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Page 8 of 12 Liu et al. Hepatoma Res 2020;6:42 I http://dx.doi.org/10.20517/2394-5079.2020.25

CHALLENGES OF CURRENT RISK PREDICTION MODELS FOR ALCOHOL-RELATED HCC
Risk prediction for alcohol-related HCC has been critically missing in the past due to lack of reproducible
genetic studies. Recent discoveries on several genetic risk associations with AC have opened the field
for using this information for risk prediction, not only for cirrhosis but also for alcohol-related HCC in
patients with alcohol use problems.

The contribution of genetic variants, especially PNPLA3 rs738409, as potential predictors for AC-
related HCC has been frequently discussed mainly because ORs often are > 2, calculated in retrospective
[46]
cohorts . However, modest to large ORs and extreme statistical significance do not automatically imply
clinical relevance and other statistical metrics such as sensitivity, specificity and negative/positive predictive
[87]
values might be more relevant . Although variants in PNPLA3, TM6SF2 and more recently HSD17B13
modulate the risk of AC-related HCC, the use of these variants in HCC surveillance programs is currently
not recommended [25,26] .

Even though predictive models for HCC have generally been successful, they have limited clinical utility
currently, especially the use of genetic-based factors identified in one ethnic population but used for
prediction in another population. Although recent use of PRS for identification/stratification of at-risk
patients is promising, one important limitation of PRS is their applicability in non-European ancestry
populations. Indeed, most of the variants used in PRS have been identified in GWAS overwhelmingly
[88]
conducted in individuals of European descent . Therefore, the applicability of current PRS is not
guaranteed . Failure to include individuals from diverse ancestry will hamper the use of PRS in the
[89]
[90]
multiethnic population seen in clinical practice . At the level of gene expression, a 186-gene signature,
initially developed to predict HCC recurrence in HCV-infected patients, has shown promising predictive
[91]
ability for hepatocarcinogenesis in AC patients .
A particular challenge with alcohol-related liver diseases, including HCC, is the complication of alcohol
dependence in these patients. Only select patients with alcohol-related HCC undergo liver transplantation
(LT). After LT, up to 50% of patients relapse to drinking with 20% returning to harmful drinking with
[92]
potential recurrence of liver disease . The heritability of alcohol dependence has previously been
estimated to be 25%-50%, and variants in genes encoding alcohol metabolism enzymes (ADH, ALDH)
[93]
and GABA neurotransmission (GABRA2) have been shown to be associated with alcohol misuse .
Whether these same markers can predict (beyond current clinical markers) recidivism post-LT is currently
unknown, so this presents an opportunity for further study. Transplanted patients identified to be at high
risk of relapse can be preferentially referred for participation in multidisciplinary relapse prevention
programs, which have been shown to be effective . The prediction of relapsers post-LT will be increasingly
[94]
important as transplant indications have recently expanded to include select patients with severe alcoholic
hepatitis without significant prior abstinence .
[95]
Overall, PRS and gene expression signatures in combination with environmental risk factors have the
potential to improve the prediction of alcohol-related HCC and pinpoint high-risk individuals. However,
to date, evidence of clinical usefulness in this field is lacking. Thus, before genetic variation/expression can
impact decision-making and be implemented in daily practice, it will need to be validated in large-scale
prospective cohorts evaluating their clinical utility and cost-effectiveness [89,96] . Moreover, many physicians
will require some training to interpret and communicate in a digestible manner the results of genetic
testing and its current limitations .
[97]

DECLARATIONS
Authors’ contributions
Led the overall concept, design, structure, writing, submission and revision of the manuscript in
consultation with all co-authors: Seth D