Genetic alterations in hepatocellular carcinoma: An update

Table 1 The characteristics of chromosomal instability and possible correlations with clinical and pathological parameters in hepatocellular carcinoma discussed in this review

Chromosome	Type of aberration	Targeted genes	Correlations with clinical and pathological parameters	Ref.
1q21	Gain	CHD1L, CKS1B, JTB, SHC1	Progression of HCC	Hyeon et al[43]
1q21-23	Gain	-	Early development	Yim et al[40]
1q21-q22	Gain	-	Metastasis	Wang et al[41]
1q21.1-q23.2	Gain	BCL9, ARNT, TPM3, MUC1, NTRK1	Poorly differentiated HCV-associated HCC	Liu et al[42]
1q22-23.1	Gain	CD1d	Diagnosis and prognosis	Zhang et al[44]
1q24.1-24.2	Gain	MPZL1	Intrahepatic metastasis	Jia et al[45]
8q24.21-24.22	Gain	MYC, DDEF1, MLZE	Prognosis (DFS and OS)	Pedica et al[47]
8q21.13	Gain	HEY1	Proliferation	Jia et al[37]
8q22.3	Gain	CTHRC1	Aggressive HCC	Tameda et al[48]
8q24.3	Gain	BOP1	Advanced-stage HCC, microvascular invasion and shorter DFS	Chung et al[50]
7q21.3	Gain	SGCE, DYNC1I1, PEG10	Hepatocarcinogenesis	Tsuji et al[51]
4q34.3-35	LOH	ING2	Progression	Zhang et al[56]
4q13.3-q35.2	LOH	ADH4, ADH1C, ADH1A, ADH6	HBV- and AFB1-related HCC carcinogenesis	Qi et al[58]
8p	LOH	DLC1, CCDC25, ELP3, PROSC, SH2D4A, SORBS3	Early stage of hepatocarcinogenesis, poor outcomes	Tornillo et al[59]; Roessler et al[30]
8p22-p23	LOH	MCPH1, KIAA1456, TUSC3, ZDHHC2	Metastasis and prognosis	Peng et al[62]
D4S2964	LOH	ARD1B, SEPT11	Prognosis (OS)	Huang et al[63]
6q26-q27	LOH	M6P/IGF2R	Poor outcomes	Jang et al[64]

HCC: Hepatocellular carcinoma; HBV: Hepatitis B virus; HCV: Hepatitis C virus; AFB1: Aflatoxin B1; DFS: Disease-free survival; OS: Overall survival; CHD1L: Chromodomain helicase/ATPase DNA binding protein 1-like; CKS1B: Cyclin-dependent kinases regulatory subunit 1; JTB: Jumping translocation breakpoint; SHC1: SHC-transforming protein 1; BCL9: B-cell CLL/lymphoma 9 protein; ARNT: Aryl hydrocarbon receptor nuclear translocator; TPM3: Tropomyosin alpha-3 chain; MUC1: Mucin 1; NTRK1: Neurotrophic tyrosine kinase receptor type 1; CD1d: Antigen-presenting glycoprotein; MPZL1: Myelin protein zero-like protein 1; MYC: Myelocytomatosis viral oncogene; DDEF1: Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 1; MLZE: Human melanomaderived leucine zipper extra-nuclear factor; HEY1: YRPW motif protein 1; CTHRC1: Collagen triple helix repeat containing 1; BOP1: Block of proliferation 1; SGCE: Epsilon-sarcoglycan; DYNC1I1: Cytoplasmic dynein 1 intermediate chain 1; PEG10: Parternal express gene 10; ING2: Interferon regulatory factor 2; ADH4: Alcohol dehydrogenase 4; ADH1C: Alcohol dehydrogenase 1C; ADH1A: Alcohol dehydrogenase 1A; ADH6: Alcohol dehydrogenase 6; DLC1: Deleted in liver cancer 1; CCDC25: Coiled-coil domain-containing protein 25; ELP3: Longator complex protein 3P; ROSC: Proline synthetase co-transcribed bacterial homolog; SH2D4A: SH2 domain-containing protein 4A; SORBS3: Sorbin and SH3 domain containing 3; MCPH1: Microcephalin 1; KIAA1456: tRNA methyltransferase 9-like; TUSC3: Tumor suppressor candidate 3; ZDHHC2: DHHC-type containing 2; ARD1B: ARD1 homolog B (S. cerevisiae); SEPT11: Mus musculus septin 11; M6P/IGF2R: Mannose 6-phosphate/insulin-like growth factor 2 receptor.

