Metabolomics for the diagnosis of bladder cancer: A systematic review

doi:10.1016/j.ajur.2022.11.005

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Abstract:

Objective: Metabolomics has been extensively utilized in bladder cancer (BCa) research, employing mass spectrometry and nuclear magnetic resonance spectroscopy to compare various variables (tissues, serum, blood, and urine). This study aimed to identify potential biomarkers for early BCa diagnosis.

Methods: A search strategy was designed to identify clinical trials, descriptive and analytical observational studies from databases such as Medline, Embase, Cochrane Central Register of Controlled Trials, and Latin American and Caribbean Literature in Health Sciences. Inclusion criteria comprised studies involving BCa tissue, serum, blood, or urine profiling using widely adopted metabolomics techniques like mass spectrometry and nuclear magnetic resonance. Primary outcomes included description of metabolites and metabolomics profiling in BCa patients and the association of metabolites and metabolomics profiling with BCa diagnosis compared to control patients. The risk of bias was assessed using the Quality Assessment of Studies of Diagnostic Accuracy.

Results: The search strategy yielded 2832 studies, of which 30 case-control studies were included. Urine was predominantly used as the primary sample for metabolite identification. Risk of bias was often unclear inpatient selection, blinding of the index test, and reference standard assessment, but no applicability concerns were observed. Metabolites and metabolomics profiles associated with BCa diagnosis were identified in glucose, amino acids, nucleotides, lipids, and aldehydes metabolism.

Conclusion: The identified metabolites in urine included citric acid, valine, tryptophan, taurine, aspartic acid, uridine, ribose, phosphocholine, and carnitine. Tissue samples exhibited elevated levels of lactic acid, amino acids, and lipids. Consistent findings across tissue, urine, and serum samples revealed downregulation of citric acid and upregulation of lactic acid, valine, tryptophan, taurine, glutamine, aspartic acid, uridine, ribose, and phosphocholine.

Key words: Metabolite Metabolomics Bladder cancer Metabolomics profile

收稿日期: 2022-01-14 接受日期: 2022-11-29 出版日期: 2024-04-20 发布日期: 2024-04-28 整期出版日期: 2024-04-20

引用本文:

. [J]. Asian Journal of Urology, 2024, 11(2): 221-241.
Herney Andrés García-Perdomo, Angélica María Dávila-Raigoza, Fernando Korkes. Metabolomics for the diagnosis of bladder cancer: A systematic review. Asian Journal of Urology, 2024, 11(2): 221-241.

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http://www.ajurology.com/CN/10.1016/j.ajur.2022.11.005 或 http://www.ajurology.com/CN/Y2024/V11/I2/221

