, human
keywords: adjuvant therapy; companion diagnostics.; hepatocellular carcinoma; interferon-alpha; miR-26