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Also, there are no second-line options in patients that progress after sorafenib. Indeed, we lack precise
knowledge of the molecular drivers responsible for tumor progression following resistance to sorafenib
that could potentially guide second-line drug development.Worldwide, HCC patients are still diagnosed
at intermediate-advanced stages with a median overall survival of less than two years. Also, co-occurrence
of HCC with underlying cirrhosis increases toxicity to systemic agents – further restricting the therapeutic
arsenal for patients with advanced HCC. In summary, despite advances in the last decade, there is still
a long way to go to improve outcomes in patients with HCC.
There are several reports on the association between HCC and T2DM, including evidence from
population-based studies and meta-analyses. The hazard ratio for HCC development among diabetics
ranges from 2-3. Indirect evidence has also underscored the potential protective effects of metformin in
HCC development. A nationwide, case-control Taiwanese study including almost 300,000 individuals
found a dose-dependent reduction in HCC risk in diabetics. Proposed mechanisms of action for
metformin include its ability to interfere with LKB1 via AMPK. NAFLD/NASH also interact with other
etiologies to increase the risk of HCC. Data from longitudinal studies, including close to 3,000 HBV
surface-antigen positive patients followed for a mean of 14 years, found an involvement of excess weight
and progression of HBV-related HCC development. There are also reports suggesting a contribution of
NAFLD/NASH to HCV hepatocarcinogenesis.
Molecular alterations and pathogenesis of NAFLD/NASH HCC
Numerous studies demonstrate how HCC can be classified based on common genomic traits identified
through whole-genome transcriptome profiling. These studies also enabled the generation of gene
signatures (i.e., combination of genes correlating with a specific phenotype) that correlate with patients’
outcome [2]. Most of these reports analysed samples from resected patients with underlying liver disease
due to either viral hepatitis or alcohol-related liver disease. Hence, there is limited information on the
genomic portrait of NAFLD/NASH HCC. There are some data on genetic risk of NAFLD/NASH
HCC. In 2008, a variant in the PNPLA3 gene was found to be strongly associated with NAFLD.
Subsequent studies suggested that this polymorphism could also be associated with NAFLD/NASH. A
case-control study that included 375 individuals found an adjusted OR of 2.26 for HCC development
in patients with NAFLD and the GG variant of PNPLA3. PNPLA3 is involved in hepatic triacylglycerol
metabolism.
There is also very limited information in terms of NAFLD/NASH and candidate oncodrivers, since
large deep-sequencing studies conducted so far mostly analysed viral hepatitis-related HCC. In these
studies, the most frequently mutated genes affected were TERT promoter (60%), TP53 (27%) and
CTNNB1 (26%) [3]. There are other less frequently mutated genes involved in chromatin remodelling
[ARID1A (6%), ARID2 (7%), MLL3 (3%)], growth factor signalling [RPS6KA3 (3%), RAS (2%)]
and oxidative stress [NFE2L2 (3%), KEAP1 (3%)]. These next-generation sequencing studies also
confirmed previously reported DNA copy number alterations with high-level amplifications affecting
chromosome 11q13 and chromosome 6p21. Potential candidate oncogenes in these regions include
FGF19, CCND1 and VEGFA.
Mechanisms for molecular pathogenesis of NAFLD/NASH HCC
Regarding molecular pathogenesis of NAFLD/NASH HCC, several mechanisms have been proposed
[4]. They can be broadly clustered in 3 major groups (Fig. 1):
1. Inflammation and microbiome: The association between chronic inflammation and cancer is well
established. A major player in this connection is the NF-kB signalling pathway. NF-kB is a master
regulator of inflammation, with a defined role in experimental HCC. In vivo de-regulation of essential
components of this pathway including IKK and NEMO induce NAFLD [5], fibrosis and ultimately
HCC. Global inhibition of NF-kB signalling protects mice from HCC development. An enrichment
of progenitor-cell derived tumors in some of these models has been suggested, but this has not been
confirmed in human NAFLD/NASH HCC. One of the potential mechanisms involved in hepatic
78 Postgraduate Course Syllabus • Metabolic Liver Disease
knowledge of the molecular drivers responsible for tumor progression following resistance to sorafenib
that could potentially guide second-line drug development.Worldwide, HCC patients are still diagnosed
at intermediate-advanced stages with a median overall survival of less than two years. Also, co-occurrence
of HCC with underlying cirrhosis increases toxicity to systemic agents – further restricting the therapeutic
arsenal for patients with advanced HCC. In summary, despite advances in the last decade, there is still
a long way to go to improve outcomes in patients with HCC.
