Review and Comparison of Cancer Biomarker Trends in Urine as a Basis for New Diagnostic Pathways
Abstract
:1. Introduction
- Diagnostic: used for risk stratification and early cancer detection.
- Prognostic: provide an indication of the likely progression of the disease.
- Predictive: used for predicting treatment measures to be taken on a patient.
2. Cancer Biomarkers in Urine
2.1. Lung Cancer
2.2. Breast Cancer
2.3. Prostate Cancer
2.4. Colorectal Cancer
2.5. Gastric Cancer
2.6. Hepatic Cancer
2.7. Bladder Cancer
2.8. Pancreatic Cancer
2.9. Renal Cancer
2.10. Testicular Cancer
3. Discussion
3.1. Design of the Experiment
3.2. Recurrent Cancer Biomarkers and Their Levels in Urine
3.3. Investigation of the Correlation between Urine Odour Alteration and Cancer Presence
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Authors (Year) [Ref] | Population | Experimental Method | Biomarkers | Results |
---|---|---|---|---|
Yang et al. (2010) [33] | 35 LC patients (47–75 years) 32 controls (34–67 years) | Sample preparation: thawing, centrifugation, treatments with chemicals and film filtration Analytical technique; LC-MS | Taurine Hippuric acid Pipecolic acid Alpha-M-phenylacetyl-L-glutamine Valine Proline betaine isotope Phenylalanine Betaine Carnitine Leucylproline 3-Hexaprenyl-4-hydroxy-5-methoxybenzoic acid | All of these biomarkers are up-regulated in LC patients than controls |
Guadagni et al. (2011) [34] | 10 LC patients 25 controls | Sample preparation: thawing, treatments with chemicals and extraction by SPME Analytical technique: GC-MS | Hexanal Heptanal | Hexanal concentration is higher in LC patients than in controls, while heptanal concentration is not so different between LC patients and controls |
Hanai et al. (2012) [35] | 20 LC patients (59–77 years) at different stages 20 controls: (38–62 years) | Sample preparation: thawing, centrifugation, filtration and extraction by SPME Analytical technique: GC-TOF MS | Tetrahydrofuran 2-chloroethanol 2-pentanone 2-methylpyrazine Cyclohexanone 2-ethyl-1-hexanol 2-phenyl-2-propanol Isophorone | All of these biomarkers are up-regulated in LC patients than controls, the most significant are six of them. 2-pentanone is important for the differentiation between patients with adenocarcinoma and those with squameous cell, because in the first one 2-pentanone is higher. |
Authors (Year) [Ref] | Population | Experimental Method | Biomarkers Proposed | Results |
---|---|---|---|---|
Fernandez et al. (2005) [44] | 22 breast cancer (BC) patients 27 controls | Sample preparation: Thawing, pre-treatment with chemicals and centrifugation Analytical technique: Gelatine zymography | Neutrophil Gelatinase-Associated Lipocalin (NGAL) Matrix metalloproteinase (MMP-9) | Increased levels of NPAL and MMP-9 were found in urine from women with breast cancer, resulting in stimulation of tumor growth |
Pories et al. (2008) [45] | 148 BC patients at different stages 80 controls | Sample preparation: Thawing, pre-treatment with chemicals and centrifugation Analytical technique: Zymography Immunoblotting ADAM 12 | Matrix metalloproteinase (MMP-9) ADAM 12 | ADAM 12 and MMP-9 are highly significant predictors of breast cancer, which can be used in conjunction with the Gail model, allowing the discrimination of control women from patients affected by breast cancer with sensitivity and specificity above 97%. |
Nam et al. (2009) [46] | 50 BC patients at different stages 50 controls | Sample preparation: Pre-treatment with chemicals and extraction Analytical technique: AMDIS | Homovanillate; 4-hydroxyphenylacetate; 5-hydroxyindoleacetate; urea | Homovanillate, 4-hydroxyphenylacetate, 5-hydroxyindoleacetate and urea were identified to be different in cancer and control urine |
Woo et al. (2009) [47] | 10 BC patients 12 cervical cancer 9 ovarian cancer 22 controls | Sample preparation: Thawing and pre-treatment with chemicals Analytical technique: GC-MS LC-MS | 8-hydroxy-2-deoxyguanosine 5-hydroxymethyl-2-deoxyuridine | Urinary biomarkers were found by metabolite profiling and validated by multivariate data analysis and ANOVA. 8-hydroxy-2-deoxyguanosine and 5-hydroxymethyl-2-deoxyuridine levels were increased probably as consequence of oxidative DNA damage involved in cancer development. |
Slupsky et al. (2010) [48] | 48 BC patients (30–86 years) at different stages 72 controls (19–83 years) | Sample preparation: Thawing and pre-treatment with chemicals Analytical technique: h-NMR | Creatinine; Acetate; Succinate; Isoleucine; Sucrose; Leucine; Urea; Ethanolamine; Dimethylamine; Creatinine; Alalnine; Uracil; Valine | Urinary metabolites levels were decreased in breast cancer patients with respect to controls. |
