Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update

Table 1 Etiological factors for gallbladder cancer pathogenesis

Major Independent Etiological factors	Dependent Etiological factors
Age[6]	Tobacco consumption[15]
Sex[6], BMI[16]	Mustard oil[17] Argemone oil (AO) and butter yellow (BY)[18]
Family history[7,19]	Early age at first pregnancy[20]
Cholelithiasis[6,22-24]	Use of Oral contraceptives[15,25,26]
Chronic cholecystitis, porcelain gallbladder[27,28]	Red Chili pepper[29,30]
Chronic infection by Salmonella species, S. paratyphi or S. typhican[6,10,31-34]	Occupational exposure, Benzene[17,35]
Helocobacter pylori[36,37]	Secondary bile acids[13,38-40]
High parity[20,21,24,26]	Xanthogranulomatous cholecystitis[41]
Anomalous pancreatobiliary duct junction[42,43]	Heavy metals[44,45]
Porcelain gallbladder[46]	Genetic factors[48]
Gallbladder polyp[47]
Obesity[49]	Free radical oxidation products[50]

Table 2 Mutations detected in gallbladder cancer by low throughput methods

Studied gene	Type of study	Methods used	Studied population	Ref.
KRAS	Mutation at codon-12 (8%)	PCR-RFLP	India	[64]
	Mutation at codon-12 (29%-30%)	PCR-RFLP	Chile	[76,77]
	Mutation at codon-12 (0%-59%)	PCR-RFLP, Direct sequencing	Japan	[60,78,79]
	Mutation at codon-12 (50%-80%)	ELMA, SAB, PCR-SSCP, Direct sequencing	Japan	[63,80]
INK4A (p16)	Mutation, deletion	PCR-RFLP, direct sequencing, IHC	Japan, Chile	[54,79,81,82]
D310 mtDNA	Mutation (Displacement loop)	PCR-based assay, direct sequencing	Chile	[83]
TP53	Mutation, overexpression, LOH	PCR-RFLP, direct sequencing, IHC	Greece, Japan, Chile	[84-86]

Table 3 Mutations studies in gallbladder cancer by high throughput methods

Platform	Number of samples	Study population	Research planned	Key findings	Ref.
Sequenom Mass ARRAY technology	49 FFPE	India	390 mutations in 30 genes	PIK3CA (4%), KRAS (2%), CTNNB1 (4%), TP53 (18%)	[95]
Mass spectroscopy-based	57 FFPE	MD Anderson Centre	159 mutations in 33 genes	14 hotspot mutations in 9 cases including (KRAS, NRAS, PIK3CA, IDH1, ALK, MET)	[94]
				26 mutations in 15cases
Next-generation sequencing (NGS)	15 FFPE		NGS of 182 cancer-related genes	(P53, STK11, RICTOR,TSC2, FGF3-TACC fusion, FGF10 amplification)	[94]
				Preponderance of mutations involving the PI3 kinase pathway
Whole Exome and transcriptome Sequencing	29 Fresh Frozen	Japan	64 non silent mutations signatures	EGFR, ERBB3, PTEN, ARID2, MLL2,	[96]
				MLL3, APOBEC, TERT
				APOBEC-associated mutation signature were observed in GBC
Exome sequencing and targeted gene sequencing	57 Fresh Frozen	China	Whole exome sequencing	TP53 (47.1%), KRAS (7.8%) and	[93]
				ERBB3 (11.8%)
				ERBB pathway genes mostly mutated

FFPE: Fresh frozen paraffin embedded.