Table 2 Summary of single-nucleotide polymorphisms associated with the risk of hepatocellular carcinoma identified from genome-wide association studies

Related gene	SNP	Etiology of HCC	Odds ratio (95%CI)	P value	Ref.
TPTE2	rs2880301	HBV/HCV, Republic of Korea	0.27 (0.19-0.39)	1.74 × 10-12	Clifford et al[96]
KIF1B	rs17401966	HBV, China	0.61 (0.55-0.67)	1.70 × 10-18	Zhang et al[82]
KIF1B	rs17401966	HBV interacting with alcohol consumption, China	2.36 (1.49-3.74)		Chen et al[84]
GRIK1	rs455804	HBV, China	0.84 (0.80-0.89)	5.24 × 10-10	Li et al[94]
HLA-DQA1/DRB1	rs9272015	HBV, China	1.28 (1.22-1.35)	1.13 × 10-19	Li et al[94]
MICA	rs2596542	HCV, Japan	1.39 (1.27-1.52)	4.21 × 10-13	Kumar et al[91]
HLA-DQ	rs9275319	HBV, China	1.51 (1.38-1.66)	8.65 × 10-19	Jiang et al[97]
DEPDC5	rs1012068	HCV, Japan	1.75 (1.51-2.03)	1.27 × 10-13	Miki et al[90]
DDX18	rs2551677	HBV/HCV, Republic of Korea	3.38 (2.07-5.53)	1.41 × 10-10	Clifford et al[96]
FasL	rs763110	HBV/HCV, Egypt	1.970 (1.250-3.105)	0.003	Khalifa et al[98]
DLC1	rs3816747	HBV, China	0.486 (0.2450.962)/ 0.51 (0.2670.974)	0.037/0.039	Xie et al[99]
STAT4	rs7574865	HBV, China	1.22 (1.15-1.29)	1.66 × 10-11	Jiang et al[97]
FOXP3	rs3761549	HBV, China	1.32 (1.03-1.70)	0.030	Chen et al[100]

SNP: Single-nucleotide polymorphism; HCC: Hepatocellular carcinoma; GWAS: Genome-wide association studies; HBV: Hepatitis B virus; HCV: Hepatitis C virus; TPTE2: Transmembrane phosphoinositide 3-phosphatase and tensin homolog 2; KIF1B: Kinesin-like factor 1 B; GRIK1: Glutamate receptor, ionotropic, kainate 1; HLA-DQA1/DRB1: Major histocompatibility complex, class II, DQ alpha 1, DR beta 1; MICA: MHC class I polypeptide-relatedsequence A; HLA-DQ: Major histocompatibility complex class II antigen; DEPDC5: DEP domain containing 5; DDX18: DEAD (Asp-Glu-Ala-Asp) box polypeptide 18; FasL: Fas ligand; DLC1: Deleted in liver cancer 1; STAT4: Signal transducer and activator of transcription 4; FOXP3: Forkhead box P3.

Table 3 The characteristics of frequent recurrent somatic mutations and their correlations with clinical and pathological parameters in hepatocellular carcinoma based on deep-sequencing analyses

Gene	Altered pathway	Correlations with clinical and pathological parameters	Ref.
TERT promoter	Telomere stability	Hepatocarcinogenesis	Nault et al[104]; Yang et al[165]
TP53	Cell cycle control	Under debate: an early event in the context of aflatoxin exposure and chronic HBV infection, or it might not play a role in carcinogenesis	Qi et al[136]
		Poor prognosis	El-Din et al[117]
			Cleary SP et al[138]
CTNNB1	Wnt/β-catenin signaling	Under debate: a late event for malignant progression or earlier during hepatocarcinogenesis	Park et al[253]; Vilarinho et al[256]
		Under debate: worse outcomes or better outcomes	Tornesello et al[263]; Wang et al[269]
AXIN1	Wnt/β-catenin signaling	Hepatocarcinogenesis and progression	Guan et al[242]
ARID1A	Chromatin remodeling	Initiation and progression of HCC	Schulze et al[106]
ARID2	Chromatin remodeling	Initiation and progression of HCC	Totoki et al[107]
NFE2L2	Oxidative stress	Hepatocarcinogenesis and progression	Nault JC et al[105]
KEAP1	Oxidative stress	Hepatocarcinogenesis and progression	Schulze et al[106]
JAK1	JAK/STAT pathway	Hepatocarcinogenesis	Kan et al[28]
RPS6KA3	RAS/MAPK signaling	Hepatocarcinogenesis	Guichard et al[102]

TERT: Telomerase reverse-transcriptase; ARID1A: AT-rich interactive domain-containing protein 1A; ARID2: AT-rich interactive domain-containing protein 2; NFE2L2/NRF2: Nuclear factor erythroid-derived 2-like 2; KEAP1: Kelch-like ECH-associated protein 1; JAK1: Janus kinase 1; RPS6KA3: Ribosomal protein S6 kinase polypeptide 3.