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protein p53 (TP53), catenin (cadherin-associated were mutated in over 10% HCC specimens, [13,14]
protein) beta 1 (β-catenin, CTNNB1), and AT-rich similar to previous reports, confirming the important
interactive domain-containing protein 2 (ARID2), with role of chromatin-remodeling in the pathogenesis
mutation frequency over 15%. [2-4] Other mutated genes of HCC. In addition, Janus kinase 1 (JAK1) mutation
such as SMAD2/SMAD4 in the transforming growth was identified with mutation rate of 9.1% through
factor beta (TGF-β) pathway, caspase 8 (CASP8), and the whole-genome sequencing of 88 HCC cases,
Kruppel-like factor 6 were identified with mutation and the JAK/STAT pathways were altered in 45.5%
frequency around 10% in HCC, [5-7] while most other of cases, inconsistent with a previous study which
[2]
mutated genes were identified with relatively low reported low frequency (1/84, 1.2%) of JAK1 mutation
frequency of < 10% in HCC. Germline mutations in HCC, implying that the JAK/STAT pathways may
[2]
[15]
in the TP53 gene have been identified in patients act as major oncogenic drivers in HCC. However, the
with Li-Fraumeni syndrome, which is an inherited fact that the most frequently mutated genes were
cancer predisposition syndrome characterized by generally previously reported, and that few novel
[8]
a wide spectrum of neoplasms. Somatic TP53 mutated genes with high mutation frequencies were
mutations were identified in virtually any tumor identified by whole-genome sequencing suggests the
type including HCC, particularly following exposure complexity regarding the role of genetic mutations
to aflatoxin. [9,10] According to the IARC database, in the pathogenesis of HCC.
1840 TP53 somatic mutations have been identified
in 31.19% of liver cancer cases (IARC TP53 Database It has been reported that genomic instability is a
R17, http://p53.iarc.fr/). The mutation of β-catenin characteristic of most cancers. Genomic instability
gene in WNT/CTNNB1 pathway has been identified results from mutations in DNA repair genes and
in HCC with a frequency of 15.9%, which can lead to drives cancer development in hereditary cancers.
the activation of CTNNB1 gene with the consequence However, in sporadic cancers, previous studies
of overexpression and accumulation of β-catenin. and recent high-throughput sequencing studies
[3]
ARID2 is a subunit of the PBAF chromatin-remodeling suggested that mutations in DNA repair genes
complex, which facilitates ligand-dependent were infrequent. Instead, the mutation patterns of
transcriptional activation by nuclear receptors. In the the tumor suppressor TP53, ataxia telangiectasia
United States and Europe, 18.2% of HCV-associated mutated (ATM), and cyclin-dependent kinase
HCC cases were identified with ARID2-inactivating inhibitor 2A (CDKN2A) support the oncogene-induced
[4]
mutations. However, studies have also reported DNA replication stress model, which attributes
mutation frequencies of approximately 5-10% for genomic instability and TP53 and ATM mutations
ARID2 in HCC and truncation of ARID2 leads to loss of to oncogene-induced DNA damage, that is, high
protein function and chromatin dysregulation. [4,11,12] frequency of TP53 mutations in human cancers could
be in response to oncogene-induced DNA damage.
[16]
With the development of whole-genome sequencing The hypothesis was confirmed by several studies
technology, the next generation sequencing of showing that deletion of the TP53 gene in mouse
genome DNA provides the possibility that more novel models and human cells did not lead to aneuploidy,
genetic and genomic alterations may be discovered and that in human precancerous lesions, genomic
and may provide new insights for understanding instability was present before the establishment
the pathogenesis of HCC. However, several recent of TP53 mutations. [17-19] Consistent with the above
studies using next generation sequencing for analysis studies, previous studies and recent whole-genome
of mutation in HCC showed that the most frequent sequencing of HCC also showed that mutations in
mutations with mutated rate over 10% were mainly DNA repair genes in HCC were infrequent, [2,13,14,20]
genes reported previously such as TP53, β-catenin, suggesting there may be similar mechanisms of
and genes of chromatin-remodeling complex genetic mutations in somatic HCC, that is, high
such as AT-rich interactive domain 1A (ARID1A) frequency of TP53 mutations and additional genetic
(14/110). [2,13,14] Only a few genes were identified mutations favoring cancer development in somatic
with mutation rates over 10%, for example, the low- HCC could be in response to oncogene-induced DNA
density lipoprotein receptor-related protein 1B gene, damage.
reported by Kan et al. to have a mutation rate of
[2]
11.4% in patients with family hypercholesterolemia. Single nucleotide polymorphism
Notably, several components of the chromatin- Single nucleotide polymorphism (SNP) is the most
remodeling complex, such as ARID1A and ARID2 common genetic variation in the human genome.

32 Hepatoma Research | Volume 2 | Issue 2 | February 29, 2016