Table 1.
List of blood-based protein markers for GC diagnosis reported over the past 10 years.
| Biomarker(s) (a) | GO Biological Process (b) | Proteomic Technology (c) | Patients | Major Findings | Ref. | |
|---|---|---|---|---|---|---|
| Tumor Characteristics (d) | Group (nr) (e) | |||||
| Plasma | ||||||
| sHLA-G [P17693] (plasma and exosomal) |
Immune response | • ELISA | • Histology: 58.4% intestinal, 26.0% single ring cell adenocarcinoma, 15.6% other • clinical stages: 24.9% I–II, 56.6 III–IV • 39.9% poorly differentiated | GC (173), benign gastric disease (307; 86.3% chronic gastritis) | A higher sHLA-G concentration was found in GC vs. benign pathologies in GC-affected women vs. men, but no significant differences were found among the GC stages. sHLA-G was proposed as a potential diagnostic marker, although not as an adequate marker for staging GC. HLA-G was found in exosome membranes. | [43] |
| 18 proteins | Miscellaneous | • LC-MS/MS combined with TMT labeling | • Early-GC • adenocarcinoma (87%) and high-grade intraepithelial neoplasia (13%) • adenocarcinoma mainly well or moderately differentiated with invasive depth mainly limited to the mucosa | early-GC (15) and C (15) | From a total of 2040 proteins identified, 11 proteins were differentially abundant between early-GC patients and C (7 increased and 4 decreased). These proteins distinguished early-GC from healthy C (sensitivity = 66.7%, and specificity = 86.7%). | [44] |
| PD-1 [Q15116] PD-L1 [Q9NZQ7] macrophage and B-cell markers |
Adaptive immune response Adaptive immune response |
• ELISA • IHC | • Histology: 82.5% adenocarcinoma, 16% signet ring cell carcinoma, 1.5% undifferentiated cancer • clinical stages: 40% I–II, 60% III–IV • depth of invasion: 21% T1–T2, 79% T3–T4 • metastasis: 86% M0, 14% M1 | GC (63) | The plasma content of the sPD-1 receptor was significantly lower in GC vs. C; it inversely correlates with plasma sPD-L1 content and directly correlates with the tissue PD-L1 expression in stromal cells. Levels of sPD-L1 in GC vs. C were similar. | [45] |
| TrxR [Q86VQ6] | Cell differentiation | • Ultraviolet spectrophotometry • ECLA | • Adenocarcinoma | GC (896), benign gastric disease (322; e.g., stomach ulcer, stomach polyps, and gastritis) and C (228) | TrxR activity in GC [8.4 U/mL] was significantly higher than that in benign disease [6.1 U/mL] or C [3.7 U/mL]. ROC analysis of TrxR [AUC = 0.945; sensitivity = 95.6%; specificity = 76.3%] showed a better capacity of GC diagnosis than that of routine tumor markers (AFP, CA50, CA72-4, CA19-9, CA242, CEA). | [46] |
| sEGFR [P00533] TSLP [Q969D9] |
Cell morphogenesis/adhesion Positive regulation of chemokine production |
• 5 Luminex bead-based multiplex assay panels | • Clinical stages: 52.5% early/localized, 34.1% advanced, 13.4% unknown | GC (446) and individuals (774) as random subcohort. | Levels of sEGFR (Ptrends = 0.017) and TSLP (Ptrends = 0.034) were associated with GC risk. However, none of the Ptrends remained statistically significant after FDR correction. | [47] |
| DEK [P35659] | Chromatin remodeling | • WB • ELISA | • Histology: 72% diffuse, 28% intestinal • depth of invasion: 35% T1–T2, 65% T3–T4 • GC undoing gastrectomy • 39% localized, 61% infiltrative • 67% lymph node metastasis, 18% distant metastasis. | GC (92) and C (120) | Data from ROC curve analysis highlighted a better diagnostic accuracy (AUC = 0.797) and sensitivity (70.4) than CEA, CA 19-9, and CRP. | [48] |
| ApoC1 [P02654] GSN [P06396] SHBG [P04278] C4-A [P0C0L4] |
