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Page 6 of 12 Liu et al. Hepatoma Res 2020;6:42 I http://dx.doi.org/10.20517/2394-5079.2020.25
[70]
[69]
and tumor microenvironment , and other regulatory components, such as mRNAs , noncoding
[73]
RNAs [65,71] , epigenetic [71,72] and mitoepigenetic factors influencing the risk of alcohol-related HCC are
few and overlap with other etiologies [69,71] . Last but not least, the role of the gut microbiota (fungi, bacteria
and viruses), is another emerging factor influencing disease risk in ALD and ALD-HCC [74,75] . The gut
microbiota also engages in alcohol metabolism, thereby altering the risk for ALD pathogenesis. Changes in
the gut microbiome significantly correlates with alcohol consumption in human and experimental models,
[74]
and there is evidence that alcohol and gut metabolites in ALD patients show carcinogenic effects ,
potentially increasing the risk of HCC.

Genomic studies have revealed several subclasses of HCC. Alcohol-related HCC is associated with
CTNNB1 mutations (WNT-β-catenin signalling pathway); however, direct translation of molecular HCC
subclasses into clinical management (i.e., personalized medicine) is yet to be achieved . The recent
[76]
success of checkpoint inhibitors in HCC has led to a renewed interest in immunological profiling of HCC
and opportunities for personalized medicine. Recently, Sia et al. analyzed the gene expression pattern
[77]
of inflammatory cells in HCCs of almost 1000 patients. The authors identified a novel molecular class
of tumors (in approximately 25% of patients) with an enriched inflammatory response characterized
by overexpression of immune-related genes and high expression of PD1 and PD-L1 which may predict
response to checkpoint inhibitor immunotherapy. A study by The Cancer Genome Atlas consortium
performed multi-platform integrative molecular subtyping on 196 HCCs and found a similar subset of
patients with high lymphocyte infiltration (in 22% of patients) . Of note, the authors showed that the
[78]
aforementioned CTNNB1 mutation was associated with a lack of immune infiltrate (so-called cold tumors),
which has been observed by others [78,79] . In a recent first report of prospective genotyping of advanced HCC
by next-generation sequencing, CTNNB1 mutations were associated with primary resistance to immune
checkpoint inhibitors . Patients exhibiting CTNNB1 mutations all had progressive disease as their best
[80]
response and a shorter median survival compared to those without mutations (9.1 months vs. 15.2 months,
respectively). Clearly, the immunological classification of alcohol-related HCCs will become increasingly
important as immune-based therapies are added to the limited therapeutic options for patients with
advanced disease.

With the discovery of new variants and risk factors, there is the potential to incorporate them for building
prediction algorithms/models for AC/ALD-HCC onset, early diagnosis and treatments.

CLINICAL APPLICATIONS OF RISK-STRATIFIED AC/ALD-HCC PATIENTS
In terms of clinical application, patients identified by the above genetic modifiers to be at high risk of
developing significant liver fibrosis may be prioritized for early referral to specialist care, with those at low
risk remaining in primary care. These select high-risk patients can then be linked with resource-intensive
multidisciplinary and evidence-based care involving hepatologists, psychiatrists, and addiction specialists
to maximize their chance of obtaining abstinence. Indeed, when prolonged abstinence is achieved, it has
been shown to lead to resolution of steatosis and inflammation and even fibrosis regression in some (but
not all) patients [81,82] . Specialist care can also facilitate access to closer monitoring of liver fibrosis using non-
invasive tests (e.g., transient elastography, magnetic resonance elastography) and prompt commencement
of HCC surveillance (discussed below) when patients are diagnosed with cirrhosis.

Risk stratification for HCC surveillance
Aside from the prediction of patients at risk of advanced fibrosis or cirrhosis, genetic variants (e.g.,
PNPLA3, TM6SF2 and HSD17B13) can also help predict HCC development. As mentioned, these genes
predisposing to alcohol-related HCC can be incorporated with other established risk factors for HCC
(e.g., male sex, age and obesity) into a validated scoring system to risk-stratify patients for tailored HCC
surveillance. Indeed, risk calculators for HCC development already exist for other liver diseases such as