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Page 2 of 12 Liu et al. Hepatoma Res 2020;6:42 I http://dx.doi.org/10.20517/2394-5079.2020.25

rs378409 and TM6SF2 rs58542926 improved HCC prediction better than with either variant alone. Incorporating
new variants and risk factors has the potential to build better algorithms/models to predict onset, early diagnosis
and treatments for AC-related HCC. However, clinical usefulness of these approaches is yet to be determined.

Keywords: Alcohol-related cirrhosis, PNPLA3, HSD17B13, TM6SF2, risk prediction

INTRODUCTION
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, with increasing incidence
[1]
worldwide . Despite screening programs in high-risk populations, long-term outcome is poor with a
5-year survival of 18%, representing the world’s third most lethal cancer. More specifically, the World
[2]
Health Organization estimates that more than a million patients will die from liver cancer in 2030 .
In almost 90% of cases, HCC occurs in the context of chronic liver disease, in particular, on the background
[1,3]
of cirrhosis . The underlying chronic liver disease promoting liver carcinogenesis varies geographically .
[1]
In Asia and sub-Saharan Africa, HCC is mostly caused by hepatitis B virus infection, while in the United
States and Europe the current leading etiologies are hepatitis C virus (HCV) infection and alcohol-related
[4]
cirrhosis (AC) followed by non-alcohol-related fatty liver disease (NAFLD) . However, the advent of new
direct-acting antiviral agents is expected to control HCV-related HCC in upcoming years, and AC will
[1]
soon become the leading cause of HCC in most high-income countries . Clinical risk factors for HCC
[5-7]
occurrence include male gender, older age, severity of cirrhosis, obesity and presence of type 2 diabetes .
[6]
Clinical risk models have shown that the individual risk of HCC development is highly variable . In
addition, case-control and cancer database studies have highlighted the impact of ethnic background and
[8,9]
a significant familial clustering . For example, individuals of African and Hispanic ancestry are less likely
to undergo curative therapies . Overall, these observations strongly suggest that inherited genetic factors
[10]
contribute to hepatocarcinogenesis.

Here, we review the current literature on risk factors, with a particular focus on genetic risk variants for
alcohol-related HCC occurrence.

EPIDEMIOLOGY AND CHARACTERISTICS OF ALCOHOL-RELATED HCC
Alcohol-related HCC occurs infrequently in patients without pre-existing cirrhosis. Cirrhosis (of any
etiology) is the single biggest risk factor for HCC development [3,11,12] . The annual incidence of HCC in
[13]
patients with AC is nearly 3% . The risk of developing AC and HCC parallels the amount of alcohol
consumed daily and significantly increases above a threshold of 20 and 30 g for females and males,
respectively [14,15] . Heavy alcohol drinking of more than 80 g per day for longer than 10 years increases the
[16]
risk of HCC by 5-fold . More specifically, AC accounts for 30% of the global incidence of HCC and HCC-
[17]
related deaths, with marked geographical differences . In Europe, HCC occurrence on the background
of alcohol-related liver disease (ALD) varies from 20% in the south (e.g., Italy or Spain), to 63% in eastern
countries. In the United States, alcohol accounts for 13% to 23% of HCC cases. Finally, the prevalence of
alcohol-related HCC reaches 6% in the Middle East and 14% in North Africa [17,18] . The influence of alcohol
consumption has also been highlighted by the impact of alcohol withdrawal on HCC development. Thus, a
[19]
meta-analysis reported an annual reduction of HCC risk by 6%-7% .
However, only up to 10%-35% of excessive drinkers develop advanced fibrosis or cirrhosis and its associated
HCC risk . Interestingly, the role of alcohol consumption seems to be milder or even negligible compared
[20]
to other environmental factors in the setting of HCC occurring in a non-fibrotic liver. For example, a recent
case-control study observed that after adjustment of smoking habits and metabolic syndrome features,