Cholesterol efflux Actin filament capping Androgen binding Complement activation |
• Label-free quantitative LC-MS/MS • bioinformatics • WB • ELISA | • Adenocarcinoma • histology: discovery cohort→25% diffuse, 71% intestinal, 4% mixed; verification cohort→29% diffuse, 71% intestinal; validation cohort→52% diffuse, 40% intestinal, 8% mixed • depth of invasion: discovery and verification cohorts→50% T1–T2, 50% T3–T4; validation cohort→34% T1–T2, 66% T3–T4 | Discovery cohort: GC (24) and C (9); verification cohort: GC (24) and C (9); validation cohort: GC (50) and C (68) | Four proteins (apolipoprotein C-1, gelsolin, SHBG, and complement component C4-A) increased in content in GC (p < 0.05). WB and ELISA confirmed higher SHBG levels in GC. Plasma SHBG levels were proposed as a potential early diagnostic biomarker for GC. | [49] |
| sHLA-G [P17693] | Immune response | • ELISA | • Histology: 37% diffuse, 49.3% intestinal, 13.7 mixed • clinical stages: 38% I–II, 62% III–IV • depth of invasion: 25.9% T1–T2, 74.1% T3–T4 • distant metastasis: 95% M0, 5% M1 | 81 GC, benign gastric disease (53, e.g., ulcer, gastritis, polypus) and C (77) | Plasma sHLA-G concentration was significantly higher in GC compared with both benign gastric disease and C. sHLA-G was proposed as a GC diagnostic marker, especially when combined with other GC markers (CA125, CA19-9, and CA72-4). | [50] |
| Serum | ||||||
| TNFα [P01375] IL-8 [P10145] |
Acute inflammatory response Angiogenesis |
• ELISA | • Histology: 10% diffuse, 48% intestinal, 22% signet ring cell, 12% mixed, 8% other types • various clinical stages | GC (82), CG (94), and C (53) | Moderate levels of TNF-α were detected in the C group (19.9 ± 19.5 pg/mL), which were significantly higher in CG patients (35.7 ± 28.0 pg/mL) but drastically decreased in GC (1.8 ± 5.9 pg/mL). TNF-α was proposed to behave as an inflammatory marker. IL-8 concentrations did not vary among patients. | [51] |
| ITGB6 [P18564] GPX3 [P22352] CRP [P02741] S100A9 [P06702] SERPINA4 [P29622] |
Cell adhesion/morphogenesis hydrogen peroxide catabolic process Acute-phase response Apoptotic process Negative regulation of endopeptidase activity |
• LC-MS/MS | • Histology: diffuse • WHO classification: 61% tubular, 39% poorly cohesive | 219 H. pylori positive and negative patients diagnosed with GC, gastritis, and ulcers | Two GC serum marker panels, 29preGC-P (with ITGB6 and GPX3) and 10GC-P (with CRP, S100A9, and SERPINA4), were proposed for the diagnosis of early stage and advanced GC independently on H. pylori status, respectively. | [52] |
| G-17 [P01350] PGI [P0DJD8] PGII [P20142] PGR [P06401] |
Response to food Digestion Digestion Cell–cell signaling |
• GastroPanel ELISA kit | • 75.0% adenocarcinoma, 11.1% mucinous carcinoma, 8.3% poorly cohesive, 2.8% tubular carcinoma, 2.8% papillary carcinoma | GC (36), AG (40), and C (40) | PGI levels significantly decreased in GC and AG compared to C groups (p < 0.05). No significant differences in PGII and G-17 levels between study groups. For GC, the optimal cut-off values of PGI and PGR (PGI to PGII ratio) were ≤35.25 ng/mL (sensitivity = 47.2%; specificity = 86.8%) and ≤5.27 ng/mL (sensitivity = 75%; specificity = 60.5%), respectively. The PGR was significantly lower in GC vs. C (p < 0.01). The combinations of PGI and PGR with risk factors were proposed to improve diagnostic accuracy (AUC for AG 74.8, 95% CI 64.0–85.7, p < 0.001; AUC for GC 75.5, 95% CI 64.2–86.8, p < 0.001). | [53] |