Table 4 Summary of global gene expression studies in gallbladder cancer

Biological sample used	Platform/studies key findings	Ref.
17 gallbladder tissue specimens (6 advanced GBC , 6 early GBC cancers and 5 normal control	Oligonucleotide Microarray platform	[97]
	Unregulated genes: 2270
	Downregulated genes: 2412
5-Normal biliary epithelial scrapings, 11- surgically resected biliary carcinomas, 9-biliary cancer cell lines	Oligonucleotide Microarray platform	[98]
	Unregulated genes : 282 genes
	Downregulated genes: 513
37 biliary tract carcinomas	cDNA array platform	[99]
(15 bile duct, 11 gallbladder, 11 of ampulla of Vater)	118 genes were identified with a prognostic value
12 advanced gallbladder carcinoma tissue 3 samples of normal control gallbladder epithelium	Oligonucleotide Array platform	[100]
	Upregulated: (TOPO II-alpha, cyclin B2, CDC28, ubiquitin-conjugating enzyme E2C), and one metabolism-related: (gamma-glutamyl hydrolase)	[101]
34 biliary tract cancers including	Oligonucleotide Array platform
13 intrahepatic (IHC), 12extrahepatic (EHC), 9 (GBC)	1281 genes with deregulated expression pattern

Table 5 Summary of single gene expression studied reported in gallbladder cancer

Studied single genes	Expression pattern	Studied population	Ref.
TP53	Expression (20%-70%)	India, Slovenia, Greece, Taiwan, Japan, Chile	[75,84-86,102-106]
p16	Overexpression	South Korea	[107]
FHIT	Expression loss (45%-75%)	Japan, Chile	[108,109]
ERBB2	Overexpression (25%-64%)	India, Japan, China, South Korea	[66,103,110,111]
	Expressed in 9.4%cases of well differentiated and stage II to stage IV tumors	India	[90]
RB	20% cases allelic loss	Japan	[54,112]
	4%-14%- loss of expression
CDKN1A	Reduced expression 49% cases	Japan	[113]
Cyclin D1, Cyclin E	Overexpression (41%-49%)	Japan	[114,115]
COX2	Over-expressed	Slovenia, Japan, Chile	[104,116,117]
BCL2	Over-expressed	Japan	[118]
CKIT	Expression 45%	Japan	[119]
SOX-4	Overexpression	China	[120]
Chemokine (C-X-C motif) ligand 12	Increased expression	South Korea	[121]
CXCR4, CXCR7	Increased expression	China	[122]
hedgehog pathway components (Shh, Ptch1 and Gli1)	Shh: 81.7% of cases expressed	China	[123]
	Ptch1: 75.3% of cases
	Gli1: 70.0% of cases
CD56, CD99	Altered expression	South Korea	[124]
CD97, CD55	CD97: 69.6% of cases expressed	China	[125]
	CD55: 65.2% of cases
HMGA2 and CD9	HMGA2 positive expression	China	[126]
	CD9 negative expression
cholecystokinin type-A	44.1% of cases expressed	India	[127]
vascular endothelial growth factor-A	53.6% of cases expressed	China	[128]
VEGF-C, VEGF-D	VEGF-C: 64.0% of cases	China	[129]
	VEGF-D: 62.0% of cases
Tumor endothelial marker 8 protein	Increased expression	India	[130]
L1 cell adhesion molecule	Increased expression	South Korea	[131]
Tissue factor pathway inhibitor-2	Down-regulated	China	[132]
HIF-1α	Increased expression	China	[133]
VHL	Reduces expression
ERCC1(excision repair cross-complementing 1)	High expression in best differentiated tumors	Chile	[134]
