Multiple “Omics” data-based biomarker screening for hepatocellular carcinoma diagnosis

Table 1 The sensitivity and specificity of biomarkers in the diagnosis of hepatocellular carcinoma

Biomarker	Full name	Sensitivity (%)	Specificity (%)	Ref.	Description
AFP	α-fetoprotein	66	82	[9]	A glycoprotein with a molecular weight of approximately 70 kDa that transports a variety of molecules, including bilirubin, fatty acids, steroids, and various drugs
		65	94	[107]
AFP-L3	AFP-L3 (binding fraction)	28	97	[9]	One of the three glycoforms of AFP. AFP-L3 is only derived from cancer cells and has a higher specificity than AFP
		37	92	[108]
DCP	Des-γ-carboxyprothrombin	77	82	[23]	Prothrombin, Des-γ-carboxyprothrombin (DCP), induced by vitamin K deletion II (PIVKAII), is an abnormal prothrombin molecule that is increased in HCC
		61	70	[9]
GPC3	Glypican-3	55.2	84.2	[11]	Glypican-3 (GPC3) belongs to the glypican family of heparan sulfate proteoglycans. GPC3 is involved in cell proliferation, survival and tumor suppression
GP73	Golgi protein-73	62	88	[9]	It is a type II Golgi-specific membrane protein that is normally expressed in epithelial cells of various human tissues, but not in hepatocytes. However, GP73 is detected in the serum of patients with liver disease, especially HCC
OPN	Osteopontin	75	62	[99]	Also known as transformation-associated protein phosphatase, a glycophosphoprotein that binds to integrin, which is overexpressed in many different types of malignancies, including lung, breast and colon cancers
MDK	Midkine	92.5	83.3	[109]	Midkine is a heparin-binding growth factor, originally identified as a retinoic acid response gene that plays a key role in cell growth, survival, migration, angiogenesis and carcinogenesis
SCCA	Squamous cell carcinoma antigen	56.1	74.9	[110]	It is the member of the high molecular weight family of serine protease inhibitors, highly expressed in epithelial tumors, and protects tumor cells from apoptosis
Annexin A2		83.2	67.5	[111]	A calcium-dependent phospholipid binding protein that is present on endothelial cells and on the surface of most epithelial cells. It is up-regulated in many tumor types and has multiple roles in various tumorigenic processes
suPAR	Soluble urokinase plasminogen activator receptor	76.0	90.4	[112]	A glycophosphatidylinositol-linked membrane protein, a circulating form of the urokinase-type plasminogen activator receptor (uPAR). Recently, suPAR has been established as a biomarker of immune system activation and cancer metastasis level
TRXs	Thioredoxins	74.9	87.5	[113]	Thiol oxidoreductase is ubiquitously expressed and involved in several biological processes, such as regulation of protein status, apoptosis and proliferation, and protection against oxidative stress.

AFP: α-fetoprotein; AFP-L3: α-fetoprotein-L3 (binding fraction); DCP: Des-γ-carboxyprothrombin; HCC: Hepatocellular carcinoma; GPC3: Glypican-3; GP73: Golgi protein-73; OPN: Osteopontin; MDK: Midkine; SCCA: Squamous cell carcinoma antigen; suPAR: Soluble urokinase plasminogen activator receptor; TRXs: Thioredoxins.

Table 2 Phases (I, II, III) of biomarker development and corresponding candidate biomarkers

Phases	Description	Biomarkers	Ref.
Phase I	Preclinical exploratory studies	miRNA	[114]
		Metabolomic	[115]
		Cell-free DNA	[116]
Phase II	Clinical essay and validation	AFP-L3	[9]
		Dickkopf-1	[101]
		DCP(Des-carboxyprothrombin)	[9]
		GPC3 (Glypican-3)	[102]
		Golgi protein-73	[117]
		Squamous cell carcinoma antigen	[118]
		miRNA	[114]
Phase III	Retrospective longitudinal studies	Osteopontin	[99]
		Midkine	[100]
		GALAD score	[85]

AFP-L3: α-fetoprotein-L3 (binding fraction); DCP: Des-γ-carboxyprothrombin; GPC3: Glypican-3.