| IGF-1 [P08069] | Insulin receptor signaling pathway | • ELISA • IHC • real-time PCR assay | • Clinical stages: 39.3% I–II, 60.7% III–IV • invasion depth: 30% T1–T2, 38.4% T3–T4, any T 31.6% • distance metastasis: 68.4% M0, 31.6% M1 • H. pylori status: 69.6 pos, 30.4% neg | GC (60) and C (30) | Early GC stages showed a significantly low IHC score for IGF-1R and phosphorylated AKT, mTOR, and ERK proteins compared to the advanced stages. IGF-1 serum levels and the expression of candidate genes increased in advanced vs. early GC and positive vs. negative H. pylori status (p < 0.05). | [54] |
| IL-6 [P05231] PGI [P0DJD8] PGII [P20142] PGR [P06401] TNF-α [P01375] |
Acute-phase response Digestion Digestion Cell–cell signaling Acute inflammatory response |
• ELISA • IMMU-NITE1000 | Not detailed | Observation group: GC (50) with H. pylori; comparison group: GC (50) without H. pylori. | In the “observation” group, PGI and PGII were lower, while TNF-α, IL-18, and IL-6 were significantly higher than those in the “comparison” group (p < 0.05). | [55] |
| CEA [P06731] SAA [P0DJI8] IL-6 [P05231] |
Apoptotic process Acute-phase response Acute-phase response |
• Commercial kits | Not detailed | GC (122), gastric benign disease (37), and C (30) | SAA and IL-6 levels were higher in GC vs. C. The ROC curve for the combined detection of SAA, IL-6, and CEA showed AUC = 0.948, sensitivity = 91.0%, and specificity = 89.2%. | [56] |
| SIRT6 [Q8N6T7] | DNA repair-dependent chromatin remodeling | • ELISA | • Histology: 36.3% diffuse, 63.7% intestinal • clinical stages: 38.5% I–II, 60.7% III–IV • invasion depth: 25.9% T1–T2, 74.1% T3–T4 • distance metastasis: 85.9% M0, 14.1% M1 | GC (135), AG (68), and C (60) | Serum SIRT6 levels were lower in GC vs. AG and C. They were positively associated with tumor stage and metastasis and proposed as a diagnostic and predictive biomarker for GC. | [57] |
| AFP [P02771] CA125 [Q8WXI7] CEA [P06731] CA153 [n.a.] CA199 [n.a.] CA242 [n.a.] |
Progesterone metabolism Cell adhesion Apoptotic process |
• Multi-tumor marker detection kit based on protein chips | Not detailed | GC (268) and C (209) | Serum GC was associated with age, gender, and positive levels of AFP, CEA, CA125, CA199, and CA242. The positive levels of AFP and CA125 were related to distant GC metastasis. | [58] |
| SNCG [O76070] | Regulation of neurotransmitter secretion | • ELISA | • Clinical stages: 45% I–II, 55% III-IV • invasion depth: 34% T1–T2, 66% T3–T4 • distance metastasis: 83% M0, 17% M1 • H. pylori status: 41% positive, 59% negative | GC (87), gastric precancerous lesions (38), and C (44) | Detection of SNCG in serum and gastric juice was a good method for the early diagnosis of GC (cut-off value = 7.716 ng/mL; AUC = 0.924; sensitivity = 95.40%; specificity = 86.36%; p < 0.0001). Serum SNCG was related to TNM stage, lymph node metastasis, and tumor size. | [59] |
| DKK1 [O94907] TK1 [P04183] CA724 [n.a.] |
Cell morphogenesis Mitotic DNA replication |
• ELISA • ECLIA • ECLA | • GC without any type of treatment • clinical stages: 77.8% I–II, 22.2% III–IV | GC (63) and gastric benign disease (considered as C; 54) | The three serological indexes were higher in GC vs. C (p < 0.001). The ROC analysis for their combined detection showed an AUC = 0.923, with sensitivity and specificity higher than those of separate detection. | [60] |
| PD-1 [Q15116] PD-L1 [Q9NZQ7] |
Adaptive immune response Adaptive immune response |