Silva et al. (2012) [49] | 26 BC patients 21 controls | Sample preparation: Thawing and pre-treatment with chemicals Analytical technique: GC-qMS | 4-carene; 3-heptanone; 1,2,4-trimethylbenzene; 2-methoxythiophene Phenol | 4-carene, 3-heptanone, 1,2,4-trimethylbenzene, 2-methoxythiophene, Phenol levels in urine samples from breast cancer patients with respect to controls. |
Authors (Year) [Ref] | Population | Experimental Method | Biomarkers | Results |
---|---|---|---|---|
Sreekumar et al. (2009) [57] | 59 prostate cancer (PrC) patients 51 controls | Sample preparation: organic and aqueous extractions of liquid urine, drying on TurboVapR Analytical techniques: LC-MS GC-MS ID GC-MS | Sarcosine Uracil; Kynurenine Glycerol-3-phosphate Leucine Proline | Sarcosine was significantly higher in urine sediments (AUC 71%) and supernatants (AUC 67%) of PrC patients; Uracil, Kynurenine, Glycerol-3-phosphate, Leucine, Proline were elevated upon disease progression. |
Jentzmik et al. (2010) [59] | 107 PrC patients at different stages 45 controls | Sample preparation: Centrifugation, no info about headspace enrichment Analytical techniques: Ez:faast amino acid analysis (SPME followed by GC-MS) | Sarcosine | Median Sarcosine/creatinine was 13% lower in PrC patients than in controls |
Jiang et al. (2010) [58] | 5 PrC patients 5 controls (18–78 years) without kidney disease | Sample preparation: thawing of frozen samples and pre-treatments with chemicals Analytical techniques: HPLC/MS/MS | Sarcosine Proline Kynurenine Uracil Glycerol-3-phosphate Creatinine | The ratio nM metabolites/µM creatinine was higher in urine from PrC patients with respect to controls |
Wu et al. (2010) [61] | 20 PrC patients at different stages 28 controls: 8 BHP 20 healthy male | Sample preparation: thawing of frozen sample, centrifugation and treatments with chemicals and membrane filtration Analytical techniques: ID GC-MS | Sarcosine; Propenoic acid Pyrimidine Dihyroxybutanoic acid Creatinine Purine Glucopyranoside Ribofuranoside Xylonic acid Xylopyranose | PrC patients average sarcosine value were 13% higher than healthy controls and 19% higher than BPH controls. Also propenoic acid, dihyroxybutanoic acid, creatinine, and xylonic acid, dihyroxybutanoic acid and xylonic acid, concentrations were higher in PrC patients. |
Stabler et al. (2011) [62] | 54 PrC patients: 29 recurrent free 25 PrC recurrence | Sample preparation: no info Analytical techniques: GC-MS | Cysteine Homocysteine Dimethylglycine Sarcosine | Higher serum homocysteine, cystathionine, and cysteine levels independently predicted risk of early biochemical recurrence and PrC aggressiveness. The methionine further supplemented known clinical variables to increase sensitivity and specificity. |
Bianchi et al. (2011) [63] | 33 PrC patients (clinically localized PrC) 23 controls: 13 healthy 10 BHP | Sample preparation: no info Analytical techniques: SPME/GC-MS | Sarcosine N-ethylglycine | µg Sarcosine/g Creatinine discriminates between healthy, BHP and PrC patients. The model built considering a cut-off 179µg/g achieved a sensitivity of 79% and a specificity of 87%. |
Shamsipur et al. (2012) [64] | 12 PrC patients 20 controls (30–65 years) | Sample preparation: thawing and centrifugation Analytical techniques: DDLLME/GC-MS | Sarcosine Alanine Proline Leucine | Sarcosine mean concentrations were higher in PrC patients; Leucine mean concentration was lower in PrC patients |
Heger et al. (2014) [65] | 32 controls 32 PrC patients at different stages | Sample preparation: pre-treatment with chemicals, centrifugation Analytical techniques: IELC IEMA | aspartic acid; threonine; methionine; isoleucine; leucine; tyrosine; arginine; sarcosine; proline; uric acid; urea; PSA; fPSA; glucose; creatinine; pH; total proteins; concentrations of K+, Na+, Cl− | All amino acids were increased in PrC patients, except for phenylalanine amounts. In controls, higher levels of K+ and uric acid and lower levels of urea and creatine were detected. PSA and free PSA were below the detection limit in controls. |
