Biomarkers in the diagnosis of pancreatic cancer: Are we closer to finding the golden ticket?

doi:10.3748/wjg.v27.i26.4045

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Gastroenterol. Jul 14, 2021; 27(26): 4045-4087
Published online Jul 14, 2021. doi: 10.3748/wjg.v27.i26.4045

Table 1 Serum protein biomarkers implicated in the diagnosis of pancreatic cancer

Class	Candidate marker
Glycolipids and proteins	CA19-9[27,28,33-38,144,160,182,187,213,221], sTRA[39-41], CEA[43], CA125[47,48,50], CA242[55,53], Osteonectin[57], Osteopontin[58-61], DUPAN-2[65-70], LAMC2[73-75], ULBP2[78-80], sCD40L[82], LRG1[84], C4BPA[86], Cofilin-1[88], sgC1qR[91], Trypsinogen-2[92,93], DKK1[96], THBS-2[99-102], THBS-1[103], AGR2[108], REG1A[108], REGIII[108], REG1β[111], REG4[114-117], SYCN[108], LOXL2[108], PARK7/DJ-1[126], TTR[129,130], TTF1[134], TTF2[134], TTF3[134], GPNMB[138], PRX-1[139], TFPI[141], TIMP-1[144], MMP-9[144], IGFBP-1^[146],IGFBP-2[147-149], IGFBP-3[147,149], MSLN[148,154], C5[152], MMP-7[155-157], cathepsin-D[156], MMP-12[157], OPG[160], Kisspeptin[165], Galectin[171], MUC16[48,182], MUC5AC[37,182], PAM4[187], HSP27[190,191], CAM17.1[192,193], Fuc-Hpt[194], SAA[196], APN/CD13[200], M2-PK[203,204], APOA2[206-208], APOC1[209], APOC2[210], APOE[211-212], ITIH[213], APOA1[213], APOL1[213]
Growth factors	TGF-B[215], VEGF[217], FGF-10/KGF-2[138], PDGF[220], TSGF[221]
Cytokines and chemokines	IP-10[220], IL-6[220,230-232], MIC-1/GDF15[227,228], IL-11[229], YKL-40[232,233], IL-8[230,234,235,237,241], IL-10[214], IL-1β[214], OSM[138], TNF-α[240-244], M-CSF[214], CXCL11[138], SCF[138,247-248], Eotaxin[250], HGF[250], MCP-1[250], CXCL10[250]
Adhesion molecules	CEACAM1[253,254], ICAM-1[160,262-263]

CEA: Carcinoembryonic antigen; TTF: Thyroid transcription factor; sTRA: Sialylated tumor-related antigen; IL: Interleukin.

Table 2 Serum based non-coding RNA biomarkers implicated in the diagnosis of pancreatic cancer

Type	Candidate marker
LncRNA	LINC-PINT[277], SNHG15[278,279], LINC01238[280], ABHD11-AS1[281], HULC[282,283], UFC1[284]
MiRNA	miR-21[285-289], miR-25[288,290,297], miR-210-3p[289], miR-29a[290], miR-19a[290], miR-210[285,291], miR-155[285,292], miR-499a-5p[293], miR-125a-3p[294], miR-6893-5p[294], miR-125b-1-3p[294], miR-6075[294], miR-6836-3p[294], miR-1469[294], miR-6729-5p[294], miR-575[294], miR-204-3p[294], miR-6820-5p[294], miR-4294[294], miR-4476[294], miR-4792[294], miR-196a[285,295], miR-18a[296,297], miR-10b[292-298], miR-106b[292], miR-642-3p[299], miR-885-5p[299], miR-22-3p[299], miR-34a[286], miR-191[297], miR-451a[300], miR-121-5p[298], miR-30c[298], miR-483-5p[290,297], miR-1290[301,302], miR-24[290,297,301], miR-134[301], miR-146a[301], miR-378[301], miR-484[301], miR-628-4p[301], miR-1825[301], miR-1246[302], miR-482-3p[287], miR-16[295], miR-27a-3p[303], miR-192[304], miR-885-5p[299], miR-22-3p[299], miR-642b-3p[299], miR-492[305], miR-663a[305], miR-194[304], miR-223[306], miR-774-5p[307], miR-409-3p[307], miR-128-3p[307], miR-20a[290,297], miR-27a[297], miR-29c[297], miR-30a.5p[297], miR-323.3p[297], miR-345[297]

MiRNA: MicroRNA; LINC-PINT: Long intergenic non-protein coding RNA, P53 induced transcript; SNHG15: Small nucleolar RNA host gene 15; ABHD11-AS1: ABHD11 antisense RNA 1; HULC: Highly up-regulated in liver cancer.

