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Page 4 of 15 Benhammou et al. Hepatoma Res 2020;6:35 I http://dx.doi.org/10.20517/2394-5079.2020.16

Table 2. Summary of NAFLD HCC polymorphisms
SNP Clinical significance Location (human Associated gene Role of the gene Ref.
chromosome)
rs738409 Associated with increased liver chr22:43928847 PNPLA3; Patatin- The PNPLA3 gene encodes Sookoian et al. [44]
C>G fat accumulation and a higher (GRCh38.p12) like phospholipase the protein Adiponutrin, Shen et al. [139]
risk for developing liver cirrhosis. domain-containing which is thought to help
Given the increased severity of protein 3 regulate the development
necroinflammation in GG sequence of adipocytes as well as
carriers, these individuals may be at lipogenesis and lipolysis in
higher risk for developing HCC the liver
rs58542926 Associated with an increased risk chr19:19268740 TM6SF2; The TM6SF2 gene is Kozlitina et al. [46]
C>T of developing diabetes and NAFLD. (GRCh38.p12) Transmembrane 6 involved in regulating liver Falleti et al. [47]
The polymorphism results in a loss Superfamily Member fat metabolism, lipoprotein Vespasiani-
of function and individuals with 2 secretion and hepatic lipid Gentilucci et al. [140]
the CT phenotype have a reduced droplet content
hepatic capability to secrete LDLs
and are at higher risk for developing
liver inflammation and potentially
HCC
rs641738 Associated with an increased risk of chr19:54173068 MBOAT7; The MBOAT7 gene Mancina et al. [48]
C>T hepatic fat accumulation, fibrosis, (GRCh38.p12) Membrane Bound encodes a protein known
and potentially HCC O-Acyltransferase as Lysophospholipid Luukkonen et al. [49]
Domain Containing 7 acyltransferase 7 that is Donati et al. [50]
involved in the re-acylation
of phospholipids as part of
the phospholipid remodeling
pathway
Sahasrabuddhe
NAFLD: nonalcoholic fatty liver disease; HCC: hepatocellular carcinoma; LDLs: low density lipoproteins

demonstrated that in a Northern European Caucasian cohort of patients with primary HCC attributed to
NAFLD, carriage of the PNPLA3 rs738409 polymorphism was associated with NAFLD fibrosis and HCC,
where GG carriers had a 5-fold increase in HCC (95%CI: 1.47-17.29) compared to CC carriers.

In subsequent studies, the transmembrane 6 superfamily member 2, TM6SF2 (rs58542926), followed
[46]
suit and was identified in an exome-wide association study of fatty liver and serum aminotransferases .
Although the association of TM6SF2 with NAFLD is well established, its association with HCC development
is disputed [45,47] . More recently, the MBOAT7 (Membrane Bound O-Acetyltransferase Domain Containing
7) variant rs641738 has also been associated with NAFLD and its histological severity [48,49] . An Italian study
[50]
of 132 NAFLD-associated HCC cases also linked the MBOAT4 variant to non-cirrhosis NAFLD HCC . In
[51]
another European study, Pelusi et al. identified rare variants of candidate genes (SMAD4, SQSTM1, TEL,
RB1, TSC1), including APOB (Apolipoprotein B) which is involved in very low-density lipoprotein secretion
and therefore export of lipids using whole exome sequencing methods. Noteworthy of these findings is the
common thread of lipid metabolism genes being identified in genetic NAFLD and NAFLD-related HCC
association studies. Although intrahepatic steatosis alone was thought to be benign and the hallmark of
NAFLD, lipid dysregulation may play an important role in promoting carcinogenesis independently of
NAFLD disease pathogenesis.

In addition to being at risk for NAFLD and NASH, Hispanic patients have been shown to be at risk
of NAFLD-associated HCC [22,52,53] , which has been attributed largely to an increase in the incidence of
[22]
cirrhosis . Similar to what has been reported in the literature, we found in our local cohort of 125 NAFLD-
associated HCC cases, of whom > 85% had histological data available for review, that of the 20% of patients
who did not have underlying cirrhosis or advanced fibrosis, none were of Hispanic background. However,
the remaining cohort that had NAFLD-associated HCC cases in cirrhotic livers was Hispanic (manuscript
submitted). Our findings and that of others suggest that although there are genetic predispositions to NAFLD
and NASH, NAFLD-associated HCC may have independent mechanisms other than those at play for
NAFLD disease progression and fibrosis. Further studies that are more inclusive of patients of non-European
descent are needed to determine if these associations remain true in other populations.