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Liu et al. Novel predictive and prognostic strategies of HBV-related HCC

Table 2: Important somatic mutations and related signaling pathways of hepatocellular carcinoma
Study Population and sequencing Etiology Mutation frequency Global gene mutation frequency of
of important genes
method
signaling pathways
n = 24 (training), Alcohol, CTNNB1 (32.8%), Wnt/β-catenin pathway (49.6%),
Guichard et al. [67] whole exome equencing; HBV, TP53 (20.8%), p53/cell cycle pathway (32.8%),
n = 125 (validation), HCV, ARID1A (16.8%), chromatin remodeling (22.4%),
Sanger sequencing NASH PIK3CA (1.6%) PI3K/Ras pathway (12.8%)
CTNNB1 (16.0%), Wnt/β-catenin pathway (62.5%),
n = 88, IL6R (26.0%), JAK/STAT pathway (45.5%),
Kan et al. [68] HBV
whole genome sequencing TP53 (35.2%), p53 pathway (43.2%),
AXIN1 (5.0%) Apoptosis (45.5%)
CTNNB1 (16%), Wnt/β-catenin pathway (31%),
TP53 (32%), p53 pathway (37%),
Ahn et al. [69] n = 231, HBV, CCND1 (5%), cell cycle pathway (23%),
whole exome sequencing HCV
RPS6KA3 (5%), PI3K/Ras pathway (12%),
ARID1A (7%) chromatin remodeling (34%)
CTNNB1 (31%), Wnt/β-catenin pathway (66%),
TP53 (31%), p53 signaling (72%),
Totoki et al. [70] n = 608, HBV, ARID2 (10%), chromatin remodeling (67%),
whole exome sequencing HCV NF1 (4%), PI3k/mTOR signaling (45%),
TERT (54%), telomere maintenance (68%),
NFE2L2 (5%) Nrf2/Keap1 pathway (19%)
Wnt/β-catenin pathway (54%),
CTNNB1 (37%), p53 pathway (49%),
TP53 (24%),
Alcohol, TERT (60%), telomere maintenance (60%),
Schulz et al. [71] n = 235, HBV, ARID1A (13%), PI3k/mTOR pathway (51%),
whole exome sequencing HCV, MAP kinase pathway (43%),
NASH ALB (13%), hepatic differentiation (34%),
AXIN1 (11%), epigenetic regulation (32%),
CDKN2A (9%)
chromatin remodeling (28%)
HBV: hepatitis B virus; HCV: hepatitis C virus; NASH: nonalcoholic steatohepatitis; CTNNB1: catenin beta 1; TP53: tumor suppressor
p53; ARID1A: AT rich interactive domain 1A; PIK3CA: phosphoinositide-3-kinase catalytic alpha polypeptide; IL6R: interleukin 6 receptor;
CCND1: cyclin D1; RPS6KA3: ribosomal protein S6 kinase polypeptide 3; ARID2: AT rich interactive domain 2; NF1: neurofibromin 1;
TERT: telomerase reverse transcriptase; NFE2L2: nuclear factor (erythroid-derived 2)-like 2; CDKN2A: cyclin-dependent kinase inhibitor
2A; JAK: Janus kinase; STAT: signal transducer and activator of transcription; MAP: methionine aminopeptidas
limits the application of a single mutation. For example, of cell cycle pathway which comprised 4 genes
RB1 somatic mutation can serve as an independent including RB1, MYC, CCND1, and RBL2. The total
predictor for poor cancer-specific survival (HR 2.5, mutation rate of those 4 genes were 23% and the
95% CI: 1.05-5.93, P = 0.038) and early recurrence signature was significantly associated with poor
(OR 3.93, 95% CI: 1.29-11.90, P = 0.015). But the cancer-specific and recurrence-free survival (P = 0.002
frequencies of RB1 somatic mutation were only 3.4% and P = 0.007, respectively). Therefore, it is promising
and 7% among different studies. [68,69] Similarly, somatic to use combo somatic mutations as predictive and
mutations of CDKN2A and FGF-CCND1 were proved prognostic biomarkers.
to be significantly associated with overall survival (P
-4
-6
= 3.0 × 10 and P = 7.4 × 10 respectively) and their DETECTING CELLS WITH MALIGNANCY
frequencies were both less than 5%. [70] POTENTIAL AND THEIR HALLMARKS IN
PERIPHERAL BLOOD
Although the spectrums and frequencies of altered
genes vary greatly among individuals, they are Circulating tumor cells
clustered to pathways or function groups that Release of cancer cells into the circulation is common
are closely related with stemness and embryonic in HCC patients. The appearance of circulating tumor
characteristics. In this regard, global mutation rates cells (CTC) in the blood stream characterizes the
of functionally related genes are added together to intermediate stage of tumor metastasis process. [72] CTC
define the mutation rate of a given signaling pathway. test can be applied to monitor early metastasis, assess
Mutation rates of Wnt/β-catenin, p53/cell cycle control, the effectiveness of therapeutic options, and predict
JAK/STAT, PI3k/mTOR, and MAP kinas signaling the prognosis. [73] A study examining blood samples of
pathways range from 12% to 72%. Similar outstanding 123 HCC patients one month before and after tumor
+
outcomes are also observed in function gene groups resection indicated that EpCAM CTCs were presented
of chromatin remodeling and telomere maintenance. in 66.67% of patients and that CTCs count in 7.5 mL
Ahn et al. [69] developed a somatic mutation signature blood (CTC7.5) is an independent prognostic factor
336 Hepatoma Research ¦ Volume 2 ¦ December 23, 2016