There are several reports on the association between HCC and T2DM, including evidence from
population-based studies and meta-analyses. The hazard ratio for HCC development among diabetics
ranges from 2-3. Indirect evidence has also underscored the potential protective effects of metformin in
HCC development. A nationwide, case-control Taiwanese study including almost 300,000 individuals
found a dose-dependent reduction in HCC risk in diabetics. Proposed mechanisms of action for
metformin include its ability to interfere with LKB1 via AMPK. NAFLD/NASH also interact with other
etiologies to increase the risk of HCC. Data from longitudinal studies, including close to 3,000 HBV
surface-antigen positive patients followed for a mean of 14 years, found an involvement of excess weight
and progression of HBV-related HCC development. There are also reports suggesting a contribution of
NAFLD/NASH to HCV hepatocarcinogenesis.
Molecular alterations and pathogenesis of NAFLD/NASH HCC
Numerous studies demonstrate how HCC can be classified based on common genomic traits identified
through whole-genome transcriptome profiling. These studies also enabled the generation of gene
signatures (i.e., combination of genes correlating with a specific phenotype) that correlate with patients’
outcome [2]. Most of these reports analysed samples from resected patients with underlying liver disease
due to either viral hepatitis or alcohol-related liver disease. Hence, there is limited information on the
genomic portrait of NAFLD/NASH HCC. There are some data on genetic risk of NAFLD/NASH
HCC. In 2008, a variant in the PNPLA3 gene was found to be strongly associated with NAFLD.
Subsequent studies suggested that this polymorphism could also be associated with NAFLD/NASH. A
case-control study that included 375 individuals found an adjusted OR of 2.26 for HCC development
in patients with NAFLD and the GG variant of PNPLA3. PNPLA3 is involved in hepatic triacylglycerol
metabolism.
There is also very limited information in terms of NAFLD/NASH and candidate oncodrivers, since
large deep-sequencing studies conducted so far mostly analysed viral hepatitis-related HCC. In these
studies, the most frequently mutated genes affected were TERT promoter (60%), TP53 (27%) and
CTNNB1 (26%) [3]. There are other less frequently mutated genes involved in chromatin remodelling
[ARID1A (6%), ARID2 (7%), MLL3 (3%)], growth factor signalling [RPS6KA3 (3%), RAS (2%)]
and oxidative stress [NFE2L2 (3%), KEAP1 (3%)]. These next-generation sequencing studies also
confirmed previously reported DNA copy number alterations with high-level amplifications affecting
chromosome 11q13 and chromosome 6p21. Potential candidate oncogenes in these regions include
FGF19, CCND1 and VEGFA.
Mechanisms for molecular pathogenesis of NAFLD/NASH HCC
Regarding molecular pathogenesis of NAFLD/NASH HCC, several mechanisms have been proposed
[4]. They can be broadly clustered in 3 major groups (Fig. 1):
1. Inflammation and microbiome: The association between chronic inflammation and cancer is well
established. A major player in this connection is the NF-kB signalling pathway. NF-kB is a master
regulator of inflammation, with a defined role in experimental HCC. In vivo de-regulation of essential
components of this pathway including IKK and NEMO induce NAFLD [5], fibrosis and ultimately
HCC. Global inhibition of NF-kB signalling protects mice from HCC development. An enrichment
of progenitor-cell derived tumors in some of these models has been suggested, but this has not been
confirmed in human NAFLD/NASH HCC. One of the potential mechanisms involved in hepatic
78 Postgraduate Course Syllabus • Metabolic Liver Disease
