Pathogenetic mechanisms in gastric cancer

Table 1 Genetic alterations in gastric cancer

Genes	Alterations	Function	Pathology	Prognosis	Ref.
Tumor suppressor genes
TP53	Mutation/LOH	Transcription factor	Both	Association with poor survival	[42,46,48,182]
APC	Mutation/ LOH	Signal transduction	Intestinal	Association with poor survival	[48,98,99]
CDHI	Mutations/LOH	Adhesion	Diffuse	Association with poor survival	[48,102,106,183,184]
hMLH1/hMSH2	Mutations	DNA mismatch repair	Both	Association with poor survival and microsatellite instability	[10,140,185]
p16	Mutations/LOH	Cell cycle	Both	LOH of p16 association with lymph metastasis	[48,136,186,187]
RIZ	Mutations/LOH	Nuclear histone/protein methyltransferase	-	Association with microsatellite instability	[188-190]
hMSH3	Mutations	DNA mismatch repair	-	Association with microsatellite instability	[191,192]
hMSH6	Mutations	DNA mismatch repair	-	Association with microsatellite instability	[191,192]
PTEN	Mutations/LOH	protein tyrosine phosphatases	Both	Association with TNM stage, lymph node metastasis and poor survival	[65,66,193,194]
bcl-2	LOH	Apoptosis inhibitor	Intestinal	Association with invasion depth and lymph node metastasis	[182,195]
DCC	LOH	Cell adhesion	Intestinal	Association with poor survival	[48,196]
NM23	LOH	Nucleoside diphosphate kinase	Both	Association with metastasis and poor survival	[197-199]
p21	Loss	Cell cycle	Both	Association with poor survival	[51]
FHIT	LOH	Purine metabolism	Both	Association with invasive depth and microsatellite instability	[200]
BRCA1	LOH	Genetic instability	Both	Association with poor survival	[201,202]
Oncogenes
β-Catenin	Mutations	Adhesion,	Intestinal	Association with poor survival and EBV-associated GC	[10,58,97]
		Signal transduction
BRAF	Mutations	Signal transduction	Both	Association with microsatellite instability	[71,203]
K-Ras	Mutations	Signal transduction	Intestinal	Association with poor prognosis and microsatellite instability	[57,71-73,204]
PIK3CA	Amplification	Signal transduction	Both	Association with poor survival	[55-58]
	Mutations
EGFR	Amplification	Growth factor receptor	Both	Association with poor survival	[57,81,205]
		Tyrosine kinases
ERBB2	Amplification	Growth factor Receptor	Intestinal	Association with poor survival	[68,81-85,205]
	Mutations	Tyrosine kinases
ERBB3	Overexpression	Growth factor receptor	Diffuse	Association with poor survival	[68,81,85]
		Tyrosine kinases
ERBB4	Amplification	Growth factor receptor	Both	Association with poor survival	[86]
		Tyrosine kinases
c-Met	Amplification	Growth factor receptor	Diffuse	Association with poor survival	[86,206]
KSAM	Amplification	Growth factor receptor	Diffuse	Association with poor survival	[207]
VEGF	Overexpression	Growth factor	Intestinal	Association with metastasis and poor survival	[153,154,208]
CD44	Amplification	Cell adhesion	Both	Association with metastasis and poor survival	[86,209]
PRL3	Amplification	Cell signaling molecules	Both	Association with metastasis and poor survival	[210,211]
c-Myc	Amplification	Transcription factor	Intestinal	Association with poor survival	[212,213]
Cyclin E	Amplification	Cell cycle regulator	Both	Association with poor survival	[208,214]

LOH: Loss of heterozygosity.

Table 2 Epigenetic alterations in gastric cancer

Genes	Function	Prognosis	Detected in serum	Ref.
DNA methylation
BRCA1	DNA repair	Association with age	-	[215]
hMLH1	DNA repair	Association with poor survival	Yes	[75,216]
MGMT	DNA repair	Association with poor survival	-	[75]
RASSF1A	DNA repair/Cell cycle	Association with poor survival	Yes	[74,76,77]
CDH1	Cell invasion/Metastasis	Association with poor survival	Yes	[105,106,138,139,216,217]
RASSF2	DNA repair/Cell cycle	Association with poor survival	-	[75]
P16	Cell cycle	Association with poor survival	Yes	[75,137-139,218]
IGFBP3	Cell cycle	Association with lymph node metastasis	-	[219]
CHFR	Cell cycle	Association with invasion depth, differentiation and lymph node metastasis	-	[218,220]
P15	Cell cycle	-	Yes	[139,221]
ADAM23	Cell invasion/metastasis	-	-	[222,223]
APC	Cell invasion, Metastasis,	Association with poor survival	Yes	[216]
	Signal transduction
LOX	Cell invasion and metastasis	Association with Helicobacter pylori-positive individuals	-	[22]
TIMP3	Cell invasion and metastasis	Association with poor survival	Yes	[74,216]
HAND1	Cell differentiation	Association with poor survival	-	[22,75]
MLF1	Cell differentiation	Association with lymph node metastasis	-	[75,223]
PRDM5	Cell differentiation	-	-	[223,224]
RORA	Cell differentiation	-	-	[223]
NDRG2	Cell differentiation	Association with lymph node metastasis	-	[225]
BNIP3	Apoptosis	Association with poor survival	-	[226,227]
DAPK	Apoptosis	Association with poor survival	Yes	[74,139,218,227,228]
TMS	Apoptosis	Association with poor survival	-	[228]
FHIT	Apoptosis	Association with lymph node metastasis	-	[105]
GSTP1	Apoptosis	Association with EBV-related gastric cancer	Yes	[139,229]
FLNc	Cell morphology	Association with poor survival	-	[75]
RUNX3	Transcriptional factor, Signal transduction	Association with poor survival	Yes	[120,122,123,218,220]
ZNF545	Transcriptional factor	Association with poor survival	-	[230]
RARβ	Signal transduction	Association with poor survival	Yes	[74,138]
HRASLS	Signal transduction	-	-	[75]
SFRP2	Signal transduction	-	-	[108,231]
SFRP1	Signal transduction	Association with lymph node metastasis	-	[231]
MicroRNAs
let-7g	Tumor suppressor	Association with invasion depth, lymph node metastasis	-	[232]
miR-433	Tumor suppressor	Association with invasion depth, lymph node metastasis	GRB2	[147,232]
miR-1	Tumor suppressor	Association with tumor stage	-	[233]
miR-20a	Tumor suppressor	Association with tumor stage	-	[233]
miR-27a	Tumor suppressor	Association with tumor stage	-	[233]
miR-34	Tumor suppressor	Association with tumor stage	Bcl-2, Notch, and HMGA2	[233,234]
miR-423-5p	Tumor suppressor	Association with tumor stage	-	[233]
miR-125a-5p	Tumor suppressor	Association with tumor size, invasion,	ERBB2	[87]
		liver metastasis, and poor survival
miR-146a	Tumor suppressor	Association with lymph node metastasis, venous invasion, and poor survival	EGFR, IRAK1	[87]
miR-9	Tumor suppressor	-	RAB34, CDX2, and NF-κB1	[147,234,235]
miR-375	Tumor suppressor	-	PDK1, 14-3-3zeta	[236]
miR-433	Tumor suppressor	-	GRB2	[147]
miR-214	Oncogenesis	Association with invasion depth and lymph node metastasis	-	[232]
miR-130b	Oncogenesis	-	RUNX3	[121]