Table 2.

Summary of important blood-based protein biomarker candidates for EC detection.

Potential Biomarker	Gene Names	Summary of Evidence	Proteomic Techniques Used	Known Biochemical Function	Limitations	Panels
Serum Amyloid A (SAA)	SAA1	Inconsistent evidence Upregulated in EC in some studies [60,61]. No difference between cases and controls in others [62,63].	Isobaric tags for relative and absolute quantification (iTRAQ) technology and 2-dimensional liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS). Particle-enhanced immunonephelometry and LS–MS/MS.	High density lipoprotein. Modulates inflammation. Metabolism and transport of cholesterol. Acute phase reactant	Lacks selectivity as also elevated in lung, colon and other cancers	SAA+HE4 had 73.3% sensitivity and 64% specificity [62]
Prolactin (PRL)	PRL	Consistent but limited evidence Sensitivity of 98.3% and specificity of 98% [57]. Upregulated in EC with 16.3% sensitivity and 100.0% specificity at PRL >30 ng/mil [64].	Multiplex xMAP™ bead-based immunoassay Electrochemoluminescence immunoassay	Single-chain protein closely related to GH Secretion by stromal cells in response to tumour growth and differentiation Cytokine with immune and inflammatory functions.	Elevated in ovarian, pancreatic and lung cancers.	Prolactin, GH, TSH, eotaxin and E-selectin had better accuracy [57]
Human Epididymis Protein 4 (HE4)	WFDC2	Consistent (evidence from meta-analysis) Sensitivity and specificity of 0.65 (95% CI 0.56–0.73) and 0.9 (95% CI (0.8–0.95) respectively [55].	Enzyme immunoassay, Microparticle immunoassay Electrochemiluminescence	A member of the Whey acidic protein family, located on chromosome 20q 12–13 and acts as a proteinase inhibitor (trypsin inhibitor properties). Possible role in sperm maturation	Expressed in ovarian, renal, lung, colon and breast cancers Suboptimal sensitivity Methodological heterogeneity across studies.	HE4+CA125 57–76% sensitivity and 90–100% specificity [65,66,67,68]
Alpha-1-beta-gylycoprotein (AIBG)	AIBG	Limited evidence Upregulated in EC [69]	2-Dimensional gel electrophoresis	Plasma glycoprotein encoded by A1BG gene with unknown function.	Limited evidence Few studies, obsolete technique	None
Complement factors (C3, C4A, C4B)	C3, C4A, C4B	Limited evidence Upregulated in EC [70]	LC–ESI–QTOF(MS1)	Complement proteins involved in immunity and tolerance.	Limited evidence Few studies, small sample size High abundance proteins with low specificity for EC.	None
Cancer Antigens CA125 CA72.4, CA15-3	MUC 16 TAG-72 MUC 1	Consistent evidence CA125 (MUC 16) sensitivity of 17.8–52.6% and specificity of 33.35% to 95% [37].	Enzyme-linked immunosorbent assay (ELISA) Electrochemiluminescence Multiplex bead-based immunoassay	Mucin family glycoprotein, a component of the female reproductive tract, respiratory and ocular surfaces.	Sub-optimal diagnostic accuracy. Elevated in several other malignancies such as ovarian and pancreatic cancers.	See above
Apolipoproteins (A-IV), C1	APOA1-4 APOC1	Limited and inconsistent evidence Apo A-IV Downregulated in EC [60,70,71]. AI showed SEN 78% and SPE 90%. Apo C1 Upregulated (SEN 82%, SPE 86%) [71].	LC–ESI–QTOF (MS1)/SELDI TOF (MSI) SELDI TOF (MSI)	Lipid transport proteins, stabilise lipoprotein structure and act as enzyme cofactors.	Sub-optimal diagnostic accuracy. High abundance blood proteins with low specificity for EC.	ApoA-1+TTR+TF 71% SEN, 88% SPE [72]
Clusterin (CLU)	CLU	Limited Upregulated in EC [69]	2 DE Electrophoresis	Also known as Apolipoprotein J, Chaperone with anti-apoptotic properties, involved in preventing the aggregation of non-native protein	Limited evidence. Involved in many conditions related to oxidative stress such as ageing, cancers, neuro- degenerative diseases.	None
