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Grant Details

Grant Number: 5R21CA159047-02 Interpret this number
Primary Investigator: Yang, Hushan
Organization: Thomas Jefferson University
Project Title: Serum Microrna Signature as Prospective Hcc Biomarker in Hbv Patients
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): Worldwide, hepatocellular carcinoma (HCC) is the fifth most common solid malignancy and the third leading cause of cancer mortality. Hepatitis B virus (HBV) infection is the most prominent etiologic factor for HCC. The total number of patients with chronic HBV (CHB) infection is in excess of 400 million, over 5% of the world's population. However, only 20% of these patients eventually develop HCC, which underscores the importance of developing a clinically applicable risk assessment model in the prevention and mortality control of HBV- related HCC. MicroRNAs (miRNAs) belong to a class of noncoding small RNA molecules that regulate the expression of over one-third of all human genes, including many oncogenes and tumor suppressor genes. MiRNAs have been significantly associated with the etiology and clinical outcome of many tumors including HBV-related HCC. Several recent studies have demonstrated that in human serum, miRNAs are highly stable and constitute the major faction of small nucleic acids. This makes serum a valuable resource for miRNA- based biomarker research, especially in prospective studies that have been followed-up for extended time periods but only collected serum samples at the time of study initiation. Although serum miRNA expression signatures have been extensively used as biomarkers of clinical outcomes of various malignancies, to date, no studies have been reported on serum miRNA profile as the predictor of HCC risk in CHB patients. In this proposed study, we will employ a prospective case-control approach to systematically identify baseline (before anti-HBV treatment and cancer diagnosis) serum miRNA expression signatures that are associated with the risk of HCC. The specific aims are: 1. To identify miRNA expression signatures as predictors of HCC development in 510 CHB patients. This study will be conducted in a unique and highly homogenous Asian American population of patients with chronic HBV infection that are completely enrolled in the United States. The 510 patients are divided into two populations: a discovery population including 30 cases and 30 controls that will be analyzed using miRNA microarray, as well as an internal validation population including 150 cases and 300 controls that will be analyzed using quantitative real-time PCR. 2. To develop a multivariate risk assessment model to analyze the cumulative and interaction effects between miRNA expression profiles and other important risk factors that modulate CHB to HCC transformation. 3. To conduct exploratory bioinformatics analyses and construct an in silico network of genes potentially targeted by miRNAs. Our study is highly cost- effective in that it capitalizes upon an established biorepository of CHB and HCC patients. It is one of the first systematic evaluations of baseline serum miRNA expression profile as prospective predictor of HCC risk in CHB patients. The strict matching between cases and controls as well as the two-stage study design greatly increases the possibility of discovering the bona fide miRNAs. The bioinformatics analyses are likely to provide us with novel insights into the mechanism of miRNAs and target genes that are important in CHB to HCC transformation. Furthermore, this study will facilitate the further establishment of our population that includes a large number of cancer-free CHB patients. Many of these patients have multiple visits to our institute and are still under intensive treatment and follow-up, which will enable us to conduct longitudinal studies in the future to in-depth evaluate the effects of antiviral treatments and other factors on the risk of HCC risk CHB patients.