Table 3 Serum based ‘liquid biopsy’ biomarkers implicated in the diagnosis of pancreatic cancer

	Biomarkers
Exosomes	Exosomes: GPC1[310,313], miR-10b[310], miR-30c[310], miR-181-a[310], miR-let7a[310], miR-17-5p[311], miR-21[311], miR-1246[312], miR-4644[312], miR-3976[312], miR-4306[312]
ctDNA	KRAS[314-317], ADAMTS1[318], BNC1[318]
CTC	CAPI+/CD45-[319], CK+[319], CEA+[319], CD45-/DAPI+/CEP8[320], CD45[321], CCK19[321], Pdx-1[321], Kras mutation[322], CEP8[323], CK[323], CD45[323], DAPI[323], chromosome 8[324], Folate-receptor positive CTCs[326]

Tspan8: Tetraspanin 8; EpCAM: Epithelial cell adhesion molecule; MET: mesenchymal-epithelial transition factor; CD104: Integrin 4-beta; GPC1: Glypican 1; GNAS: Guanine Nucleotide binding protein; KRAS: KRAS Proto-Oncogene, GTPase; ADAMTS1: A disintegrin and metalloproteinase with thrombospondin motifs 1; BNC1: Basonuclin 1; CD45: Leukocyte common antigen; CK19: Cytokeratin 19; Pdx-1: Pancreatic and duodenal homeobox 1; ADAMTS1: A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; BNC1: Zinc finger protein basonuclin-1.

Table 4 Urinary biomarkers implicated in the detection of pancreatic cancer

Type	Candidate marker
Protein	LYVE1[334], REG1A[334], TTF1[334], TIMP1[335], MMP-2[335], NGAL[336], PGE2 metabolites[337], CD59 glycoprotein (CD59)[338], ANXA2[338], 21 kDA gelsolin fragment[338], S100A9[338]
Liquid biopsy	UcfDNA: KRAS mutation[341]; Exosomal miRNA: miR-3940-5p[342], miR-8069[342]
RNA	MiRNA: miR-143[340], miR-223[340], miR30e[340], miR-1246[18]
Metallomics	Calcium[344], magnesium[344]
Other	VOCs[343]

MiRNA: MicroRNA; ANXA2: Annexin A2; S200A9: Protein S100-A9.

Table 5 Pancreatic Juice biomarkers implicated in the detection of pancreatic cancer

Type	Candidate marker
Protein	CA19-9[345-347,349], MIC-1[349], NGAL[349], CEA[347,348,350-352], AMYP[353], PRSS1[353], glycoprotein GP2-1[353], CCDC132[353], REG1A[353], REG1B[353], REG3A[353], LIPRP2[353], KL-6/MUC1[354], CPA5[355], inactive LIPRP1[355], KLK1[355], HBD[355], TTR[355], S100P[356], MMP-9[357], MMP-7[155], DJ-1[357] A1BG[357], PAP-1[358], AGR2[359], IL-8[360], Cathepsin E[361]
RNA	MiRNA: miR-21[362], miR-155[362] , miR-205[363], miR-210[363], miR-492[363], miR-1427[363]; mRNA: mesothelin[364]; Other: hTERT[365,366], telomerase activity[367-369]
Liquid biopsy	Exosomes: CEACAM1[371], CEACAM 5[371], tenascin C[371], MMP7[371], LAMB3[371], LAMC2[371], MUC1[372], MUC4[372], MUC5AC[372], MUC6[372], MUC16[372], CFTR[372], MDR1[372], ex-miR-21[373], ex-miR-155[373]; Methylated DNA: KRAS[374,377], ppENK[375,376], p16[375,376], Cyclin D2[376], FOXE1[376], NPTX2[376], TFPI2[376], CD1D[377], KCNK12[377], CLEC11A[377], NDRG4[377], IKZF1[377], PKRCB[377], MUC1[378], MUC2[378], MUC4[378]

MiRNA: MicroRNA; PRSS1: Trypsin-1; CPA5: Carboxypeptidase A5; KLK1: Kallikrein-1; HBD: Hemoglobin Subunit Delta; LAMB3: Laminin subunit beta-3; CFTR: Cystic fibrosis transmembrane conductance regulator; MDR1: Multidrug resistance protein 1; KCNK12: Potassium channel, subfamily K, member 12; CLEC11A: C-Type lectin domain containing 11A; NDRG4: NDRG family member 4; IKZF1: Ikaros family zinc finger protein 1 gene; PKRCB: Protein kinase C beta; FOXE1: Forkhead Box E1; NPTX2: Neuronal pentraxin-2.