Khalid et al. (2015) [66] | 59 PrC patients (50–88 years) 43 controls (41–81 years) | Sample preparation: Thawing of frozen samples, pre-treatment with chemicals and incubation at 60 °C in a water bath for 30 min Analytical techniques: SPME/GC-MS | 2,6-dimethyl-7-octen-2-ol Pentanal 3-octanone 2-octanone | Except for pentanal, all of these compounds were down-regulated and/or less frequently present in the urine samples from PrC patients. Model AUC based on 4 biomarkers discovered was 63–65%, while it was 74% (RF) and 65% (LDA) if combined with PSA level. |
Tsoi et al. (2016) [67] | 66 PrC patients at different stages of disease 99 controls: 88 BHP 11 healthy | Sample preparation: Thawing, centrifugation, pre-treatment with chemicals Analytical techniques: UPLC-MS/MS | Putrescine (Put) Spermidine (Spd) Spermine (Spm) | Normalized Spd was significantly lower in PrC than in BHP patients and controls The AUC for normalized Put, Spd and Spm were found to be 0.63 ± 0.05, 0.65 ± 0.05 and 0.83 ± 0.03 respectively |
Sroka et al. (2016) [68] | 25 PrC patients at different stages of disease 25 controls with BHP | Sample preparation: Pre-treatment with chemicals, centrifugation, incubation at 55 °C for 10 min. Analytical techniques: LC-ESI-QqQ-MS | Arginine Homoserine Proline Tyramine | In PrC samples, higher concentrations of arginine both before (P = 0,018) and after (P = 0,009) prostate massage and higher levels of proline only after prostate massage (P = 0,032) were detected. Higher levels of proline and homoserine and tyramine correlate with GS7 with respect to GS 6 and GS 5. |
Fernandez-Peralbo et al. (2016) [69] | 62 PrC patients 42 controls | Sample preparation: Thawing, centrifugation, pre-treatment with chemicals Analytical techniques: LC-QTOF | Derivatives of lysine, histidine, arginine, tyrosine, tryptophan, taurine, alanine, aspartate, glutamate, glutamine, purine, pyrimidine | Almost all metabolites were present at lower concentrations in PrC patients than in controls, Training: Specificity 92.9%; Sensibility 88.4% Validation: Specificity 78.6%; Sensibility 63.2% |
Gkotsos et al. (2017) [60] | 52 PrC patients 49 controls | Sample preparation: Thawing, centrifugation, pre-treatment with chemicals Analytical techniques: UPLC-MS/MS | Sarcosine; Uracil; Kynurenic acid | Decreased median sarcosine and kynurenic acid and increased uracil concentrations were observed for patients with prostate cancer compared to participants without malignancy. |
Derezinski et al. (2017) [70] | 49 PrC patients with different stages of disease 40 controls | Sample preparation: Thawing, centrifugation, pre-treatment with chemicals Analytical techniques: LC-ESI-MS/MS | 1-methylhistidine 3-methylhistidine Alanine, Arginine, Argininosuccinic acid, Asparagine, Aspartic acid, Citrulline Carnosine | In PrC samples, taurine was present at significant higher level. The PLS-DA model built on selected metabolites achieved sensitivity and specificity of 89.47% and 73.33%, respectively, whereas the total group membership classification value was 82.35%. |
Author (Year) [Ref] | Population | Experimental Method | Biomarkers | Results |
---|---|---|---|---|
Qiu et al. (2010) [73] | 60 colorectal cancer (CrC) patients (42–76 years) at different stages 63 controls without any diseases or interferences | Sample preparation: Thawing, centrifugation and pre-treatment with chemicals Analytical techniques: GC-MS | Succinate; Isocitrate; Citrate; 5-hydroxytryptophan; 5-ydroxyindoleacetate; Tryptophan; Glutamate; 5-oxoproline; N-acetyl-aspartate; 3-methyl histidine; Histidine; p-cresol; 2-hydroxyhippurate; Phenylacetate; Phenylacetylglutamine; p-ydroxyphenylacetate | Considering preoperative CrC patients and healthy controls, levels of succinate, isocitrate, citrate, 3-methyl-histidine and histidine were lower in CrC patients than healthy patients. Levels of 5-hydroxytryptophane, 5-hydroxyindoleacetate, tryptophan, glutamate, 5-oxoproline, N-acetyl-aspartate, p-cresol, 2-hydroxyhippurate, phenylacetate, phenylacetylglutamine and p-hydroxyphenylacetate were higher in CrC patients than healthy ones. The experiments on rats indicate what are the biological mechanisms for the different metabolites’ beahaviour. |
Chen et al. (2012) [76] | 20 CrC patients (37–87 years) with tumor at different stages 14 controls without other diseases or interferences (50–86 years) | Sample preparation: Centrifugation and pre-treatments with chemicals Analytical techniques: CE-ESI-MS | Lactic acid; Arginine; Isoleucine; Leucine; Valine; Citric acid; Histidine; Methionine; Serine; Aspartic acid; Malic acid; Succinic acid | Levels of lactic acid, arginine, isoleucine, leucine and valine were higher in CrC patients. Levels of citric acid, histidine, methionine, serine, aspartate, malic acid and succinate were lower in CrC patients. The values of valine and isoleucine were lower in CrC patients at III–IV stages than those at I–II stages. |
