Grant Number:	1U01CA320916-01 Interpret this number
Primary Investigator:	Wu, Hui-Chen
Organization:	Columbia University Health Sciences
Project Title:	Environment, Genetics, and Epigenetics of Hepatocellular Carcinoma Risk in the Us
Fiscal Year:	2026

Abstract Hepatocellular carcinoma (HCC) incidence in the US has tripled since the early 1980s. In particular, HCC incidence is increasing for non-viral HCC (those without a history of hepatitis B or hepatitis C infection). HCC is often diagnosed at advanced stages when treatments are not effective, leading to poor survival where 79% of those diagnosed with HCC die within five years. Moreover, recently, both globally and in the US, HCC etiology has shifted from viral to non-viral-related causes, and up to 40% of cases is unexplained by known risk factors. Thus, identifying novel risk factors contributing to the rising incidence and underlying molecular mechanisms is critical to reduce morbidity and mortality, particularly for non-viral HCC. Emerging research has shown that exposures to harmful environmental toxins and metals are positively associated with HCC risk in Asia and Africa. These environmental toxins are ubiquitous and increasingly prevalent in the US and may play an instrumental role in HCC risk. Yet, aflatoxin and inorganic arsenic, human carcinogens, have been largely unexplored with HCC risk in US populations. In addition, individual genetic predisposition to HCC may independently influence HCC risk and interact with environmental exposures to modify risk. Emerging evidence shows that these environmental exposures affect DNA methylation profiles in genes important for hepatocarcinogenesis. Thus, we hypothesize that DNA methylation could serve as an important susceptibility marker of HCC that could be used to identify at-risk individuals and provide important mechanistic clues to disease etiology. Given most research has focused on high-incidence countries with a strong viral HCC etiology, and exposure to harmful environmental toxins and metals are ubiquitous and increasingly prevalent in the US, we propose to fill the evidence gap on these associations in US populations and assess risk among groups disproportionately exposed to higher levels of exposure (e.g., low socioeconomic status) and HCC risk. We will conduct a comprehensive study of the effect of ubiquitous carcinogens including aflatoxin, arsenic and cadmium on HCC risk in the largest pooled, nested, case-control study (n=741 incident HCC cases and 741 individually matched controls) from four US-based prospective cohorts: the Multiethnic Cohort Study; Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; Sister Study; and Southern Community Cohort Study. We will evaluate the association between exposure to environmental carcinogens including aflatoxin and metal elements (Aim 1) with HCC risk. We aim to identify genetic variants of HCC in our diverse US populations and explore potential gene-environment interaction (Aim 2). In addition, we will conduct an epigenome-wide association study of HCC and evaluate the independent and mediational effect of DNA methylation on HCC risk (Aim 3). Led by a multidisciplinary team, this project will provide the most robust evidence on the role of carcinogen exposure levels on HCC risk and on relevant biological pathways involved in hepatocarcinogenesis to inform prevention strategies for this highly fatal disease.





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