Molecular alterations in gastric cancer with special reference to the early-onset subtype

Table 1 Sporadic gastric cancer factors

Factors1	Sporadic gastric cancer	Ref.
SNP	IL-1, IL-17, TNFα, TLRs (inflammatory response)	[55-68]
	MUC1 (protection against invaders)	[69,70]
	CDH1 (cell-to-cell adhesion)	[71-73]
	XPA, XPC, ERCC2 (repair of DNA damage related to H. pylori infection)	[32,74-76]
	MTHFR (metabolism of foliate)	[77,78]
	GSTT1, SULT1A1, NAT2, EPHX1 (metabolism of polycyclic aromatic hydrocarbons)	[79,80]
	Cyp2e1 (metabolism of xenobiotics)	[82]
	PSCA	[83]
CIN	gain of copy number at 8q, 17q, 12q, 13q and 20q	[105-109]
	amplification of EGF and c-ErbB2	[110,111]
	amplification of FGFR	[112,113]
	amplification of ERBB2	[116,117]
	overexpression of HGF and c-myc	[112,114,115]
	SLC1A2-CD44 fusion	[119]
	ROS1 rearrangement	[120]
LOH	APC, TP53, NME1	[121,122]
MSI	TGFβRII, IGFIIR,RIZ, TCF4, DP2 (cell growth-regulating genes)	[125,127-136]
	BAX, BCL10, FAS, CASPASE5, APAF1 (apoptosis genes)
	hMSH6, hMSH3, MED1, RAD50, BLM, ATR, MRE11 (DNA repair genes)
Somatic gene mutations	TP53, CDH1, SMAD4, PIK3CA, RHOA, ARID1A, KRAS, MUC3, APC, ERBB1, PTEN, HLAB, B2M, FAT4	[150-153]
Epigenetic alterations	CpG island methylation of the promoters of CDH1, CDKN2A, CDKN2B and hMLH1	[137,138]
	miRNA variations	[141]
Environment	Diet	[200]
	H. pylori infection	[163,165,168]
	EBV infection	[150,154-156]
	Hyper/hypogastrinaemia	[168,173,174]
	Smoking	[200]
Others	COX-2 overexpression	[182-189]

¹All of the above factors may overlap. The division is the simple generalization done to outline the problem. SNP: Single-nucleotide polymorphism; CIN: Chromosomal instability; LOH: Loss of heterozygosity; MSI: Microsatellite instability; H. pylori: Helicobacter pylori.

Table 2 Early-onset gastric cancer features

Factors	Early-onset gastric cancer	Ref.
SNP	rs10052016 at 5p15	[198]
CIN	Gain of copy number at 17q, 19q, and 20q	[10]
	No loss of RUNX3
	Infrequent loss of TFF1 expression
	More frequent expression of low-molecular-weight isoforms of cyclin E
LOH	Infrequent LOH	[10]
MSI	Lack of MSI	[10]
	vs 30% incidence	[124]
Others	Low COX-2 expression	[10]
	Male predominance	[195]
	Tendency to metastases	[196]

SNP: Single-nucleotide polymorphism; CIN: Chromosomal instability; LOH: Loss of heterozygosity; MSI: Microsatellite instability.

Table 3 Hereditary gastric cancer factors

Factors	Hereditary gastric cancer	Ref.
Germline mutations	CDH1	[23-34]
	TP53 (Li-Fraumeni syndrome)	[36,42,43]
	CTNNA1	[37]
	MSH2, MSH6, PMS2, MLH1 (Lynch syndrome)	[40,41]
	APC (Familial adenomatous polyposis)	[46,47]
	STK11 (Peutz-Jeghers syndrome)	[44,45]
	BRCA2	[48]