Cheng et al. (2012) [77] | 101 CrC patients (24–83 years) at different stages 103 controls without other diseases or interferences (31–76 years) | Sample preparation: Centrifugation and pre-treatments with chemicals Analytical techniques: GC-TOFMS UPLC-QTOFMS | Citrate; Hippurate; p-cresol; 2-aminobutyrate; Myristate; Putrescine; Kynurenate | The levels of 2-aminobutyrate and putrescine are higher in CrC patients than healthy ones. The levels of citrate, hippurate, p-cresol, myristate and kynurenate are lower in CrC patients than healthy ones. |
Authors (Year) [Ref] | Population | Experimental Method | Biomarkers | Results |
---|---|---|---|---|
Dong et al. (2009) [82] | 144 gastric cancer (GC) patients (50–68 years) 144 controls (50–67 years) | Sample preparation: thawing of urine samples, addition with chemicals and extraction Analytical technique: LC-MS | Prostaglandin E2 metabolite (PGE-M) | The level of urinary PGE-M is higher in GC patients than controls. |
Chen et al. (2014) [83] | 26 GC patients at different stages 14 controls | Sample preparation: Pre-treatment with chemicals and centrifugation. Analytical technique: MRB-CE-MS | Arginine Leucine Isoleucine Valine Citric acid Succinate Histidine Methionine Serine Aspartate | Arginine. Leucine, Isoleucine and Valine were significantly higher in RCC patients with respect to controls, while citric acid, Histidine, Methionine, Serine, aspartate, malic acid and succinate were remarkably lower in RCC patients compared to controls. Moreover, Valine and Isoleucine levels differed in advanced stage RCC and early stage RCC (urine from early stage RCC patients were characterized by higher levels) |
Jung et al. (2014) [79] | 50 GC patients (38–81 years) at different stages 50 controls (38–78 years) | Sample preparation: thawing samples, centrifugation and addition with chemicals Analytical technique: H NMR | 2-Oxobutyrate, 3-Aminoisobutyrate, 3-Indoxylsulfate, 4-Hydroxyphenylacetate, Acetate, Acetone, Alanine, Arginine, Betaine, Formate, Glycine, Glycolate, Histidine, Lactate, Leucine, Mannitol, Methionine, N-Methylhydantoin, O-Acetylcarnitine, Phenylacetylglycine, Phenylalanine, Putrescine, Succinate, Taurine, Tyrosine and Valine,1-Methylnicotinamide, Hypoxanthine | 2-Oxobutyrate, 3-Aminoisobutyrate, 3-Indoxylsulfate, 4-Hydroxyphenylacetate, Acetate, Acetone, Alanine, Arginine, Betaine, Formate, Glycine, Glycolate, Histidine, Lactate, Leucine, Mannitol, Methionine, N-Methylhydantoin, O-Acetylcarnitine, Phenylacetylglycine, Phenylalanine, Putrescine, Succinate, Taurine, Tyrosine and Valine levels are higher in GC patients than controls. 1-Methylnicotinamide and Hypoxanthine levels are lower in GC patients than controls. |
Chan et al. (2016) [78] | 43 GC patients (53–77 years) at different stages 40 controls (54–72 years) 40 resemble benign (BN) (54–72 years) | Sample preparation: thawing, addition with chemicals and centrifugation Analythical technique: H NMR | 2-hydroxyisobutyrate 3-indoxylsulfate Alanine | Among the 25 metabolites investigated, only 2-hydroxyisobutyrate, 3-indoxylsulfate and alanine proved to provide useful information for diagnostic purposed and were considered to build the discrimination model, achieving a diagnostic accuracy of 95%. |
Authors (Year) [Ref] | Population | Experimental Method | Biomarkers Proposed | Results |
---|---|---|---|---|
Wu et al. (2009) [89] | 20 hepatic cancer (HC) patients (30–53 years) 20 controls (35–58 years) All studied groups were males. | Sample preparation: centrifugation, addition of chemicals and evaporation. Analytical technique: GC-MS | glycine; octanedioic acid; tyrosine; threonine and butanedioic acid heptanedioic acid; ethanedioic acid; xylitol; urea; phosphate; propanoic acid; primidine; butanoic acid; trihydroxypentanoic acid; hypoxanthine; arabinofuranose; hydroxy proline dipeptid; xylonic acid | The levels of glycine, octanedioic acid, tyrosine, threonine and butanedioic acid are higher in HC patients than healthy ones. The levels of heptanedioic acid, ethanedioic acid, xylitol, urea, phosphate, propanoic acid, primidine, butanoic acid, trihydroxypentanoic acid, hypoxanthine, arabinofuranose, hydroxy proline dipeptid and xylonic acid are lower in HC patients than in control ones. |