Antithrombin III (SERPINC I)	SERPINC 1	Limited Upregulated in EC [69]	2 DE Electrophoresis	Glycoprotein produced by the liver, involved in the coagulation system. May inhibit angiogenesis.	Limited evidence, low specificity for EC.	None
Alpha 1 antitrypsin (SERPINA1)	SERPINA1	Limited Downregulated in EC [69]	2 DE Electrophoresis	A serine protease inhibitor, inhibits enzymes such as trypsin and neutrophil elastase, produced in the liver and transported to the lungs	Limited evidence, low specificity for EC.	None
Human chitinase-3 like protein1 (YKL-40)	CHI3L1	Consistent, limited Upregulated in EC, 76% sensitivity, 89% specificity [73,74].	Enzyme-linked immunosorbent assay (ELISA)	Glycoprotein of the chitinase family, involved in degradation of extracellular matrix.	Nonspecific. Elevated in colorectal, breast, leukaemia, lung, melanoma cancers, rheumatoid arthritis etc.	None
Dickkopf-related protein 3 precursor (DKK3)	DKK3	Limited, inconsistent Upregulated in EC [75] No difference between cases and controls [74]	Enzyme-linked immunosorbent assay (ELISA)	Member of the Wnt signalling pathway important in cell division, formation and cell death during embryogenesis. Reported pro-angiogenic effect in tumour growth.	Limited and inconsistent evidence. Implicated in bone disease, cancer and Alzheimers’ disese.	None
Visfatin (NAMPT)	NAMPT	Limited Upregulated in EC, 14.9± 10.6 ng/mL and 8.1± 6,9 ng/mL in EC vs. controls respectively (p:0.011) [76]	Enzyme-linked immunosorbent assay (ELISA)	Secreted by visceral fat, mimics insulin. Possible involvement in metabolic pathways, immune response and cancers.	Limited evidence, may be surrogate for EC risk factors.	None
VEGFA, VEGFVEGFC	PDGFC	Limited, Inconsistent Upregulated in EC [77,78] in some studies, Down regulated in EC [57] in others.	Enzyme-linked immunosorbent assay (ELISA)	Endothelial cell growth factor involved in physiological and pathological angiogenesis.	Limited and inconsistent evidence, non-specific, elevated in many physiological and pathological states.	None
TSH, ACTH, FSH	CGA, POMC, CGA	Limited TSH and ACTH upregulated in EC while FSH is downregulated [57]	Enzyme-linked immunosorbent assay (ELISA), multiplex bead based immunoassay.	TSH and ACTH: communication between immune cells and regulation. FSH: Glycoprotein regulating growth and reproductive processes.	Limited evidence, all non-specific.	Prolactin, GH, TSH, eotaxin and E-selectin had better accuracy [57]
ICAM1/CD54	ICAM 1	Limited Upregulated in EC [79]	Flow cytometry	Leucocyte-endothelial transmigration	Limited evidence	None
Interleukin s/receptors (IL31, 33, IL2R)	IL31, IL33, IL2R	Limited Upregulated in EC [57]	Enzyme-linked immunosorbent assay (ELISA), multiplex bead based immunoassay.	Protein expressed on the surface of immune cells and response to cytokines.	Limited evidence	None
Cyclophilin A (CypA)	PPIA	Limited Upregulated in EC [80,81]	Two-dimensional gel electrophoresis and MALDI-Q-TOF MS/MS	Ubiquitous protein, ubiquitous protein, regulates protein folding and trafficking. Plays role in malignant transformation.	Limited evidence, non-specific, high abundance protein, increases with aging and pro-inflammatory conditions such sepsis.	None
Sperm associated antigen-9	SPAG9	Limited Upregulated in EC vs. controls: 18.3 (12.7–53.8) vs. 14.1(4.3–65.3); SEN 70.4% & SPE 82.5% at SPAG9 > 17 ng/mL [82]	Enzyme-linked immunosorbent assay (ELISA).	Scaffold protein involved in signalling pathways, Expressed in testicular haploid germ cells, implicated in infertility.	Limited evidence, non-specific, elevated in cervical, bladder and lung cancers.	None
