This project will continue to focus on the identification of environmental risk factors for hepatocellular cancer (HCC) and the development of early biomarkers of disease. In ongoing studies, we demonstrated that, in conjunction with hepatitis B or C virus infection, elevated levels of biomarkers of aflatoxin B1 (AFB1) and polycyclic aromatic hydrocarbon (PAH) exposure and oxidative stress are associated with increased HCC risk in Taiwan. These studies are using cases and controls nested in the Cancer Screening Program (CSP) cohort established by our collaborator Dr. Chien-Jen Chen in Taiwan. A total of almost 24,000 subjects were recruited between 1990-1991 and by the end of the next grant period (July 2014), at least 700 HCC cases will have been identified. We will continue to determine levels of several biomarkers (AFB1- and PAH-albumin, urinary aflatoxin metabolites, 8-oxo-guanine and 15-F2t-isoprostane) in baseline samples from newly identified cases and controls in the CSP cohort. The larger sample size will provide more statistical power to test new hypotheses related to methylation and HCC risk. Repeat blood samples from this cohort have allowed us to demonstrate that gene-specific methylation of tumor DNA circulating in blood can be detected years prior to clinical diagnosis and that the frequency of methylation is significantly higher in those who go on to develop HCC than in those who do not. While these studies analyzed one candidate gene at a time, we now propose to use Illumina arrays interrogating 27,000 CpG sites to analyze liver tissues to more broadly select appropriate genes to improve screening. We will use our sample bank to assay paired tumor/adjacent tissues from Taiwan but also expand these studies to US HCC cases. Genes determined to be differentially methylated will be analyzed in DNA from plasma collected in the CSP cohort from cases prior to diagnosis and in controls to determine the predictive value of the methylation markers. We will use the same approach in US cases to determine whether plasma DNA methylation predicts recurrence in those undergoing surgery for HCC. We will also explore whether WBC DNA gene-specific methylation of these genes in baseline bloods predicts HCC risk within the CSP cohort. In addition to gene-specific methylation, it is now known that global methylation levels are decreased (hypomethylation) in tumors and several studies have now demonstrated decreased WBC DNA methylation in cases compared to controls. Thus, we propose to also investigate global methylation in tissue and WBC DNA, determining their correlation. We will determine whether global methylation is decreased in tumor compared to adjacent tissues and decreased in WBC DNA of cases compared to controls. We will also determine the correlations of methylation to biomarkers of environmental exposures. These studies will help in the identification of high risk individuals and development of screening methods.

Public Health Relevance

Understanding the role of environmental factors in development of HCC will assist in the identification of high risk populations that could be targeted for screening or prevention strategies. The development of screening methods for the early detection of disease in high risk populations will lead to better treatment and survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES005116-21
Application #
8208157
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Mcallister, Kimberly A
Project Start
1990-01-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
21
Fiscal Year
2012
Total Cost
$399,466
Indirect Cost
$151,350
Name
Columbia University (N.Y.)
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Wu, Hui-Chen; Wang, Qiao; Yang, Hwai-I et al. (2013) Global DNA methylation in a population with aflatoxin B1 exposure. Epigenetics 8:962-9
Shen, Jing; Wang, Shuang; Zhang, Yu-Jing et al. (2013) Exploring genome-wide DNA methylation profiles altered in hepatocellular carcinoma using Infinium HumanMethylation 450 BeadChips. Epigenetics 8:34-43
Sun, Hokeun; Wang, Shuang (2013) Network-based regularization for matched case-control analysis of high-dimensional DNA methylation data. Stat Med 32:2127-39
Shen, Jing; Wang, Antai; Wang, Qiao et al. (2013) Exploration of genome-wide circulating microRNA in hepatocellular carcinoma: MiR-483-5p as a potential biomarker. Cancer Epidemiol Biomarkers Prev 22:2364-73
Shen, Jing; Wang, Shuang; Zhang, Yu-Jing et al. (2012) Genome-wide DNA methylation profiles in hepatocellular carcinoma. Hepatology 55:1799-808
Sun, Hokeun; Wang, Shuang (2012) Penalized logistic regression for high-dimensional DNA methylation data with case-control studies. Bioinformatics 28:1368-75
Wu, Hui-Chen; Wang, Qiao; Yang, Hwai-I et al. (2009) Aflatoxin B1 exposure, hepatitis B virus infection, and hepatocellular carcinoma in Taiwan. Cancer Epidemiol Biomarkers Prev 18:846-53
Wang, Lin; Li, Haiyang; Zhang, Yujing et al. (2009) HINT1 inhibits beta-catenin/TCF4, USF2 and NFkappaB activity in human hepatoma cells. Int J Cancer 124:1526-34
Zhang, Yu-Jing; Li, Haiyang; Wu, Hui-Chen et al. (2009) Silencing of Hint1, a novel tumor suppressor gene, by promoter hypermethylation in hepatocellular carcinoma. Cancer Lett 275:277-84
Liu, Zhi-Ming; Li, Le-Qun; Peng, Min-Hao et al. (2008) Hepatitis B virus infection contributes to oxidative stress in a population exposed to aflatoxin B1 and high-risk for hepatocellular carcinoma. Cancer Lett 263:212-22

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