Chen et al. (2011) [84] | 82 HC patients (29–76 years) at different stages 71 controls (42–65 years) 24 benign liver tumor patients (18–65 years) as hemangioma, focal nodular hyperplasia of liver, liver cirrhosis, liver cyst, intrahepatic bile duct stone and recurrent hemangioma after surgery | Sample preparation: centrifugation, pre-treatments with chemicals and drying Analytical technique: GC-TOFMS UPLC-QTOFMS | Glycocholic acid; cysteine; tyrosine; phenylalanine; dopamine; adenosine; uric acid; xanthine; hypoxanthine; hypotaurine; taurine; 5-Hydroxy-tryptophan; N-Acetyl-L-aspartic acid; pyridoxal; threonine; dihydrouracil; agmatine; O-Phospho-L-serine; N-Acetyl-neuraminic acid4-Hydroxyphenylacetate; trimethylamine N-oxide; cysteine; alanine; homovanillate; normetanephrine; adenine; cysteic acid; nicotinic acid; succinic acid; carnosine; 2-pyrrolidone-5-carboxylic acid; 6-aminocaproic acid; creatine | Glycocholic acid, cystine, tyrosine, phenylalanine, dopamine, adenosine, uric acid, xanthine, hypoxanthine, hypotaurine, taurine, 5-Hydroxy-tryptophan, N-Acetyl-L-aspartic acid, pyridoxal, threonine, dihydrouracil, agmatine, O-Phospho-L-serine and N-Acetyl-neuraminic acid levels in HC patients are higher than healthy ones. 4-Hydroxyphenylacetate, trimethylamine N-oxide, cysteine, alanine, homovanillate, normetanephrine, adenine, cysteic acid, nicotinic acid, succinic acid, carnosine, 2-pyrrolidone-5-carboxylic acid, 6-aminocaproic acid, creatine levels in HC patients are lower than in healthy ones. Trimethylamine N-oxide, alanine, homovanillate, normetanephrine, cysteic acid, 6-Aminocaproic acid, creatine and 5-hydroxylysine levels in HC patients at I-II stages are lower than healthy ones. Glycocholic acid, cystine, homoserine, tyramine, tyrosine, dopamine, adenosine, xanthine, hypoxanthine, hypotaurine, 5-Hydroxy-tryptophan, N-Acetyl-L-Aspartic acid, threonine, dihydrouracil, ethymalonic acid, agmatine and N-Acetyl-neuraminic acid levels in HC patients at III-IV stages are higher than healthy ones. Trimethylamine N-oxide, cysteine, adenine, cysteic acid, citrulline, 6-Aminocaproic acid, creatine levels in HC patients at III-IV stages are lower than healthy ones. |
Osman et al. (2016) [90] | 55 HC patients (41–58 years) 40 LC patients (40–59 years) with HCV infection 45 controls (39–57 years) All the studied groups were males. | Sample preparation: centrifugation and pre-treatments with chemicals. Analytical technique: GC-MS. | Glycine Serine Threonine Proline Citric acid Phosphate Pyrimidine Arabinose Xylitol Hippuric acid Xylonic acid Glycerol | Glycine, serine, threonine, proline, and citric acid levels in HC patients are higher than healthy ones. Urea, phosphate, pyrimidine, arabinose, xylitol, hippuric acid, xylonic acid and glycerol levels in HC patients are lower than control ones. |
Shariff et al. (2016) [91] | 13 HC patients (29–82 years) at different stages 25 LC patients (28–79 years) at different stages No controls involved | Sample preparation: Pre-treatments with chemicals and centrifugation. Analytical technique: HNMR spectroscopy | Carnitine Formate Ciitrate doublet Hippurate p-cresol sulfate Creatinine methyl Creatinine methylene | Carnitine and formate levels in HC patients are higher than liver cirrhosis patients. Citrate doublet, hippurate, p-cresol sulfate, creatinine methyl and creatinine methylene levels in HC patients are lower than liver cirrhosis patients. |
Authors(Year) [Ref] | Population | Experimental Method | Biomarkers | Results |
---|---|---|---|---|
Jin et al. (2014) [92] | 138 Bladder cancer (BlC) patients at different tumor stages (53–78 years) 121 controls (55–73 years): 69 healthy people 52 patients with hematuria due to non-malignant disease | Sample preparation: thawing of urine sample, centrifugation and treatments with chemicals Analytical technique: GC-MS | Succinate Pyruvate Oxoglutarate Carnitine Phosphoenolpyruvate Trimethyllysine Melatonin Isovalerylcarnitine Glutarylcarnitine Octenoylcarnitine Decanoylcarnitine Acetyl-CoA Carnitine palmitoyltransferase Carnitine acylcarnitine translocaselike protein Dihydrolipoyl dehydrogenase | The levels of succinate, pyruvate, oxoglutarate, carnitine, phosphoenolpyruvate, trimethyllysine, isovalerylcarnitine, octenoylcarnitine, acetyl-CoA, carnitine palmitoyltransferase and carnitine acylcarnitine translocaselike protein were found to be higher in BlC patients than controls The levels of melatonin, glutarylcarnitine, decanoylcarnitine and dihydrolipoyl dehydrogenase were found to be lower in BlC patients than controls |