• ELISA | • GC without any type of treatment • clinical stages: 66.6% I–II, 33.4% III–IV • patients undergoing gastrectomy and lymph node dissection | GC (30) and C (30) | Preoperative sPD-1 and sPD-L1 were lower in GC vs. C. The ROC analysis showed an AUC equal to 0.675 and 0.885 for sPD-1 and sPD-L1, respectively. | [61] |
| CXCL8 [P10145] CXCR2 [P25025] CEA [P06731] CA19.9 [n.a.] |
Angiogenesis Immune response Apoptotic process |
• ELISA • CMIA • turbidimetric assay | • Histology: 53% intestinal, 47% diffuse • clinical stages: 28% I–II, 69% III–IV, 3% undefined • invasion depth: 15.6% T1–T2, 84.4% T3–T4 • distant metastasis: 72% M0, 28% M1 | GC (64) and C (34) | Higher levels of CXCL8 and CXCR2 in GC vs. C. Serum CXCL8 was proposed as a promising biomarker for GC diagnosis, especially in combination with CA19-9 (sensitivity = 89%; specificity = 53%). | [62] |
| ITIH4 [Q14624] | Acute-phase response | • LC-MS/MS • WB • IHC | • Clinical stages: 53% I–II, 47% III–IV | Early-GC (38), advanced GC (70), LGN (28, precancerous group), CSG (37), OST (49, patients with other system malignant tumors), and C (178) | ITIH4 abundance in early GC (specificity = 94.44%) was significantly higher than those in the C and other GC groups. ITIH4 was proposed as a diagnostic marker for early-GC. | [63] |
| SOX3 [P41225] | Cell differentiation | • LC-MS/MS combined with TMT/iTRAQ labeling | • Locally advanced GC (55 cases) and early GC (5 cases) • invasion depth: 31.7% T1–T2, 68.3% T3–T4 • clinical stages: 33.3% I–II, 66.7% III–IV • degree of differentiation: 26.7% poorly, 31.7% moderately, 41.6% well • distant metastasis: 90% M0, 10% M1 | GC (60) and C (60) | Among proteins significantly differentially abundant, SOX3 was found to be higher in GC vs. C sera. | [64] |
| 19 proteins | Miscellaneous | • PEA (over 300 proteins tested) | • Clinical stages: 28% I–II, 71% III–IV, 1% undefined | GC (100) and C (50) | In total, 19 serum proteins distinguished GC from C, with a diagnostic sensitivity of 93%, specificity of 100%, and AUC of 0.99 (95% CI: 0.98–1). This protein signature increased diagnostic capacity, particularly in patients at TNM I-II stages (sensitivity = 89%; specificity = 100%; AUC = 0.99) and with high microsatellite instability (MSI) (91%, 98%, and 0.99) compared to individual proteins. | [65] |
| GKN1 [Q9NS71] | Digestion | • ELISA | Not detailed | Early GC (140), advanced GC (360), other cancers (768), and C (200) | Serum GKN1 levels in GC (median: 3.48 ng/μL) were lower than in C (median: 6.34 ng/μL). GKN1 levels were significantly higher in early GC (median: 4.31 ng/μL) than in advanced GC (median: 3.11 ng/μL). The ROC curve analysis distinguished early from advanced GC (AUC = 0.870). Serum GKN1 appeared as a promising and highly specific diagnostic biomarker for both early and advanced GC. | [66] |
| EphA1 [P21709] EREG [O14944] FGF-12 [P61328] FR-β [P14207] Galectin-8 [O00214] GHR [P10912] IFNGR1 [P15260] Integrin α 5 [P08648] Notch-3 [Q9UM47] SLAMF8 [Q9P0V8] TNFRSF19L [Q969Z4] |
Angiogenesis Angiogenesis Cell–cell signaling Cell adhesion Lymphatic endothelial cell migration Cytokine-mediated signaling pathway Positive regulation of gene expression Angiogenesis Notch signaling pathway Signaling receptor activity Apoptotic process |
• Human cytokine antibody • ELISA | • Clinical stages: IA • undifferentiated • tumor location: mucosa • no metastasis | Antibody array assay: GC (15) and C (10); ELISA: GC (20) and C (20) | In total, 11 serum cytokines increased in GC (p < 0.05) and were proposed as novel biomarkers for the early diagnosis of GC. | [67] |
