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Grant Details

Grant Number: 5R03CA153099-02 Interpret this number
Primary Investigator: Yang, Hushan
Organization: Thomas Jefferson University
Project Title: Inflammation Variants and Risk of Hepatocellular Carcinoma in Hbv Patients
Fiscal Year: 2011


Abstract

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the fifth most common solid malignancy and the third leading cause of cancer mortality worldwide. Chronic hepatitis B virus (HBV) infection is the most prominent established etiologic factor for HCC. Worldwide, there are over 400 million HBV patients, over 5% of the world's total population. However, only 20% of these patients eventually develop HCC. Previous studies have reported non- genetic predisposition factors for HCC. However, bona fide genetic determinants largely remain to be identified. This application builds on and seeks to further extend our previous studies on the molecular epidemiology of inflammation and immune response-related genes in cancer susceptibility. In the proposed study, our goal is to use a comprehensive pathway-based polygenic approach to identify genetic variations in inflammation and immune response-related genes that can be used to predict the risk of HCC in patients with chronic HBV infection. The efforts will be essential for our ultimate aim to build up an HCC risk assessment model that can be applied in clinical settings. Our specific aims are: 1. We will assess the genetic susceptibility of inflammation and immune response-related single nucleotide polymorphisms (SNPs) in the development of HCC in chronic HBV 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. 2. We will develop an exploratory multivariate risk assessment model that incorporates epidemiological, viral, clinical, and genetic factors to predict the risk of HCC in patients with chronic HBV infection. The significant SNPs identified in this study will become promising targets for independent validation, genetic fine-mapping, deep re-sequencing, and functional characterizations. The results of this study will help us further identify HBV patients and select those with the highest risk of malignant transformation to receive more intensive, targeted, and personalized interventions. In addition, our HBV patient population is still undergoing intensive follow-up and treatment. Therefore, we have a unique opportunity to develop this growing patient cohort into a clinic- based prospective longitudinal study to evaluate the antiviral treatment efficacy and other factors that influence HCC development in HBV patients. PUBLIC HEALTH RELEVANCE: Project Narrative About 20% of the 400 million patients worldwide infected with chronic hepatitis B virus (HBV) will develop hepatocellular carcinoma (HCC). Previous studies have identified non-genetic predisposition factors for HBV- induced HCC. However, bona fide genetic components contributing to HCC development in HBV patients largely remain to be identified. In this study, we aim to identify genetic variants in inflammation and immune response-related genes that are associated with the risk of HCC in chronic HBV patients. The incorporation of both genetic and non-genetic components will allow for further stratification of HBV patients and selection of those with the highest risk of malignant transformation to receive more intensive, targeted, and personalized preventive intervention.



Publications

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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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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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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Postoperative hyperphosphatemia significantly associates with adverse survival in colorectal cancer patients.
Authors: Ye Z. , Palazzo J.P. , Lin L. , Lai Y. , Guiles F. , Myers R.E. , Han J. , Xing J. , Yang H. .
Source: Journal of gastroenterology and hepatology, 2013 Sep; 28(9), p. 1469-75.
PMID: 23611210
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Preoperative platelet count associates with survival and distant metastasis in surgically resected colorectal cancer patients.
Authors: Wan S. , Lai Y. , Myers R.E. , Li B. , Hyslop T. , London J. , Chatterjee D. , Palazzo J.P. , Burkart A.L. , Zhang K. , et al. .
Source: Journal of gastrointestinal cancer, 2013 Sep; 44(3), p. 293-304.
PMID: 23549858
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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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Genetic polymorphisms in pre-microRNA genes as prognostic markers of colorectal cancer.
Authors: Xing J. , Wan S. , Zhou F. , Qu F. , Li B. , Myers R.E. , Fu X. , Palazzo J.P. , He X. , Chen Z. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2012 Jan; 21(1), p. 217-27.
EPub date: 2011-10-25.
PMID: 22028396
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