Nakai et al. (2015) [95] | 61 BlC patients with different stage of tumor (34–91 years) 50 controls (25–92 years) with no cancer-related findings | Sample preparation: thawing, centrifugation and treatments with chemicals Analitycal technique: spectrophotometer | Protoporphyrin IX | There are a lot of differences in protoporphyrin IX between BlC patients and controls. These differences are present in BlC patients with different tumor stages and between MIBC patients and NMIBC patients too. |
Alberice et al. (2013) [93] | 48 BlC patients at different stages | Sample preparation: centrifugation and treatments with chemicals Analytical technique: CE-TOF-MS LC-QTOF-MS | Betaine; Leucine; Hypoxanthine; Hystidine; Phenylalanine; Uric acid; 1-Methylhistidine Nε,Nε,Nε-trimethyllysiine; Nε,Nε-dimethyllysine; Tyrosine; Galacticol7sorbitol/mannitol; 3-Amino-2-naphthoic acid; Dopaquinone; Acetylcarnitine; Tryptophan; Carnosine; 2,6,10-Trimethyl undecanoic acid; Cystine N-acetyltryptophan; Palmitic amide Heptanoylcarnitine; 12S-hydroxyoctadienoic acid, Decanoylcarnitine; 6-Keto-decanoyl carnitine | Hystidine, phenylalanine, tyrosine and tryptophan levels are higher in BlC patients than controls. Tryptophan is significant in low risk patients, so important for detection at early stage. Hystidine and tyrosiine are higher in high-risk patients with respect to low-risk patients, while N-acetyltryptophan, leucine, hypoxanthine and uric acid levels are higher in low risk patients. Dopaquinone, Nε,Nε,Nε-trimethyllysiine, Nε,Nε-dimethyllysine and carnine derivatives concentrations are higher in patients with recurrence of the disease. |
Huang et al. (2011) [94] | 27 BlC patients: (42–71 years) at different stages 32 controls (46–67 years) | Sample preparation: thawing, centrifugation, treatment with chemicals and filtration through cellulose filters Analytical technique: HPLC-MS with two different columns | Octenoylcarnitine (carnitine C8:1), Carnitine C9:1, 9-Decenoylcarnitine (carnitine C10:1), Acetyl-carnitine, 2,6-dimethylheptanoyl carnitine, Hippuric acid | The level of carnitine C8:1, carnitine C9:1, carnitine C10:1,2,6-dimethylheptanoyl carnitine and hippuric acid is lower in BlC patients than controls, while the level of acetyl-carnitine is higher in BlC patients than controls. |
Cauchi et al. (2016) [96] | 72 BlC patients (56–88 years) at different stages 205 controls: (18- 89 years) | Sample preparation: thawing, treatments with chemicals and extraction on a carbon/PDMS fiber Analitycal technique: GC-TOF-MS | 2-pentanone; 2;3-butanedione; 4-heptanone; Dimethyl disulphide; Hexanal; Benzaldehyde; Butyrophenone; 3-hydroxyanthranilic acid; Benzoic acid; trans-3-hexanoic acid; cis-3-hexanoic acid; 2-Butanone; 2-propanol Acetic acid; Piperitone; Thujone | 2-pentanone, 2,3-butanedione, 4-heptanone, dimethyl disulphide, 2-Butanone, 2-propanol, acetic acid, piperitone and thujone levels are lower in BlC patients than controls. Hexanal, benzaldehyde, butyrophenone,3-hydroxyanthranilic acid, benzoic acid, trans-3-hexanoic acid and cis-3-hexanoic acid levels are higher in BlC patients than controls. |
Authors (Year) [Ref] | Population | Experimental Method | Biomarkers | Results |
---|---|---|---|---|
Napoli et al. (2012) [116] | 33 pancreatic cancer (PaC) patients (56–68 years) 54 controls (55–67 years) | Sample preparation: thawing samples, addition of chemicals and centrifugation Analytical technique: H-NMR | Acetoacetate; Acetylated compounds; Adenine; Alanine; Bile salts; Citrate; Creatinine; Formate; Glucose; Glycine; Hippurate; 2-hydroxyisobutyrate; 3-hydroxyisovalerate; 4-hydroxyphenylacetate; Isobutyrate; Lactate; Leucine; Dimethylamine; Trimethylamine-N-oxide; 3-methylhistidine; 1-methylnicotinamide; 2-phenylacetamide; Trigonelline; Valine | The level of acetoacetate, acetylated compounds, glucose, leucine and 2-phenylacetamide is higher in PC patients than in controls. The level of citrate, creatinine, glycine, hippurate, 3-hydroxyisovalerate and trigonelline is lower in PaC patients than in controls. |
Davis et al. (2013) [117] | 32 PaC patients (48–83 years) at different stages 25 benign pancreatitis patients (42–77 years) 32 controls (47–84 years) | Sample preparation: thawing samples and addition with chemicals Analytical technique: H-NMR | Acetone; Hypoxanthine; O-Acetylcarnitine; Dimethylamine; Choline; 1-Methylnicotinamide; Threonine; Fucose; Cis-Aconitate; 4-Pyridoxate; Glucose; Trimethylamine-N-oxide; Aminobutyrate; Tryptophan; Trigonelline; Xylose; Trans-Aconitate; Methanol; 4-Hydroxyphenylacetate; 2-Hydroxyisobutyrate; Taurine | The level of acetone, hypoxanthine, O-Acetylcarnitine, dimethylamine, choline, 1 Methylnicotinamide, threonine, fucose, cis-Aconitate, 4-Pyridoxate, glucose, trimethylamine-N-oxide, aminobutyrate, tryptophan, xylose, trans-Aconitate, 4-Hydroxyphenylacetate, 2 Hydroxyisobutyrate and taurine is higher in PaC patients than in controls. The level of trigonelline and methanol is lower in PaC patients than in controls. |