Growth-regulated oncogene alpha (CXCL1)	CXCL1	Limited Upregulated in EC vs. controls (145(70–270)/90(45–237), p < 0.001. AUC = 0.80 [83]	Immunoassay	Chemokine involved in inflammation and tumorigenesis.	Non-specific, elevated in colorectal, melanoma, gastric cancer, ovarian cancer etc.	None
Growth differentiation factor 15 (GDF-15)	GDF15	Limited Upregulated in EC vs. controls. AUC 0.86 [84]	Immunoradiometric sandwich assay with polyclonal goat antihuman GDF-15 antibodies.	A transforming growth factor involved in tissue differentiation and maintenance.	Nonspecific, elevated in ovarian thyroid, pancreatic and colon cancers	None
Adiponectin, Leptin	ADIPOQ LEP	Consistent Adiponectin: Downregulated in EC vs. control (mean g/mL 11.3 vs. 17.2 (p < 0.0001) [85] Leptin: Upregulated in EC vs. control, mean ng/mL (19.5 vs. 13.4, p = 0.03) [85]	Enzyme-linked immunosorbent assay (ELISA) and RIA	Adipokines with metabolic, inflammatory and immune functions. Leptin is pro-inflammatory and adiponectin is anti-inflammatory.	Markers of obesity and metabolic syndrome. Non-specific.	None
FAS (APO1, CD95)	FAS	Limited Upregulated in EC [86].	Enzyme-linked immunosorbent assay (ELISA) and RIA	Fas-Fas ligand system important in CTL and NK mediated apoptosis.	Limited evidence	None
Leucine-rich glycoprotein (LRG1)	LRG1	Limited Upregulated in EC vs. controls [69].	2 DE Electrophoresis	Involved in protein-protein interaction signal transduction, cell adhesion and neovascularization.	Limited evidence, non-specific.	None
Matrix metalloproteinase 2,7,9	MMP2 MMP7 MMP9	Inconsistent, limited MMP7 upregulated in EC, MMP2 and MMP9 downregulated [87].	Enzyme-linked immunosorbent assay (ELISA), multiplex bead based immunoassay.	Enzymes involved in the degradation of extracellular matrix proteins during organogenesis, growth and tissue turnover.	Limited evidence	None
Transthyretin (TTR)/Transferin (TF)	TTR TF	Limited evidence Upregulated in EC [88]	Immunoassay	TTR: Transport protein that carries thyroid hormone and retinol-binding protein.TF: Iron-binding glycoprotein	Limited evidence, non-specific, associated with amyloidosis, cardiomyopathy etc.	TTR+TF+ ApoA:71%SEN &88% SPE
Inter-alpha-trypsin inhibitor family heavy chain-related protein (HRP)	ITIH4	Limited evidence Upregulated in EC [69]	2 DE Electrophoresis LC-ESI-QTOF (MS1)	Plasma glycoprotein, Serine protease inhibitors.	Limited evidence, non-specific. Dysregulated in multiple solid tumours.	None
Cleaved high molecular weight kininogen	KNG1	Limited evidence Down-regulated in EC vs. Controls [69,89].	2 DE Electrophoresis ITRAQ technology and 2D LC–MS/MS.	Multifunctional plasma proteins involved in the blood coagulation cascade.	Limited evidence, non-specific, high abundance plasma proteins.	None
Tumor necrosis factor receptor 1A (TNFRSF1A)	TNFRSF1A	Limited evidence Upregulated in EC [57].	Enzyme-linked immunosorbent assay (ELISA).	A ubiquitous receptor binding TNF, activating the NF-KB transcription factor, mediating apoptosis and regulating inflammation.	Limited evidence, few studies, not specific elevated in multiple sclerosis, dementia, schizophrenia etc.	None
Colony stimulating factor 1(CSF1)	CSF1	Limited evidence Upregulated in EC vs. Controls [90].	Enzyme-linked immunosorbent assay (ELISA).	Regulatory cytokine involved in the proliferation and differentiation of haematopoietic stem cells.	Limited evidence, few studies, non-specific.	None
Alpha fetoprotein (AFP)	AFP	Limited evidence Downregulated in EC [64]	Electrochemiluminescence	Plasma protein whose function in adult humans is less clear. Prevents transport of estradiol across placenta in rodents.	Limited evidence, non-specific, elevated in hepatic cancers germ cell tumours etc.	None