| BIRC5 [A0A7L8XZM3] | Regulation of apoptotic process | • ELISA | Not detailed | 10.4% together with prostate cancer and glioblastoma from 67 patients with diagnosed cancer | Serum survivin level was high at GC diagnosis (p < 0.05). The optimal cut-off value of serum survivin was determined at >120.8 pg/mL. | [68] |
| CD59 [P13987] COF1 [P23528] S100A8 [P05109] ITIH4 [Q14624] |
Blood coagulation Actin cytoskeleton organization Acute inflammatory response |
• TMT labeling • LC-MS/MS and bioinformatics • WB | •Adenocarcinoma • stages: I/II | GC (10) and C (10) | A total of 105 proteins differed (p < 0.05) between GC and C, 69 being glycoproteins. The decrease in COF1 and the increase in ITIH4, S100A8, and CD59 could be useful in GC diagnosis. | [69] |
| IL-8 [P10145 ] TNF-α [P01375] CEA [P06731] IL-6 [P05231] CA72-4 [n.a.] |
Angiogenesis Acute inflammatory response Apoptotic process Acute phase response |
• Luminex 200 bead-based assay for IL-6, IL-8, and TNF-α determination • electrochemiluminescence | • Clinical stages: discovery cohort →36% early stage and 64% advanced stage; validation cohort→33% early stage and 67% advanced stage | Discovery cohort: GC (176) and C (204); validation cohort: GC (58) and C (66) | Serum IL-6 had the best diagnostic value in discriminating GC (AUC of joint analysis = 0.95). The multiparameter model with CEA, CA72-4, IL-6, IL-8. and TNF-α discriminated GC, early GC, and advanced GC from the healthy C one (sensitivity = 89.66%, 84.21%, and 92.31%; specificity = 92.42%, 90.91%, and 90.91%). | [70] |
| TK1 [P04183] CEA [P06731] CA19.9 [P15391] CA72-4 [n.a.] |
DNA synthesis Apoptotic process Antigen receptor-mediated signaling pathway |
• Cell Cycle Assay Kit • ECLIA assay kits | Not detailed | GC (169) and C (75) | TK1 was a good independent marker for GC. Its combination with CA19.9, CA72-4, and CEA performed better. The combined detection of the 4 markers was proposed to be useful for GC diagnosis. | [71] |
| AHSG [P02765] APOA-I [P02647] FGA [P02671] |
Acute-phase response Blood vessel endothelial cell migration Blood coagulation |
• MB-IMAC-Cu, MALDI-TOF-MS, and peptide pattern analysis • Nano Acquity UPLC MS/MS • ELISA | • Clinical stages: discovery cohort→50% I/II and 44% III/IV; validation cohort→38% I/II and 62% III/IV | Discovery cohort: GC (32) and C (30); validation cohort: GC (42) and C (28) | Among the 12 differential peptide peaks (p < 0.0001), the serum levels of FGA increased in GC vs. C (AUC = 0.98, p < 0.05), similar to AHSG and APOA-I (AUC = 0.92 and 0.83; p < 0.05), and these 3 proteins were proposed as valuable biomarkers for GC. | [72] |
| Leptin | Energy homeostasis, neuroendocrine function, and metabolism [Kelesidis 2010] | • ELISA | • Clinical stages: 16% I/II and 70% III/IV • invasion depth: 22% T1–T3 and 35% T4 • metastasis: 51% M0 | GC (63) and C (30) | Leptin concentrations were lower in GC vs. C (p = 0.009). A diagnostic role was proposed for serum leptin levels. | [73] |
| CA19.9 [P15391] CEA [P06731] AFP [P02771] CA125 [Q8WXI7] |
Antigen receptor-mediated signaling pathway Apoptotic process Progesterone metabolism Cell adhesion |
Not reported | • Invasion depth: 43% T1a and 57% T1b | Early GC (587) | The positive rates of CEA, CA19.9, AFP, and CA125 (4.3%, 4.8%, 1.5%, and 1.9%, respectively) were low for early GC. The combination of CEA, CA125, and CA19–9 has been reported to lead to higher sensitivity than CEA alone. | [74] |