Table 6 Pancreatic cyst fluid biomarker studied in relation to high grade dysplasia and pancreatic cancer diagnosis

Type	Candidate marker
Protein	CEA[383,384,399,402-407], Glucose[385], MUC4[386,412], PGE2[387,388], IL-1B[386,387], PGE synthetase 2[386], IL-4[389], CA72-4[389], sFASL[389], MMP9[389] AREG[390,391], SPINK1[392], mAB Das-1[393,394], IL-10[395], GM-CSF[395], MUC1[413], MUC2[413], MUC5AC[413]
RNA	MiRNA: miR-21[396], miR-221[396], miR-18a[397,398], miR-24[397,398],miR-30a-3p[397,398], miR-92a[397,398], miR-99b[397,398], miR-106b[397,398], miR-142-3p[397,398], miR-342-3p[397,398], and miR-532-3p[397,398]
Other	DNA based-KRAS mutations[399-407,409-411] GNAS mutations[409-411]

MiRNA: MicroRNA; CA72-4: Cancer antigen 72-4; sFASL: Soluble Fas; AREG: amphiregulin; SPINK1: serine peptidase inhibitor kazal type 1; GM-CSF: granulocyte macrophage colony-stimulating factor.

Table 7 Salivary fluid biomarkers studied in relation to pancreatic cancer diagnosis

Type	Candidate marker
RNA	LncRNA: HOTAIR[428], PVT1[428]; MiRNA: miR-21[286,423,431], miR-23a[423], miR-23b[423], miR-29c[423], miR-1246[422], miR-4644[422], miR-34a[286], miR-155[286], miR-200b[286], miR-376a[286], miR-216[423], miR-940[424], miR-3679-5p[424], miR-17[425], miR-181b[425], miR-196a[425]
Other	Salivary polyamines: Alanine[427], N₁-acetylspermidine[427], 2-oxobutyrate[427], 2-hydroxybutyrate[427]

MiRNA: MicroRNA.

Table 8 Biliary fluid diagnostic biomarkers studied with relation to pancreatic cancer

Type	Candidate marker
Protein	VEGF[217,429], CA19-9[431], CA125[432], CA72-4[432], CEA[432,433], sLR11[434], MUC4[435], IGF-1[217,430], NGAL[436-439], CEAM6[436,440], LG3BP[436], MMP7[436], MUC5B[436], MCM5[441,442], Trypsinogen-1[443], Trypsinogen-2[443]
Liquid biopsy	Methylated DNA: TFP12[444], NPTX2[444], CCND2[444]
RNA	MiRNA: miR-10b[292,445], miR-106b[292,445], miR-30c[292,445], miR-155[292,445], miR-212[292,445], miR-1247[446], miR-200a[446], miR-200b[446]

MCM5: Minichromosome maintenance protein 5; NGAL: Neutrophil gelatinase-associated lipocalin; sLR11: Soluble LDL receptor relative with 11 ligand-binding repeats; IGF1: Insulin-like growth factor 1; LG3BP: Galectin-3-binding protein; CEAM6: Carcinoembryonic cell adhesion molecule 6; TFP12: Methylated tissue factor pathway inhibitor 2; NPTX2: Neuronal pentraxin II gene; CCND2: G1/S-specific cyclin-D2; VEGF: Vascular endothelial growth factor; CEA: Carcinoembryonic antigen; MiRNA: MicroRNA.

Table 9 Faecal diagnostic biomarkers implicated in pancreatic cancer

Type	Candidate marker
Protein	Adnab-9[450,451]
RNA	MiRNA: miR-181b[452], miR-210[452], miR-155[453], miR-216a[453], miR-196a[452,453], miR-143[453]
Liquid biopsy	Mutant KRAS[454,455], mBMP3[456]

MiRNA: MicroRNA.

Citation: O'Neill RS, Stoita A. Biomarkers in the diagnosis of pancreatic cancer: Are we closer to finding the golden ticket? World J Gastroenterol 2021; 27(26): 4045-4087
URL: https://www.wjgnet.com/1007-9327/full/v27/i26/4045.htm
DOI: https://dx.doi.org/10.3748/wjg.v27.i26.4045