Prospective evidence of a circulating microRNA signature as a non-invasive marker of hepatocellular carcinoma in HBV patients
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Chun Wang1,2,*, Hie-Won Hann3,*, Zhong Ye1,*, Richard S. Hann3, Shaogui Wan1,4, Xishan Ye1, Peter D. Block1, Bingshan Li5, Ronald E. Myers1, Xiaowei Wang6, Hee-Soon Juon1, Jesse Civan3, Mimi Chang7, Ho S. Bae7, Jinliang Xing8, Hushan Yang1
1Division of Population Science, Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
2Department of Environmental Health, School of Public Health, Nantong University, Nantong, Jiangsu 226000, China
3Liver Disease Prevention Center, Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA
4Institute of Pharmacy, Pharmaceutical College, Henan University, Kaifeng, Henan 475004, China
5Center for Human Genetics Research, Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37232, USA
6Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, USA
7Asian Pacific Liver Center, Saint Vincent Medical Center, Los Angeles, CA 90057, USA
8Experimental Teaching Center, School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China
*These authors have contributed equally to this work
Hushan Yang, e-mail: email@example.com
Keywords: hepatocellular carcinoma, risk, microRNA, serum
Received: December 15, 2015 Accepted: May 4, 2016 Published: May 24, 2016
The predictive value of circulating microRNAs (miRNAs) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) has been demonstrated in retrospective studies, but it has rarely been tested in prospective studies. In a cohort of 373 cancer-free HBV patients with a median follow-up of 4.5 years, we measured the expression of 24 retrospectively identified HCC-related miRNAs in baseline serum samples. When we analyzed the prospective associations of miRNA expression with HCC risk using the Cox proportional hazards model, we found that 15 of the 24 miRNAs exhibited a significant association with HCC risk. In particular, 7 miRNAs (miR-122, miR-99a, miR-331, miR-125b, miR-23b, miR-92a, and miR-26a) were associated with an increased risk, and 8 miRNAs (miR-652, miR-23a, miR-27a, miR-34a, miR-145, miR-10a, miR-150, and let-7f) were associated with a decreased risk. Compared to HBV patients with a low miRNA-based risk score, those with a high miRNA-based risk score exhibited a significantly elevated HCC risk in both univariate (hazard ratio [HR] 6.56, 95% confidence interval [CI] 2.74-15.70) and multivariate (HR 3.57, 95% CI 1.34-9.48) analyses. The risk score significantly increased the HCC prediction performance of alpha-fetoprotein (concordance index increased from 0.68 to 0.82, P < 0.0001). In silico analyses indicated that the genes targeted by the 15 miRNAs are mainly enriched in the transforming growth factor-beta signaling pathway. Collectively, these results provide prospective evidence that circulating miRNAs serve as non-invasive markers for risk prediction of HCC in HBV patients.
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