Epigenetic dysregulation in Epstein-Barr virus-associated gastric carcinoma: Disease and treatments

Table 1 Clinical and pathological features of Epstein-Barr virus-associated gastric carcinoma

Clinical and pathological features
Age	Younger1
Gender	Male predominance
Associations	Smoking
Prevalence	10% of gastric carcinoma cases
Location	Gastric body/cardia
	Remnant stomach
Clinical	Multiple carcinomas1
	Thickening of gastric wall
	Ulcerated (saucer-like) neoplasm
	Lower rate of lymph node involvement1
Histology	Lymphoepithelioma-like
	Lymphocytic infiltration in various degrees
	Atrophic gastritis
	Lace pattern within the mucosa
	Moderate to poorly differentiated adenocarcinoma
Prognosis	Longer survival1

¹Items are controversial and subject to on-going research.

Table 2 Latent gene expression patterns in Epstein-Barr virus infected malignancies

Genes	Latency Ia	Latency Ib	Latency II	Latency III
EBNA1	+	+	+	+
EBNA2	–	–	–	+
EBNA3a	–	–	–	+
EBNA3b	–	–	–	+
EBNA3c	–	–	–	+
EBNA-LP	–	–	+	+
LMP1	–	–	+	+
LMP2A	–	+	+	+
LMP2B	–	–	+	+
EBER1	+	+	+	+
EBER2	+	+	+	+
BARTs	+	+	+	+
Disease	EBVaGC, Burkitt’s lymphoma	EBVaGC	NPC, Hodgkin’s lymphoma, NK/T-cell lymphoma	AIDS-associated B-cell lymphomas, Pyothorax-associated lymphoma

EBVaGC: Epstein-Barr virus-associated gastric carcinoma; NPC: Nasopharyngeal carcinoma; AIDS: Acquired-immunodeficiency-syndrome.

Table 3 Epstein-Barr virus-driven miRNAs and their target genes

Gene name	Gene targets in EBV	Gene targets in host cell
miR-BHRF1-1	-	GUF1[58], SCRN1[58]
miR-BART1-5p	LMP1[24]	CLEC2D[58,59], LY75[58,59], SP100[58,59], DICER1[58,59], MICB[58,59]
miR-BART1-3	-	CXCL11[60]
miR-BART2-5p	BALF5[61]	MICB[62]
miR-BART3	-	DICER1[58], MICB[58]
miR-BART3-3p	-	IPO7[63]
miR-BART5	LMP1[59]	PUMA[66]
miR-BART6	LMP1[24]	DICER1[65]
miR-BART10	BHRF1[59]	-
miR-BART13	-	CAPRIN2[59]
miR-BART16	LMP1[24]	TOMM22[63]
miR-BART17-p	LMP1[24]	-
miR-BART19	LMP1[59]	-
miR-BART22	LMP2A[25]	-
miR-BARTs	-	BIM[66]

EBV: Epstein-Barr virus.

Table 4 Hypermethylated genes verified in Epstein-Barr virus-associated gastric carcinoma tissue

Function	Hypermethylated genes
Apoptosis	DAPK[30], BNIP3[29], FAM3B[5], HRK[29], IL15RA[17], MINT31[32], p16[29-35], p73[30,32-34], PTEN[31,67], RASSF1A[31]
Cell adhesion	EPHB6[17], FLNc[30], FSD1[34], REC8[17], CSPG2[29]
Cell-cell interactions	MDGA2[17], THBS1[31]
Cell cycle regulation	APC[31], p15[30], p16[29-35], p57[29], p73[30,32-34]
Cell invasion	E-Cadherin[30,68,69]
Cell migration	EPHB6[17]
Cell proliferation	E-Cadherin[30,68,69], HRASLS[30], IL15RA[17], MINT31[32], NKX3.1[34], RUNX3[32], TIMP2[21], TIMP3[30]
Cell signalling	14-3-3Sigma[31], CSPG2[29], MINT1[31], MINT2[31,32], PLXND1[21]
Differentiation	HAND1[30]
Dna repair	hMLH1[32,43,53], MGMT[31]
Exocytosis	SCRN1[34]
Metastasis	E-Cadherin[30,68,69], LOX[30]
Other	BCL7A[34], BLU[34], CHFR[29], CXXC4[21], GSTP1[30,31,40], HLTF[29], HOXA10[70], IHH[5], MARK1[34], MINT25[31], PAX5-β[29], SCARF2[17], SSTR1[17,39], THBD[30], WNT5A[71]

Table 5 Selection of epigenetic therapeutics in cancer chemotherapy

Target	Drug name	Status	Ref.
DNA methylation	Azacitine (5-Aza-CR)	Approved	[72]
	Decitabine (5-Aza-CdR)	Approved	[72]
	Hydralazine	Phase II/III	[73]
	Epigallocatechin-3-gallate (EGCG)	Phase II	[74-76]
	5-Fluoro-deoxycytidine (FdCyd/FDAC)	Phase I/II	[77]
	5-fluoro-2′-deoxycytidine (FCdR)	Phase I/II	[78]
	Procainamide	Phase I	[79]
	Procaine	Phase I	[80]
	Psammaplin A	Phase 0	[81,82]
	RG108	Phase 0	[83-86]
	Zebularine	Phase 0	[87-89]
Histone deacetylases	Vorinostat	Approved	[90]
	Romidepsin	Approved	[90]
	Panobinostat	Phase II	[91]
	SEN196	Phase II	[92]
	Phenyl butyrate	Phase I/II	[93-95]
	Valporic acid	Phase I	[93-95]
	Compound 6J (R = -C4H8)	Phase 0	[96]