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Liu et al. Hepatoma Res 2020;6:42 I http://dx.doi.org/10.20517/2394-5079.2020.25 Page 5 of 12

It is suggested that for risk of AC/ALD-related HCC, PNPLA3 may be most relevant for the development
of steatosis and ALD/AC, and TM6SF2 and MBOAT7 contributing towards HCC through inflammation-
[51]
driven fibrosis . Intriguingly, SNPs reported so far in PNPLA3, HSD17B13, TM6SF2 and MBOAT7 as
being associated with AC/ALD are involved in lipid metabolism and processing, but their role in developing
AC-ALD and HCC is yet to be clarified. Further investigations are required into the contribution of genetic
factors individually and in combination with other variants, especially those influencing the effect on each
other, such as PNPLA3 and HSD17B13. Understanding the roles of SNPs in the biology of liver disease
is still in its infancy, and there is limited literature on specific functions of these recently identified SNPs.
Although some SNPs are shared among different etiologies of cirrhosis and HCC, the role or interaction
of these SNPs remains unclear in complex etiologies that co-exist with AC, such as viral hepatitis and
NAFLD-related HCC. Further investigations are required to delineate the contribution of these SNPs to
HCC development.

RISK STRATIFICATION FOR AC/ALD-RELATED HCC
Using a combination of genetic risk factors with other phenotypic/clinical risk factors has been explored
for the identification and stratification of patients for HCC development [46,48,52-56] . Using the rs378409 risk
variant in PNPLA3 in combination with other phenotype/clinical factors (BMI, age, sex) enabled HCC risk
[53]
stratification of low-, intermediate- and high-risk AC patients (hazard ratio (HR 4.3, 95%CI: 2.7-6.4) .
Similarly, a combination of the two genetic variants PNPLA3-G and TM6SF2-T was independently
[48]
associated with risk of HCC onset (HR 2.3, 95%CI: 1.5-3.4) . Furthermore, the same study also reported
that the number of HCC cases with carriage of both PNPLA3-G and TM6SF2-T risk alleles was significantly
higher than carriers of only one risk allele in either SNP.

Most recently, a combination of all reported SNPs in AC, rs738409 (PNPLA3), rs6834314 (HSD17B13),
rs58542926 (TM6SF2) and rs626283 (MBOAT7), when added to phenotypic factors (BMI, diabetes status,
wine and coffee consumption), performed better [area under the curve (AUC) 0.748, 95%CI: 0.721-
0.774], compared to only genetic factors (AUC 0.689, 95%CI: 0.660-0.717) or only phenotypic factors
[57]
(AUC 0.681, 95%CI: 0.651-0.710), in stratifying drinkers with AC from drinkers with no liver disease .
It is encouraging that combining information on genetic variants with other risk factors can improve the
identification of patients at risk. Furthermore, these genetic variants have also been shown to modulate
severity of NAFLD (and its progression to steatohepatitis, fibrosis and cirrhosis) which commonly co-exists
with alcoholic liver disease patients as “dual-etiology fatty liver disease” and accelerates liver injury [58,59] .

Recently, the approach of incorporating several genetic variants in a so-called polygenic risk score (PRS)
[60]
has been shown to be a successful strategy to improve the prediction of various complex phenotypes .
Thus, this method has been shown to outperform existing clinical models for the prediction of breast
cancer with personalized recommendation on screening . Of note, the addition of other risk factors
[61]
[62]
into a global predictive model improves the overall performances compared to PRS alone . At the
transcriptional level, gene expression signatures gathering several dozens of genes (i.e., Prosigna and
MammaPrint) have been included by the European Society for Medical Oncology to its clinical practice
guidelines as prognostic and predictive tools to determine the benefit from chemotherapy .
[63]
The use of PRS to predict HCC occurrence in AC-related HCC patients is emerging [52,64] . More specifically,
the prognostic performance of PRS including PNPLA3 rs738409 and TM6SF2 rs58542926 was higher than
when considering PNPLA3 and TM6SF2 variants alone [52,64] .

Several other SNPs have been identified as being associated with the risk of HCC, particularly with a viral
etiology, but the literature is sparse regarding genetic variants specifically in relation to alcohol-related
[68]
HCC. Similarly, contributions of molecular markers [65-67] , somatic mutations , chromosomal instability