NF-E2-related factor 2 (Nrf2)	Increased expression	China	[135]
CD34 , CA15-3	Highly expressed in stroma and in epithelium	Italy	[136]
ADAM-17	Overexpression	China	[137]
Cdx2	Aberrant expression	Japan	[138]
TLR4	Expressed in glandular and luminal epithelium	China	[139]
MiRNA	Loss of Dicer and Drosha expression	China	[140]
Inducible Nitric Oxide Synthase iNOS	Expressed	China	[141]
Prostate stem cell antigen (PSCA)	Down-regulated	Japan, China	[142]
OCT-4	Down-regulated	China	[143]
hTERT/Telomerase	Expressed in 56.66% cases	India	[144]
Aquaporins (AQPs)	Positive expression	Japan	[145]
Ornithine decarboxylase (ODC) and glutamate decarboxylase 65 (GAD65)	Overexpression	China	[146]
Alpha-methylacyl coenzyme A (racemase) AMACR	Overexpression	Taiwan	[147]
Sonic Hh (Shh)	Elevated expression	Japan	[148]
TGF-β induced miR-182	Overexpression	China	[149]
SLP-2	Overexpression	China	[150]
TMPRSS4	Higher expression	China	[151]
zinc finger X-chromosomal protein	Suppressed	China	[152]
multidrug resistance-associated protein 2 (MRP2)	Overexpression	South Korea	[153]
HuR	Overexpression	Taiwan	[154]
miR-155	Overexpression	Japan	[155]
LAPTM4B-35	Overexpressed(76%)	China	[156]
p27, P21	p21 (75% cases) and p27 (25% cases)	Jordan	[157]
Thymidylate synthase (TS)	Low expression	Japan	[158]
CD146	Elevated expression	China	[159]
AEG-1	Highly expressed (63.4%)	China	[160]
CCKAR	Expression increased (76.6%)	India	[127]
Nemo-like kinase (NLK)	Overexpression of NLK	China	[161]
C-erbB2	Overexpression (9.4%)	India	[90]
Phospho-mTOR expression	Positive expression (64.1%)	Chile	[162]
human telomerase reverse transcriptase (hTERT)	Expression increased	India	[163]
Phosphoglycerate kinase 1 (PGK1)	Decreased expression (54.7%)	China	[164]
Notch 1 and Notch 3	Positive expression	China	[165]
CCK-A	Decreased expression	India	[166]
3-phosphoinositide-dependent protein kinase 1 (PDK1)	Positively expressed	China	[167]
Zinc finger X-chromosomal protein (ZFX)	Overexpression	China	[151]
miR-138	Over expression	China	[168]
HSP gp96	Expression (90.7%)	China	[169]
Long non-coding RNA-LET	Overexpression	China	[170]
Survivin	higher expression (2.9- fold)	India	[171]
Long non-coding RNA CCAT1	Overexpressed	China	[172]
TEM8	Expression increased	India	[130]
Fhit,MIh1, P53	Reduced expression of Fhit and Mlh1 protein and Overexpression of P53	Japan	[108]
NDRG2, CD24	NDRG2 down-regulation, CD24 up-regulation	China	[173]
IL-6	Overexpressed	China	[174]
SLP-2	Overexpression	China	[150]
BCL6, p19(ARF)	BCL6 overexpression , p19 (ARF) Low Expression	Taiwan	[175]
VEGF-A	High expression of VEGF-A	Chile	[176]
MALAT1	Upregulation of MALAT1	China	[177]
miR-182	Upregulation of miR-182	China	[149]
miR-155	High expression level of miR-155	Japan	[155]
p53, S100A4, p27, p16, RB, Smad4, FHIT, E-cadherin and PML	p53 and S100A4 overexpressed,	South Korea	[178]
	Loss of p27, p16, RB, Smad4, FHIT, E-cadherin and PML expression
PEG10, TSG101	PEG10 and TSG101 overexpressed	China	[179]
CK7, CK20	CK7 (69.05%), CK20 (28.57%) expressed	Greece	[180]

