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Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study
  1. Angela M Liu1,2,3,4,
  2. Tzy-Jyun Yao5,
  3. Wei Wang2,
  4. Kwong-Fai Wong2,
  5. Nikki P Lee1,
  6. Sheung Tat Fan1,
  7. Ronnie T P Poon1,
  8. Chunfang Gao6,
  9. John M Luk1,2,3,4,7
  1. 1Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
  2. 2Department of Pharmacology, National University of Singapore, Singapore, Singapore
  3. 3Department of Surgery, National University of Singapore, Singapore, Singapore
  4. 4Cancer Science Institute, National University of Singapore, Singapore, Singapore
  5. 5Clinical Trials Center, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
  6. 6Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
  7. 7Roche R&D Center (China) Ltd., Department of Oncology, Shanghai, China
  1. Correspondence to Dr Chunfang Gao; gaocf1115{at}163.com Dr John M Luk; john.luk{at}roche.com

Abstract

Objective Serum α-fetoprotein (AFP) is the most commonly used biomarker for screening hepatocellular carcinoma (HCC) but fails to detect about half of the patients. Thus, we investigated if circulating microRNAs (miRNAs) could outperform AFP for HCC detection.

Design A retrospective cohort study.

Setting Two clinical centres in China.

Participants The exploration phase included 96 patients with HCC who received primary curative hepatectomy, and the validation phase included 29 hepatitis B carriers, 57 patients with HCC and 30 healthy controls.

Main outcome measures Expression of miRNAs was measured by real-time quantitative reverse transcription–PCR. Areas under receiver operating characteristic curves were used to determine the feasibility of using serum miRNA concentration as a diagnostic marker for defining HCC. A multivariate logistic regression analysis was used to evaluate performances of combined serum miRNAs.

Results In the exploration phase, miRNA profiling on resected tumour/adjacent non-tumour tissues identified miR-15b, miR-21, miR-130b and miR-183 highly expressed in tumours. These miRNAs were also detectable in culture supernatants of HCC cell lines and in serum samples of patients. Remarkably, these serum miRNAs were markedly reduced after surgery, indicating the tumour-derived source of these circulating miRNAs. In a cross-centre validation study, combined miR-15b and miR-130b demonstrated as a classifier for HCC detection, yielding a receiver operating characteristic curve area of 0.98 (98.2% sensitivity and 91.5% specificity). The detection sensitivity of the classifier in a subgroup of HCCs with low AFP (<20 ng/ml) was 96.7%. The classifier also identified early-stage HCC cases that could not be detected by AFP.

Conclusion The combined miR-15b and miR-130b classifier is a serum biomarker with clinical value for HCC screening.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

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Footnotes

  • To cite: Liu AM, Yao T-J, Wang W, et al. Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study. BMJ Open 2012;2:e000825. doi:10.1136/bmjopen-2012-000825

  • Contributors AML: experimental design, experimental performance, analysis of data and drafting of the manuscript; T-JY: statistical analysis and revision of the manuscript; WW: experimental performance; K-FW: drafting and revision of the manuscript; NPL: revision of the manuscript and material support; STF: acquisition of clinical samples and revision of the manuscript; RTPP: acquisition of clinical samples and study supervision; CG: acquisition of clinical samples and revision of the manuscript; JML: study design, study supervision and revision of the manuscript.

  • Funding The research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional data available.

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