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Liu et al. Hepatoma Res 2020;6:42 Hepatoma Research
DOI: 10.20517/2394-5079.2020.25

Review Open Access

Genetics of alcohol-related hepatocellular
carcinoma - its role in risk prediction

Ken Liu , Gontran Verset , Eric Trepo , Devanshi Seth 1,2,5
3,4
3,4
1,2
1 Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW 2006, Australia.
2 Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia.
3 Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de
Bruxelles, Brussels 1070, Belgium.
4 Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels 1070, Belgium.
5 Drug Health Services, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia.
Correspondence to: Dr. Devanshi Seth, Centenary Institute, Building 93, Missenden Road, Camperdown, NSW 2050, Australia.
E-mail: d.seth@sydney.edu.au
How to cite this article: Liu K, Verset G, Trepo E, Seth D. Genetics of alcohol-related hepatocellular carcinoma - its role in risk
prediction. Hepatoma Res 2020;6:42. http://dx.doi.org/10.20517/2394-5079.2020.25
Received: 12 Mar 2020 First Decision: 21 Apr 2020 Revised: 6 May 2020 Accepted: 14 May 2020 Published: 10 Jul 2020

Academic Editor: Darrell Crawford Copy Editor: Jing-Wen Zhang Production Editor: Jing Yu
Received: First Decision: Revised: Accepted: Published:

Science Editor: Copy Editor: Production Editor: Jing Yu Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, with increasing incidence
worldwide. Alcohol-related cirrhosis (AC) accounts for 30% of the global incidence of HCC and HCC-related
deaths. With the decline of hepatitis C virus (HCV) and decreasing HCV-related HCC, AC will soon become the
leading cause of HCC. Excess alcohol consumption (> 80 g per day for > 10 years) increases the risk of HCC by
5-fold. However, only up to 35% of excessive drinkers develop cirrhosis and its associated HCC risk. Individual
variation in susceptibility to HCC is known, but there is limited information to predict who among the patients
is at high risk of progressing to HCC. Clinical risk factors for HCC include male gender, older age, severity of
cirrhosis, obesity and presence of type 2 diabetes. In addition to ethnic variability in HCC risk, genetic variants
are known to alter the risk of alcohol-related HCC. For example, single nucleotide polymorphisms in PNPLA3
(rs738409, C>G) and TM6SF2 (rs58542926, C>T) increase the risk of AC-related HCC, whereas HSD17B13
(T>A) reduces the risk for HCC. Studies have also confirmed PNPLA3 and TM6SF2 to be independent risk factors
for AC-related (but not HCV-related) HCC. Combining genetic risk factors with phenotypic/clinical risk factors
has been explored for stratification of patients for HCC development. Risk allele rs378409-G in PNPLA3 when
combined with phenotypic/clinical risk factors (BMI, age, sex) has enabled HCC risk stratification of AC patients
into low-, intermediate- and high-risk subgroups. Similarly, a combination of the two genetic variants PNPLA3-G
and TM6SF2-T has been independently associated with risk of HCC onset. Using a polygenic risk score approach
of incorporating several genetic variants, prognostic performance of polygenic risk score that included PNPLA3

© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0
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