Table 6 Loss of heterozygosity and microsatellite instability studies reported in gallbladder cancer

Studied reported in respective population	LOH/MSI	Ref.
Chilean	LOH reported in : 3p, 6q, 7q, 8p, 9p, 9q, 11q, 12q, 17p, 18q, 19p, 22q, and Xq	[57]
Japan	LOH reported in : 2p, 4p, 4q, 8q,9q, 10p,14p,14q,16p, 19p, 21p and Xp [Maximum deletion- 2p24, 14q22 and 21q22]	[68]
Chilean, Japan	p53, 9p.8p, DCC, KRAS, p16, 16q24, 3p,9q, 22q and p161NK4	[54,66,109,112,185]
Greece	BAT-26	[186]
Chile, Japan	MSI reported (20%-33%)	[187,188]
India	E-cadherin (CDH1) 2p, 2q, 6q, 7q,17p	[189]
India	Fragile histidine triad (FHIT) MSI-H 17.5% LOH :27.5%	[190]
Japan	High incidences of LOH at 1p36 (19/36:53%), 9p21 (12/32:38%), 13q14 (20/36: 56%), 16q24 (31/54: 61%), and 17p13 (15/36: 42%)	[191]
Chile	FHIT gene locus (3p14.2)	[109]
India	LOH at 8 loci, that is 3p12, 3p14.2, 5q21, 9p21, 9q, 13q, 17p13, and 18q for tumor suppressor genes (DUTT1, FHIT, APC, p16, FCMD, RB1, p53, and DCC genes)	[192]
India	genomic instability at 2p, 2q, 6q, 7q, and 17p loci	[189]
Chile	DUTT1 (3p12), FHIT (3p14.2), BLU, RASSF1A, SEMA3B and hMLH1 (3p21.3)	[193]

LOH: Loss of heterozygosity; MSI: Microsatellite instability.

Table 7 Aberrant promoter methylation gene studies summary in gallbladder cancer

Gene	Full name	Function	Meth Freq	Population	Ref.
CDH1	Cadherin 1, type 1,	Tissue invasion (cell-cell adhesion)	11%-65%	Japan, Chile	[194-200]
	E-cadherin (epithelial)
FHIT	Fragile histidine triad gene	Regulation of DNA Replication, and apoptosis	30%-57%	Chile	[81,193-195,199]
APC	Adenomatous polyposis coli	Tumor suppressor gene (Cell migration, adhesion and apoptosis)	26%-35%	Chile, United States	[81,194,195,198,199]
hMLH1	Human homologs of	Mismatch repair	0%-14%	Chile, United States	[81,193-195,199]
	MutL gene of bacteria
p16	Cyclin-dependent kinase	Cell cycle regulation	15%-60%	Chile, United States, Germany	[81,82,195,197-199,201,202]
	inhibitor 2A
p15	Cyclin-dependent kinase inhibitor 2B	Cell cycle regulation	22%-44%	Chile	[81,198]
DAPK1	Death-associated protein kinase 1	Serine-threonine kinase	8%-61%	Japan, Chile	[81,197,198]
DLC1	Deleted in liver cancer 1	GTPase-activating protein	39%	Chile	[81]
RASSF1	RAS association domain family protein 1A	Signal transduction	0%-36%	Japan, Chile South Korea	[81,193,197,198,203]
MGMT	O-6-methylguanine-DNAmethyltransferase	Methyltransferase	13%-30%	Chile, United States	[81,195]
CDH13	CDH13 Cadherin 13, H-cadherin(heart)	Tissue invasion (cell-cell adhesion)	44%-70%	Chile	[81,198]
TIMP3	Metallopeptidase inhibitor 3	Degradation of extracellular matrix	0%-39%	Chile	[81,198]