| DcR3 [O95407] | Apoptotic process | • ELISA | • Metastasis: 30% M0 and 70% M1 | GC (10) and C (25) | DcR3 levels increased in GC patients (2.04 ± 1.01, p = 0.0061). ROC analysis showed high specificity (90%), sensitivity (85.7%), and AUC (82.3%; threshold = 243.7 pg/mL) to distinguish GC. DcR3 was proposed as a biomarker for GC diagnosis. | [75] |
| IL-2R [P01589] VEGF [P15692] TGF-β1 [P01137] |
Activated T cell proliferation Angiogenesis ATP biosynthetic process/cell migration |
• ELISA | • Clinical stages: 5.8% II, 94.2% III-IV | GC (35) and C (32) | Serum levels of sIL-2R, VEGF, and TGF-β1 were higher in GC vs. C. Serum sIL-2R levels were also positively associated with VEGF and TGF-β1 levels. | [76] |
| IL-16 [Q14005] | Cytokine-mediated signaling pathway | • ELISA • WB | Not detailed | GC (98) and C (98) | IL-16 levels in GC vs. C were higher (2.59-fold; p < 0.05). It differentiated GC from C (AUC = 0.882, sensitivity = 79.6%, and specificity = 78.6%). IL-16 was proposed as a novel diagnostic marker for GC. | [77] |
| CLU-1 [P10909] SRMS [Q9H3Y6] THB1 [P10828] VN [P04004] |
Cell morphogenesis Cell differentiation Cell differentiation Cell adhesion |
• Label-free quantitative LC-MS/MS • MS-based MRM • WB | • Discovery cohort: 50% early and 50% advanced; validation cohort: 52% early and 48% advanced | Discovery cohort: GC (6) and C (3); validation cohort: GC (60) and C (29) | In early GC, 119 and 176 proteins were up- and downregulated, respectively. Four proteins (VN, CLU-1, THB1, SRMS) changed in GC vs. C and discriminated GC with sufficient specificity and selectivity. | [78] |
| Cat S [P25774] | Antigen processing and presentation | • ELISA • WB • immunohistochemistry | • Clinical stages: 44.5% I–II, 55.5% III–IV | GC (119) and C (99) | Serum Cat S levels increased in GC (AUC = 0.803, sensitivity = 60.7%, and specificity = 90.0%). | [79] |
| COPS2 [P61201] CTSF [Q9UBX1] NT5E [P21589] TERF1 [P54274] |
Negative regulation of transcription by RNA polymerase II Antigen processing and presentation of exogenous peptide antigen via MHC class II Adenosine biosynthetic process Cell division |
• Proteome microarray • ELISA | • Invasion depth: discovery phase I→54% T1–T2, 46% T3–T4; training/testing phase→52% T1–T2, 48% T3–T4 • metastasis: 96% M0 and 4% M1 | Discovery phases I and II→GC (37–300) and C (50–300); training set→GC (108) and C (108), testing set→GC (192) and C (192); validation phases I and II→ GC (100–200) and C (100–200) | A final panel of 4 biomarkers (COPS2, CTSF, NT5E, and TERF1) provided high diagnostic power (sensitivity = 95% and specificity = 92%) to differentiate GC from C, and it was proposed as a non-invasive diagnostic index for GC. | [80] |
| ADAM8 [P78325] VEGF [P15692] PGI [P0DJD8] PGII [P20142] IgG to H. pylori |
Angiogenesis Angiogenesis Digestion Digestion |
• Multiplex assay | • Newly diagnosed primary adenocarcinoma • invasion depth: 36% T1–T2, 64% T3–T4 • clinical stages: 23.1% I, 32.6% II, and 44.2% III; 17% early stage and 83% advanced stage | Training set: GC (228) and C (190); validation set: GC (48) and C (47) | The selected panel of markers differentiated between the majority of GC and C with high accuracy (RF 79.0%, SVM 83.8%, logistic regression 76.2%) in the training set as well as in the validation one (RF 82.5%, SVM 86.1%, logistic regression 78.7%). | [81] |
| FGA carboxyl-terminal fraction [P02671] | Coagulation | • SELDI ProteinChip analysis • LC-MS/MS • immunodepletion • chemiluminescence | • Invasion depth: training set→30% T1–T2, 70% T3–T4; validation set→20% T2, 80% T3–T4 | Training set: GC (30) and C (30); validation set: GC (10) and C (10) | Peak 5910 showed good performance in distinguishing GC from C with high sensitivity and specificity (AUC = 0.89; training set→sensitivity = 86.3% and specificity = 91.3%; validation set→sensitivity = 100% and specificity = 93.3%). | [82] |