Lusczek et al. (2015) [118] | 5 PaC patients (42–63 years) at different stages 92 chronic pancreatitis patients (42–77 years) 87 controls (24–62 years) | Sample preparation: thawing samples, addition with chemicals and centrifugation Analytical technique: NMR | Adenosine; citrate | The level of citrate is lower in PaC patients than in controls. |
Radon et al. (2015) [119] | 192 PaC patients at different stages 92 chronic pancreatitis patients 87 controls | Sample preparation: pre-treatments with chemical and extraction Analytical technique: GeLC/MS/MS ELISA | LYVE1; REG1A; TFF1 | LYVE1, REG1A and TFF1 levels were significantly higher in PaC patients with respect to controls. The LYVE1, REG1A and TFF1 levels increase with tumor stage, allowing the discrimination between early and late PaC. |
Mayerle et al. (2017) [120] | 271 PaC patients at different stages 282 chronic pancreatitis patients 100 liver cirrhosis 261 controls | Sample preparation: pre-treatments with chemical and extraction Analytical technique: GeLC/MS/MS ELISA | histidine, proline, sphingomyelin d18:2, sphingomyelin d17:1, phosphatidylcholine, isocitrate, sphingagine-1-phosphate, pyruvate, and ceramide | The model based on those 9 metabolites and CA19–9 achieved a diagnostic accuracy of 96%. |
Authors (Year) [Ref] | Population | Experimental Method | Biomarkers Proposed | Results |
---|---|---|---|---|
Han et al. (2005) [126] | 42 renal or kidney cancer (RC) patients 30 controls 10 PCa patients | Sample preparation: Centrifugation and pre-treatment with chemicals Analytical technique: ELISA | human kidney injury molecule-1 (hKIM-1) | hKIM-1 levels in urine were significantly higher in patients with RC (0.39 ± 0.06 ng/mgUcr) compared with levels in urine from PCa patients (0.12 ± 0.03 ng/mgUcr) or normal control subjects (0.05 ± 0.01 ng/mgUcr). |
Bosso et al. (2008) [127] | 39 RC patients (52–88 years) at different stages 29 controls (44–86 years) | Sample preparation: Centrifugation and pre-treatment with chemicals Analytical technique: MALDI-TOF | Three different fragments of uromodulin (A, B and C) | Diagnostic accuracy of biomarkers A and B was above 90%, while the diagnostic accuracy of biomarker C was of 84%. The model built considering all fragments achieved showed better performance in classifying RC patients and controls (training: specificity 100% and sensitivity 95%; test: specificity 100% and sensitivity 85%). |
Ganti et al. (2011) [128] | 29 RC patients at different stages 33 controls | Sample preparation: Addition of chemicals and centrifugation. Analytical technique: Untargeted metabolic analysis GC-MS | Isobutyrylcarnitine Suberoylcarnitine Acetylcarnitine | Isobutyrylcarnitine, Suberoylcarnitine and Acetylcarnitine levels were higher in RC patients than in controls. Acylcarnitines levels in urine increased as function of tumor grade. |
Authors (Year) [Ref] | Population | Experimental Method | Biomarkers | Results |
---|---|---|---|---|
Lipsett et al. (1966) [133] | 1 testicular cancer (TC) patient | Sample preparation: Collection of 24 h urine and pre-treatment with chemicals Analytical techniques: GC-MS | 17-ketosteroid 17-hydroxycorticoids | Monitoring of response to cancer treatments |
Eyben (1978) [134] | 27 TC patients with different stages of disease 18 controls (15–50 years) | Sample preparation: Collection of 24 h urine Analytical techniques: Extractor, radioimmunoassay, fluorimetric method | Human chorionic gonadotropin HCG | Higher HCG levels in sick patients (above 300 IC/24 h) Correlation between post-operative HCG and prognosis |
Recurrent Cancer Biomarkers in Urine | Concentration Levels in Urine from Cancer Patients with Respect to Controls | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
LC | BC | PrC | CrC | GC | HC | BlC | PaC | RC | TC | |
Glycine | - | - | - | - | > | > | - | < | - | - |
Serine | - | - | - | < | < | > | - | - | - | - |
Threonine | - | - | > | > | - | > | - | > | - | - |
Alanine | - | - | nd | - | > | < | - | nd | - | - |
Phenylalanine | > | - | < | - | > | > | > | - | - | - |