GSTP1	Glutathione S-transferase pi 1	Conjugation of hydrophobic and electrophilic compounds	13%	Chile	[198]
RARβ2	Retinoic acid receptor, beta	Encodes retinoic acid receptor beta	4%-44%	Chile, United States	[81,198]
REPRIMO	TP53 dependent G2 arrest mediator candidate	Cell cycle regulation (p53 mediator)	62%	Chile	[204]
SHP1	Protein tyrosine phosphatase,	Regulate cell growth,	80%	Chile	[198]
	non-receptor type 6	differentiation, mitotic cycle
3-OST-2	Heparan sulfate (glucosamine)	Osulfotransferase	72%	Chile	[198]
	3-O-sulfotransferase 2
RUNX3	Runt-related transcription factor 3	TGF-beta signal pathway	22%-32%	Chile	[197,198]
RIZ1	PR domain containing 2, with ZNF domain	Histone/protein methyltransferase	26%	Chile	[198]
HPP1	Transmembrane protein with EGF-like and two follistatin-like domains 2	TGF-beta signal pathway	20%		[198]
P73	Tumor protein p73	Induction of apoptosis and cell cycle regulation	14%-28%	Chile, United States	[81,198]
SOCS-1	Suppressor of cytokine signaling 1	JAK-STAT pathway	12%	Chile	[198]
DCR2	Tumor necrosis factor receptor superfamily, member 10d	TNF-receptor superfamily	6%	Chile	[198]
SEMA3B	Sema domain, immunoglobulin domain (Ig), short basic domain, secreted,(semaphorin) 3B	Induction of apoptosis	92%	Chile	[193]
DUTT1	Human homolog of	Cell migration and metastasis	22%	Chile	[193]
	Drosophila Roundabout
	(ROBO1)
BLU	Zinc finger, MYND-type containing 10	Cell cycle regulation	26%	Chile	[193]
p14	Ribonuclease P/MRP 14 kDa subunit	Cell cycle regulation	40%	Germany	[201]
MASPIN	Mammary serine protease inhibitor	Tumor suppressor gene	70%	India	[205]
THBS1	Thrombospondin 1	Platelet aggregation, angiogenesis, and tumorigenesis	52%
HLTF	Helicase-like transcription factor	Regulate transcription	16%
MYC	V-Myc Avian Myelocytomatosis Viral Oncogene Homolog transcription factor	Cell cycle progression, apoptosis and cellular transformation	80%	Brazil	[206]
APC	Adenomatous polyposis coli	Tumor suppressor gene	71%-95%	Chile	[207]
CDKN2A	Cyclin-dependent kinase inhibitor 2A	Cell cycle
ESR1	Estrogen receptor 1	Transcription factor
PGP9.5	Protein gene product 9.5	Neural and/or nerve sheath differentiation
SSBP2	Single-stranded DNA-binding protein 2	Microsatellite instability
PGP9.5	Protein gene product 9.5	Neural and/or nerve sheath differentiation	27.2%	South Korea	[208]
MLH1, CDKN2A	MutL homolog 1	Mismatch repair	5%	Chile	[194]
	Cyclin-dependent kinase inhibitor 2A	Cell cycle	35%
FHIT	Fragile histidine triad protein	Purine metabolism	21%
APC	Adenomatous polyposis coli	Tumor suppressor genes	25%
CDH1	Cadherin-1	Cell cycle	66%