| ITIH4 [Q14624] SAA1 [P0DJI8] |
Acute-phase response Acute-phase response |
• iTRAQ labeling • SCX fractionation • LC-MS/MS • LC-MRM | • Histology: discovery cohort→100% at III; validation cohort→60% at III, 30% at II, 10% signet ring cell | Discovery cohort: GC (10) and C (10); validation cohort: GC (10) and C (10) | In GC, a total of 59 proteins were differentially abundant, 48 being up- (iTRAQ ratios of ≥2) and 11 being downregulated (iTRAQ ratios of ≤0.5). Validation analyses confirmed the increased levels of ITIH4 and SAA1 (p < 0.05) in GC. | [83] |
| IL-18 [Q14116] | Angiogenesis | • ELISA | • Clinical stages: 16% I-II, 70% III, and 14% undetermined • invasion depth: 22% T1–T3, 35% T4, and 43% unknown | GC (63) and C (30) | The baseline IL-18 levels of GC were higher than those of C (p < 0.001), indicating that IL-18 was a good serological diagnostic GC marker. No correlation was observed between IL-18 concentrations and clinical characteristics (p > 0.05). | [84] |
| ANXA2 [P07355] | Angiogenesis | • ELISA | • Clinical stages: 16% I-II, 70% III, and 14% undetermined • invasion depth: 22% T1–T3, 35% T4, and 43% unknown | GC (63) and C (30) | The baseline ANXA2 levels of GC were higher than those of the C group (p < 0.001). The known clinical variables were not correlated with ANXA2 concentrations (p > 0.05). | [85] |
| ANGPTL2 [Q9UKU9] | Cell–cell signaling | • IHC • ELISA | • Clinical stages: screening phase→50% I and 50% IV; validation phase→51% I, 16% II, 18% III, and 15% IV | Screening phase: GC (16) and C (23); validation phase: GC (194) and C (45) | Serum ANGPTL2 in GC was higher than in C (p < 0.05) and distinguished GC patients from C patients (AUC = 0.865). The validation step confirmed higher ANGPTL2 levels in GC vs. C (p < 0.0001). | [86] |
| SERPINA1 [P01009] ENOSF1 [Q7L5Y1] |
Acute-phase response Amino acid/carbohydrate catabolic process |
• WCX fractionation and MALDI-TOF MS • LC-MS/MS • ELISA | • Invasion depth: discovery cohort→9% I, 20% II, 46% III, and 25% IV (characteristics of patients belonging to the validation cohort not detailed) | Discovery cohort: GC (70); validation cohort: GC (36) and C (36) | Peptides with m/z values of 1546.02 and 5335.08 showed a higher concentration in the spectra of GC vs. controls (p < 0.001) and were identified as belonging to SERPINA1 and ENOSF1. Only ENOSF1 concentration was higher in GC (1.55-fold, p < 0.001) and it was proposed as a biomarker for GC diagnosis. | [87] |
Abbreviations: ADAM8, adisintegrin and metalloproteinase domain-containing protein 8; AFP, α fetoprotein; AG, atrophic gastritis; AHSG, α-2-HS-glycoprotein; AKT, protein kinase B; ANGPTL2, angiopoietin-like protein 2; ANXA2, annexin A2; APOA-I, apolipoprotein A1; ApoC1, apolipoprotein C-1; AUC, area under curve; BIRC5, baculoviral IAP repeat containing 5 isoform 5 transcript variant 6 (surviving); C, healthy controls; C4-A, complement component; CA19.9, carbohydrate antigen 19.9; CA72-4, carbohydrate antigen 72-4; CA125, cancer antigen 125; CA153, cancer antigen 153; CA199, cancer antigen 199; CA242, cancer antigen 242; CA724, cancer antigen 724; Cat S, cathepsin S; CD-59, CD-59 glycoprotein; CEA, carcinoembryonic antigen; CLIA, chemiluminescence immunosorbent assay; CLU-1, clusterin isoform 1; CMIA, chemiluminescent