Tyrosine | - | - | > | - | > | > | > | - | - | - |
Hippurate | - | - | - | < | - | < | - | < | - | - |
Hydroxyhippurate | - | - | - | > | - | - | - | - | - | - |
Tryptophan | - | - | - | > | - | - | > | > | - | - |
Kynurenate | - | - | - | < | - | - | - | - | - | - |
Lactate | - | - | - | - | > | - | - | nd | - | - |
Lactic acid | - | - | - | - | > | - | - | - | - | - |
Indoleacetate | - | nd | - | > | - | - | - | - | - | - |
Taurine | > | - | > | - | > | > | - | > | - | - |
Hypotaurine | - | - | - | - | - | > | - | - | - | - |
Citrate | - | - | - | < | - | < | - | < | - | - |
Isocitrate | - | - | - | < | - | - | - | - | - | - |
Putrescine | - | - | nd | > | > | - | - | - | - | - |
Succinate | - | < | - | < | >/< | - | > | - | - | - |
Aconitate | - | - | nd | - | - | < | - | > | - | - |
Citrulline | - | - | nd | - | - | < | - | - | - | - |
Valine | > | < | - | > | > | - | - | nd | - | - |
Leucine | - | < | >/< | > | > | - | > | > | - | - |
Isoleucine | - | > | > | > | > | - | - | - | - | - |
Arginine | - | - | > | > | > | - | - | - | - | - |
Creatinine | - | < | > | - | - | < | - | < | - | - |
Adenosine | - | - | - | - | - | < | - | < | - | - |
Uridine | - | > | - | - | - | - | - | - | - | - |
Carnitine | > | - | - | - | - | > | >/< | - | > | - |
Purine | - | - | nd | - | - | - | - | - | - | |
Xanthine | - | - | - | - | - | < | - | - | - | - |
Adenine | - | - | - | - | - | < | - | nd | - | - |
Guanosine | - | > | - | - | - | - | - | - | - | |
Xanthine | - | - | - | - | - | < | - | - | - | - |
Aspartic acid | - | - | > | nd | - | - | - | - | - | |
Malic acid | - | - | - | < | - | < | - | - | - | - |
Succinic acid | - | - | nd | nd | - | < | - | - | - | - |
Xylonic acid | - | - | > | - | - | < | - | - | - | - |
Kynureic acid | - | - | < | - | - | - | - | - | - | - |
Octanedionic acid | - | - | - | - | - | > | - | - | - | - |
Butanedionic acid | - | - | - | - | - | > | - | - | - | - |
Heptanedionic acid | - | - | - | - | - | < | - | - | - | - |
Ethanedioic acid | - | - | - | - | - | < | - | - | - | - |
Propanoic acid | - | - | - | - | - | < | - | - | - | - |
Butanoic acid | - | - | > | - | - | < | - | - | - | - |
Trihydroxypentanoic acid | - | - | < | - | - | - | - | - | - | - |
Glicholic acid | - | - | - | - | - | > | - | - | - | - |
Uric acid | - | - | > | - | - | < | > | - | - | - |
Citric acid | - | - | - | < | < | > | - | - | - | - |
Nicotinic acid | - | - | - | - | - | < | - | - | - | - |
Hippuric acid | > | - | - | - | - | < | < | - | - | - |
Acetic acid | - | - | - | - | - | - | < | - | - | - |
Recurrent Urinary Cancer Biomarker | [151,152] | Odor Description [152] | Cancer Type |
---|---|---|---|
Acetic acid | 0.004–204 | Sour, pungent, vinegar | BlC |
Succinic acid | - | Pungent | CrC, PrC, HC |
Diethylamine and derivatives | 0.0033–14.3 | Musty, fishy, amine | CrC, PrC, TC, HC, BC, HC |
Trimethylamine and derivatives | 0.00002–1.82 | Fishy, pungent | HC |
Pyridine | 0.01–12 | Burnt, pungent, nauseating | PrC |
Cresol (all isomers) | 0.00005–0.009 | Phenol, irritating, smoky, empyreumatic, burnt plastic | CrC, HC |
Phenol | 0.0045–1.95 | Acid | BC |
Cyclohexanone | 0.052–219 | Sweet, sharp | LC |
L-cysteine | 24.2 | Sulphur, rotten eggs | PrC, HC |
D-cysteine | 26.7 | Sulphur, rotten eggs | PrC, HC |
L-methionine | 11.9 | Moldy, rotten dairy products | CrC, PrC, GC |
D-methionine | 1.5 | Moldy, rotten dairy products | CrC, PrC, GC |
L-proline | 11,513 | Chlorine, semen, sperm | CrC, PrC, HC, LC |
D-proline | 8635 | Chlorine, semen, sperm | CrC, PrC, HC, LC |
Histidine | - | Slightly bitter acid | CrC, PrC, BlC, GC |
Arginine | - | Bitter | CrC, PrC, GC |
Glycine | - | Sweet, refreshing | PrC, HC, GC |
Tyrosine | - | Soft, flat, stale | PrC, HC, BlC, GC |
Indole | 21–140 | Fecal | CrC, PrC, BC |
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Bax, C.; Lotesoriere, B.J.; Sironi, S.; Capelli, L. Review and Comparison of Cancer Biomarker Trends in Urine as a Basis for New Diagnostic Pathways. Cancers 2019, 11, 1244. https://doi.org/10.3390/cancers11091244
Bax C, Lotesoriere BJ, Sironi S, Capelli L. Review and Comparison of Cancer Biomarker Trends in Urine as a Basis for New Diagnostic Pathways. Cancers. 2019; 11(9):1244. https://doi.org/10.3390/cancers11091244
Chicago/Turabian StyleBax, Carmen, Beatrice Julia Lotesoriere, Selena Sironi, and Laura Capelli. 2019. "Review and Comparison of Cancer Biomarker Trends in Urine as a Basis for New Diagnostic Pathways" Cancers 11, no. 9: 1244. https://doi.org/10.3390/cancers11091244