Table 8 Candidate gene studies (low susceptibility genes) in gallbladder cancer

Pathway involved	Gene	Polymorphism	Population	Ref.
DNA repair pathway genes	XPC	(rs2228000) Ala499Val	China	[236]
		(rs2228001) Lys939Gln	China
	ERCC2	(rs1799793) Asp312Asn	North Indian	[232]
		(rs13181) Lys751Gln	North Indian
	MSH2	(rs2303426) IVS1+9G>C
		(rs2303425) -118T>C
	OGG1	(rs2072668) 748-15C>G
	TP53	(rs1042522) Pro72Arg	Chilean, Hungary, Japanese	[237-239]
	XRCC1	(rs1799782) Arg194Trp	North Indian Shanghai, China	[222,231]
		(rs25487) Arg399Gln
	APEX1	(rs3136820) Asp148Glu	Shanghai, China	[222]
	RAD23B	(rs1805335) IVS5-15A>G		[223]
		(rs1805329) EX7+65C>T
	FEN1	FEN1-69G>A and haplotypes	China	[240]
Hormonal pathway genes	CCKAR	(rs1800857) IVS1-5T>C	North Indian	[227]
	CCK and CCKAR	(rs2071011G>C, rs915889C/T, rs3822222C/T, rs1800855T/A	Shanghai, China,	[241]
	ESR1	(rs2234693) IVS1-397T>C	Shanghai, China, North India	[241-243]
		(rs3841686) IVS5-34->T
		(rs2228480) Ex8+229G>A
		(rs1801132) Ex4-122G>C
		(rs9340799) IVS1-351A>G
	ESR2	(rs1256049) Val328Val	Shanghai, China
	PGR	Ins/Del	North India
	AR	(CAG)n	Shanghai, China	[244]
		(rs4633) His62His	Shanghai, China	[224]
	COMT	(rs4818) Leu136Leu
	CYP1A1	(rs2606345) IVS1+606G>T
	CYP1B1	(rs10012)Arg48Gly
		(rs1065778) IVS4-76A>G	Shanghai, China	[224]
	CYP19A1	(rs700518) Val80Val
		(rs2304463) IVS7-106T>G
		(rs700519) Arg264Cys
		(rs1065779) IVS9-53G>T
		(rs4646) Ex11+410G>T
	HSD3B2	(rs1819698) Ex4-133C>T	Shanghai, China	[224]
		(rs1361530) Ex4-88C>G
	HSD17B3	(rs2066479) Gly289Arg
	HSD17B1	(rs2830) Ex1-486G>A
	SHBG	(rs6259) Ex8+6G>A
	SRD5A2	(rs523349) Ex1-17G>C
	RXR-a	(rs1536475) IVS6+70A>G	Shanghai, China	[245]
		(rs1805343) IVS1-27A>G
	RXR-b	(rs2744537) G392T
		(rs2076310) C51T
	INS	(rs689) A-6T	Shanghai, China	[245]
	PPARD	(rs2016520) Ex4+15C>T	Shanghai, China
	PPARG	(rs3856806) His477His	Shanghai, China
Inflammatory pathway genes	CR1	(rs2274567) His1208Arg	North Indian	[230]
		( rs12144461) Intron 27, HindIII
	IL1RN	86-bp VNTR	North Indian	[220]
		(rs689466) -1195G>A		[233]
	PTGS2	(rs20417) -765G>C
		(rs5275) +8473T>C	North Indian Shanghai, China	[233,246]
	IL1B	(rs16944) -1060T>C	Shanghai, China north Indian	[220,247]
	IL10	rs1800871)- 7334T>C	Shanghai	[247]
		(rs1800872) -6653A>C	Shanghai
	IL-8	(rs10805066) IL8 -13985C>G	China	[248]
	EGF	(rs4444903) +61A>G	North Indian	[221]
	TGFb1	(rs1800469)-509C>T	Shanghai, north Indian	[219,221,247]
	TNF-α	(rs1800629) -308G>A
	IL6	(rs1800795) 236C>G)
	IL8	(rs10805066) -13985C>G	China	[248]
	MMP-2	(rs2285053) -735 C>T	North Indian	[249]
		(rs9340799) -1306 C>T
	MMP-7	(rs11568818) -181 A>G
		(rs2250889) P574R
	MMP9	(rs 17576) R279Q
		(rs 17577) R668Q
	TIMP2	(rs8179090) -418 G>C
Metabolic pathway genes	MTHFR	(rs1801133) Ala222Val	Indian	[228]
	APOB	(rs17240441) 35_43del9	Indian	[217]
	NAT2	(rs1799929) NAT2*5A	Indian	[216]
		(rs1799930) NAT2*6B
		rs1799931, NAT2*7A
	GSTT1	Null polymorphism	Indian	[215]
	GSTP1	(rs1695) Ile105Val
	CYP17	(rs743572) Ex1+27T>C	Shanghai Indian (265)	[250,251]