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Publications

Cancer driver gene discovery through an integrative genomics approach in a non-parametric Bayesian framework.
Authors: Yang H. , Wei Q. , Zhong X. , Yang H. , Li B. .
Source: Bioinformatics (Oxford, England), 2017-02-15; 33(4), p. 483-490.
PMID: 27797769
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Alterations of telomere length and mtDNA copy number are associated with overall survival in hepatocellular carcinoma patients treated with transarterial chemoembolization.
Authors: Bao D. , Ba Y. , Zhou F. , Zhao J. , Yang Q. , Ge N. , Guo X. , Wu Z. , Zhang H. , Yang H. , et al. .
Source: Cancer chemotherapy and pharmacology, 2016 10; 78(4), p. 791-9.
EPub date: 2016-08-24.
PMID: 27558242
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Prospective changes in global DNA methylation and cancer incidence and mortality.
Authors: Joyce B.T. , Gao T. , Zheng Y. , Liu L. , Zhang W. , Dai Q. , Shrubsole M.J. , Hibler E.A. , Cristofanilli M. , Zhang H. , et al. .
Source: British journal of cancer, 2016-08-09; 115(4), p. 465-72.
EPub date: 2016-06-28.
PMID: 27351216
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Cell-free circulating mitochondrial DNA content and risk of hepatocellular carcinoma in patients with chronic HBV infection.
Authors: Li L. , Hann H.W. , Wan S. , Hann R.S. , Wang C. , Lai Y. , Ye X. , Evans A. , Myers R.E. , Ye Z. , et al. .
Source: Scientific reports, 2016-04-11; 6, p. 23992.
EPub date: 2016-04-11.
PMID: 27063412
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The Doylestown Algorithm: A Test to Improve the Performance of AFP in the Detection of Hepatocellular Carcinoma.
Authors: Wang M. , Devarajan K. , Singal A.G. , Marrero J.A. , Dai J. , Feng Z. , Rinaudo J.A. , Srivastava S. , Evans A. , Hann H.W. , et al. .
Source: Cancer prevention research (Philadelphia, Pa.), 2016 Feb; 9(2), p. 172-9.
EPub date: 2015-12-28.
PMID: 26712941
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CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Akt/mTOR/SREBP1c and P38/PPARα pathways.
Authors: Li J. , Huang Q. , Long X. , Zhang J. , Huang X. , Aa J. , Yang H. , Chen Z. , Xing J. .
Source: Journal of hepatology, 2015 Dec; 63(6), p. 1378-89.
EPub date: 2015-08-15.
PMID: 26282231
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ARID2, p110α, p53, and β-catenin protein expression in hepatocellular carcinoma and clinicopathologic implications.
Authors: You J. , Yang H. , Lai Y. , Simon L. , Au J. , Burkart A.L. .
Source: Human pathology, 2015 Jul; 46(7), p. 1068-77.
PMID: 26284269
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Circulating mitochondrial DNA content associated with the risk of liver cirrhosis: a nested case-control study.
Authors: Wang C. , Hann H.W. , Hann R.S. , Wan S. , Myers R.E. , Ye Z. , Xing J. , Yang H. .
Source: Digestive diseases and sciences, 2015 Jun; 60(6), p. 1707-15.
EPub date: 2015-01-15.
PMID: 25588520
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AT-rich interactive domain 2, p110α, p53, and β-catenin protein expression in hepatocellular carcinoma and clinicopathologic implications.
Authors: You J. , Yang H. , Lai Y. , Simon L. , Au J. , Burkart A.L. .
Source: Human pathology, 2015 Apr; 46(4), p. 583-92.
EPub date: 2015-01-14.
PMID: 25701229
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Network-based stratification analysis of 13 major cancer types using mutations in panels of cancer genes.
Authors: Zhong X. , Yang H. , Zhao S. , Shyr Y. , Li B. .
Source: BMC genomics, 2015; 16 Suppl 7, p. S7.
EPub date: 2015-06-11.
PMID: 26099277
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Polymorphisms in Genes of Tricarboxylic Acid Cycle Key Enzymes Are Associated with Early Recurrence of Hepatocellular Carcinoma.
Authors: Wan S. , Wu Y. , Zhou X. , Chen Y. , An J. , Yu X. , Zhang H. , Yang H. , Xing J. .
Source: PloS one, 2015; 10(4), p. e0124471.
EPub date: 2015-04-20.
PMID: 25894340
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Aspartate aminotransferase to platelet ratio index as a prospective predictor of hepatocellular carcinoma risk in patients with chronic hepatitis B virus infection.
Authors: Hann H.W. , Wan S. , Lai Y. , Hann R.S. , Myers R.E. , Patel F. , Zhang K. , Ye Z. , Wang C. , Yang H. .
Source: Journal of gastroenterology and hepatology, 2015 Jan; 30(1), p. 131-138.
PMID: 24995497
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Genetic variants in genes of tricarboxylic acid cycle key enzymes predict postsurgical overall survival of patients with hepatocellular carcinoma.
Authors: Du X. , Wan S. , Chen Y. , Qu P. , Huang X. , Yu X. , Yang H. , Zhang Y. , Xing J. .
Source: Annals of surgical oncology, 2014 Dec; 21(13), p. 4300-7.
EPub date: 2014-08-01.
PMID: 25081338
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CD147 promotes reprogramming of glucose metabolism and cell proliferation in HCC cells by inhibiting the p53-dependent signaling pathway.
Authors: Huang Q. , Li J. , Xing J. , Li W. , Li H. , Ke X. , Zhang J. , Ren T. , Shang Y. , Yang H. , et al. .
Source: Journal of hepatology, 2014 Oct; 61(4), p. 859-66.
EPub date: 2014-05-05.
PMID: 24801417
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Post-diagnosis hemoglobin change associates with overall survival of multiple malignancies - results from a 14-year hospital-based cohort of lung, breast, colorectal, and liver cancers.
Authors: Wan S. , Lai Y. , Myers R.E. , Li B. , Palazzo J.P. , Burkart A.L. , Chen G. , Xing J. , Yang H. .
Source: BMC cancer, 2013-07-10; 13, p. 340.
EPub date: 2013-07-10.
PMID: 23841898
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Profiling HBV integrations in hepatocellular carcinoma.
Authors: Wan S. , Civan J. , Rossi S. , Yang H. .
Source: Hepatobiliary surgery and nutrition, 2013 Apr; 2(2), p. 124-6.
PMID: 24570928
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Predictive value of alpha-fetoprotein in the long-term risk of developing hepatocellular carcinoma in patients with hepatitis B virus infection--results from a clinic-based longitudinal cohort.
Authors: Hann H.W. , Fu X. , Myers R.E. , Hann R.S. , Wan S. , Kim S.H. , Au N. , Xing J. , Yang H. .
Source: European journal of cancer (Oxford, England : 1990), 2012 Oct; 48(15), p. 2319-27.
EPub date: 2012-03-19.
PMID: 22436980
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Telomere length in circulating serum DNA as a novel non-invasive biomarker for cirrhosis: a nested case-control analysis.
Authors: Wan S. , Hann H.W. , Myers R.E. , Fu X. , Hann R.S. , Kim S.H. , Tang H. , Xing J. , Yang H. .
Source: Liver international : official journal of the International Association for the Study of the Liver, 2012 Sep; 32(8), p. 1233-41.
EPub date: 2012-04-04.
PMID: 22471856
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Relative telomere length: a novel non-invasive biomarker for the risk of non-cirrhotic hepatocellular carcinoma in patients with chronic hepatitis B infection.
Authors: Fu X. , Wan S. , Hann H.W. , Myers R.E. , Hann R.S. , Au J. , Chen B. , Xing J. , Yang H. .
Source: European journal of cancer (Oxford, England : 1990), 2012 May; 48(7), p. 1014-22.
EPub date: 2012-03-21.
PMID: 22444598
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Comprehensive analysis of common serum liver enzymes as prospective predictors of hepatocellular carcinoma in HBV patients.
Authors: Hann H.W. , Wan S. , Myers R.E. , Hann R.S. , Xing J. , Chen B. , Yang H. .
Source: PloS one, 2012; 7(10), p. e47687.
EPub date: 2012-10-24.
PMID: 23112834
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