microparticle immunoassay; COF1, cofilin-1; COP9, constitutive photomorphogenic homolog subunit 2; COPS2, COP9 signalosome complex subunit 2; CRP, C-reactive protein; CSG, chronic superficial gastritis associated with H. pylori; CTSF, cathepsin F; CXCL8, interleukin 8; CXCR2, C-X-C chemokine receptor type 2; DcR3, decoy receptor 3; DEK, protein DEK; DKK1, dickkopf-1 protein; ECLA, enhanced chemiluminescence assay; ECLIA, electro-chemiluminescence immunosorbent assay; ELISA, enzyme-linked immunosorbent assay; EphA1, erythropoietin-producing hepatocellular A1; ELISA, enzyme-linked immuno assay; ENOSF1, mitochondrial enolase superfamily member 1; EREG, proepiregulin; ERK, extra-cellular signal-regulated kinase; FGA, fibrinogen α chain; FGF-12, fibroblast growth factor 12; FIB, fibrinogen; FR-β, folate receptor β; G-17, gastrin-17; GC, gastric cancer; GHR, growth hormone receptor; GKN1, gastrokine 1; GPX3, glutathione peroxidase 3; GSN, gelsolin; IFNGR1, interferon gamma receptor 1; IGF-1, insulin-like growth factor 1; IHC, immunohistochemistry; IL-6, interleukin 6; IL-8, interleukin 8; IL-16, interleukin 16; IL-18, interleukin 18; IL-2R, Interleukin-2 receptor subunit α; ITGB6, integrin β-6; ITIH4, inter-α-trypsin inhibitor heavy chain H4; iTRAQ, isobaric tags for relative and absolute quantitation; LC, liquid chromatography; M0, non-metastatic; M+, metastatic; MB, magnetic bead-based; MS, mass spectrometry; MB-IMAC-Cu, magnetic beads-based immobilized metal-ion affinity chromatography; MRM, multiple reaction monitoring; Notch-3, neurogenic locus notch homolog protein 3; NT5E, ecto-5E-nucleotidase; OST, patients with other system malignant tumors; PD-1, programmed cell death protein 1; PDL-1, Programmed death-ligand 1; PEA, multiplex proximity extension assay; PGI, pepsinogen I; PGII, pepsinogen II; PGR, PGI to PGII ratio; ROC, receiver operating characteristic; S100A8, protein S100-A8; S100A9, protein S100A9; SAA, serum amyloid A; SAA1, serum amyloid A protein; sEGFR, soluble epidermal growth factor receptor; SELDI, surface-enhanced laser desorption/ionization; sIL-2R, soluble interleukin-2 receptor; SERPINA4, kallistatin; SHBG, sex hormone-binding globulin; SIRT6, sirtuin 6; sHLA-G, soluble human leukocyte antigen G; SLAMF8, signaling lymphocytic activation molecule family; SNCG, synuclein gamma protein; SOX3, transcription factor SOX-3; SRMS, tyrosine-protein kinase; TERF1, telomeric repeat binding factor 1; TGF-β1, transforming growth factor beta-3 proprotein; THB1, thrombospondin 1; TK1, thymidine kinase 1; TMT, tandem mass tags; TNFα, tumor necrosi factor α; TrxR, thioredoxin reductase; TSLP, thymic stromal lymphopoietin; TNFRSF19L, tumor necrosis factor receptor superfamily member 19L; VEGF, vascular endothelial growth factor; VN, vitronectin; WB, Western blot; WCX, weak cation exchange. (a) Protein name abbreviation is followed by the UniProtKB ID; (b) gene ontology biological process after interrogation with UniProtKB (https://www.uniprot.org/uniprotkb/; accessed on 30 September 2023): only the first main GO term is reported; (c) proteomics techniques used to analyze proteins are reported; (d) among the clinical characteristics detailed by authors, only those about tumor clinical stages (from I to V), histological types (intestinal, diffuse, mixed), gastric anatomic subsites (proximal, distal), pathological stages with the TNM system (pTNM stages, from T1 to T4), and presence of metastasis (M0, M1) are, if present, reported; (e) nr, number of individuals per group.