	GSTM1	Null polymorphism	Indian, Chilean Hungary Japanese	[215,237,238]
	CYP1A1	(rs4646903) CYP1A1*2A	Indian, Chilean Hungary Japanese	[218,237,239]
		(rs1048943) Ile462Val (*2C)	China, Chilean, Hungary Japanese	[224,237-239]
	Cyp1a1 cyp1b1	CYP1A1-MspI, CYP1A1-Ile462Val, and CYP1B1-Val432Leu	India	[252]
		(rs5930) EX10+55G>A	Shanghai	[253]
	LDLR	(rs6413504) IVS17_42A>G	Shanghai
		(rs14158) EX18+88G>A
	LPL	(rs263) IVS5-540C>T
	ALOX5	(rs2029253) IVS3+100G>A
	ApoB	rs693) Thr2515Thr	Indian Chilean	[30,217]
	ABCG8	(rs11887534) Asp19His	North Indian Shanghai China	[229,254]
	CETP	(rs708272) TaqIB	Chilean Shanghai China	[30,254]
		(rs1800775) -629C>A	Shanghai China	[254]
	LRPAP1	(rs11267919)752_177_752_176 I 37	North Indian Shanghai China	[214,254]
	CYP7A1	(rs3808607) -204 A>C	North Indian	[255]
	CYP7A1	(rs3824260) -469 T>C	North Indian
	CYP17	(rs743572)A/G	North Indian	[250,251]
	ApoB	(rs676210) Pro2739Leu	Shanghai	[253]
		(rs673548) IVS23-79T>C
		rs520354) IVS6+360C > T
		(rs1367117) Thr98Ile
		(rs440446) IVS1+69C>G
	CYP2C19	(rs4244285) CYP2C19*2,	Japanese	[256]
		(rs4986893) CYP2C19*3
	ADRB3	(rs4994)A/G	North Indian	[257]
Apoptosis pathway	CASP8	(rs3834129) -652 6N ins/del	North Indian	[258]
		(rs1045485) Asp302His
		(rs3769818 A) IVS12-19 G>A
Nuclear Receptors	Lxr-alpha, Beta	LXR-α (rs7120118) and LXR-β (rs35463555 and rs2695121)	North Indian	[259]
Cancer Stem cell gene	CD44	CD44 (rs13347) C>T, CD44 (rs353639)A>C, CD44 (rs187116) G>A, CD44 (rs187115) T>C	North Indian	[260]
	NANOG, ALCAM, EpCAM, SOX-2, OCT-4, NANOG	NANOG (rs11055786)T>C,	North Indian	[261]
		ALCAM (rs1157)G>A
		EpCAM (rs1126497)T>C,
		SOX-2(rs11915160)A>C
		OCT-4 (rs3130932)T>G,
		NANOG (rs11055786)T>C
Prostate stem cell antigen	PSCA	(rs2294008) T/C and rs2978974)	India, Japan	[262,263]
miRNA	hsa-miR-146a	(rs2910164) G>C	North Indian	[264]
	hsa-mir-196a2	(rs11614913) C>T
	hsa-mir-499	(rs3746444)T>C
	miR-27,miR-570,miR-181	miR-27a (rs895819)A>G,	North Indian population	[265]
		miR-570(rs4143815)G>C,
		miR-181a(rs12537)C>T
GWAS-associated genes	DCC	(rs7504990)C>T	Japan	[234]
		( rs2229080) C>G	North Indian	[235]
		(rs4078288) A>G
		(rs7504990) C>T
		(rs714) A>G
Wnt signaling pathway	SFRP4, DKK2, DKK3, APC, AXIN-2, Β-CATENIN, GLI-1	SFRP4 (rs1802073) G>T,	North Indian	[266]
		DKK2 (rs17037102) C>T
		DKK3 (rs3206824) C>T,
		APC (rs4595552)A/T
		APC ( rs11954856) G>T,
		AXIN-2 (rs4791171)C>T
		β-CATENIN (rs4135385) A>G,
		GLI-1(rs222826) C>G
Other genes	KRAS	codon 25 Gln25His	Eastern India	[267]
	ACE I/D	(rs4646994) 289 bp del	North Indian	[268]
	DNMT3B	(rs1569686) -579 G>T	North Indian	[269]
	TLR2	-196-174del	North Indian	[270]
	TLR4	(rs4986791) Thr399Ile	North Indian
	Adrenergic receptors (ADRA)	ADRA2A C-1291G, ADRβ3 T190C or Trp64Arg, and ADRβ1 C1165G or Arg389Gly	North Indian	[271]
	Death Receptors and their ligands (DR4)	DR4 (rs20575, rs20576 and rs6557634), FAS (rs2234767) FASL (rs763110)	North Indian
	PlCE1	(rs2274223) A>G and. (rs7922612) T>C	North Indian	[272]
	Vitamin D receptor (VDR)	FokI C>T	China	[273]