Study	Country	Participant, n	Gender	Age, year	Analytical platform	Sample type	Cancer Pt, n	Control, n	Metabolite up-regulated in BCa	Metabolite down-regulated in BCa
Srivastava et al., 2010 [21]	India	103	? Male and female	? BCa: 45±25^a (range 20-70) ? Control: 35±15^a (range 20-50)	? H-NMR	Urine	33	? 70 o- HC: 37 o- UTI: 31 o- BS: 2	? Tau	? Hippuric acid, citrate, and Phe
Kim et al., 2010 [23]	Republic of Korea	19	? Male	? BCa: range 47-78 ? Control: range 42-78	? GC-MS	Urine	11	? HC: 8	? Val, Leu, pyroglutamic acid, Thr, Phe, Asp, glutamic acid, asparagine, alpha-aminoadipic acid, Tyr, and Trp	? Ala, Gly, a-aminobutyric acid, serine, ornithine, Gln, and Lys
Pasikanti et al., 2010 [22]	Singapore	75	? Male and female	? BCa: 67.2±12.3^a ? Control: 61.3±12.4^a	? GC/TOFMS	Urine	24	? Non-BCa Pts: 51	? Melibiose, uridine, and Val	? Senecioic acid, 2-butenedioic acid, ribonic acid, 2,5-furandicarboxylic acid, sumiki’s acid, 2-propenoic acid, glycerol, gluconic acid, valerate, fructose, citric acid, and ribitol
Putluri et al., 2011 [24]	USA	134	? Male and female	NR	? LC-MS	Urine	83	? HC: 51	? Val, carnitine, Tyr, creatine, histidine, Leu/Ile, kynurenine, Phe, Lys, serine, thymine, guanine, and uracil	? Histamine and palmitic acid
Gamagedara et al., 2012 [26]	USA	23	? NR	NR	? LC-MS	Urine	11	? Non-BCa Pts: 12	? Tau	? NR
Huang et al, 2011 [25]	China	59	? Male and female	? BCa: mean 56 (range 42-71) ? Control: mean 53 (range 46-67)	? LC-MS	Urine	27	? HC: 32	? NR	? Carnitine and hippuric acid
Cao et al., 2012 [27]	China	110	? Male	? HC: 67.43±8.75^a ? Calculi: 55.04±11.34^a ? LBC: 60.26±14.52^a ? HBC: 70.27±11.0^a ? Post-TURBT: 66.65±9.42^a	? H-NMR	Serum	37	? 73 o- HC: 25 o- CP: 28 o- Post-TURBT: 20	? Glucose, acetoacetate, and very low-density lipoprotein	? Ile, Leu, Tyr, Phe, choline, lactate, Gly, and citrate
Huang et al., 2013 [31]	China	43	? Male and female	? BCa: mean 60.5 (range 45-74) ? Control: mean 50.5 (range 26-65)	? LC-MS	Urine	19	? HC: 24	? Tau	? Carnitine and hippuric acid
Jobu et al., 2012 [32]	Japan	16	? NR	? NR	? GC-MS	Urine	9	? HC: 7	? Ethylbenzene, nonanoyl chloride, dodecanal, (Z)-2-nonenal, and 5-dimethyl-3(2H)-isoxazolone	? NR
Lin et al., 2012 [28]	China	68	? Male and female	? HC: mean 45 (range 21-68) ? Nephrolithiasis: mean 54; range (31-74) ? BPH: mean 70 (range 65-82) ? BCa: mean 61 (range 45-74)	? LC-MS	Serum	20	? 48 o- HC: 20 o- Nephrolithiasis: 18 o- BPH: 10	? Eicosatrienol, azaprostanoic acid, docosatrienol, retinol, and 14-apo-beta-carotenal	? NR
Tripathi et al., 2013 [35]	USA	59	? Male and female	? HC: 69.4±10.6^a (range 51?87) ? BCa: o- Ta-T1: 60.1±11.5^a (range 33?78) o- ≥T2: 68.8±11.7^a (range 43?87)	? HR-MAS-NMR GC-MS	Tissue	33	? HC: 26	? Triglycerides, Leu, Ile, Val, lactate, Ala, acetate, Lys, glutamate, glutathione, Gln, aspartate, creatine, choline, phosphocholine, glycerophosphocholine, Tau, Gly, inositol, uridine diphosphate sugars, Phe, and Tyr	? NR
Bansal et al., 2013 [30]	India	99	? Male	? >40	? H-NMR	Serum	67	? HC: 32	? Dimethylamine, malonate, lactate, histidine, Val, and Gln	? NR
Pasikanti et al., 2013 [29]	Singapore	99	? Male and female	? BCa: 68.3±10.9^a ? Control: 60.5±12.7^a	? GC×GC-TOFMS	Urine	38	? Non-BCa Pts: 61	? Adipic acid, anthranilic acid, coumaric acid derivative, cyclopentane-1, 2-diamine, erythritol, erythro-pentonic acid, ethylmalonic acid, gluconic acid derivative, heptadecanoic acid, hydroxybutyric acid, itaconic acid, lactic acid, melibiose, N-acetylanthranilic acid, p-cresol, pseudouridine, uridine, vanillylmandelic acid, 2,3,4,5-tetrahydroxypentanoic acid-1,4-lactone, 2-aminoisobutyric acid, 2-hydroxymalonic acid, 2-pentadecanol, 3,4-dihydroxyphenyl pyruvate, 3-hydroxysebacic acid, 3-methyladipic acid, and 4-methoxycinnamic acid	? Citric acid, dihydroxyacetone, ethyl tartrate, gluconic acid, glycerol, levulinic acid enol, pinene, ribitol, ribonic acid, sebacic acid, Sumiki’s acid, 2,5-furandicarboxylic acid, 2-butanedioic acid, and 2-hydroxyglutaric acid
Jin et al., 2014 [33]	Republic of Korea	259	? Male and female	? BCa: 65.64±12.65^a ? Control: 64.31±9.18^a	? HPLC-QTOFMS	Urine	138	? 121 o- HC: 69 o- HU: 52	? Succinate, pyruvate, oxoglutarate, carnitine, phosphoenolpyruvate, trimethyllysine, isovalerylcarnitine, octenoylcarnitine, acetyl coenzyme A, carnitine palmitoyltransferase, and carnitine acylcarnitine	? Melatonin, glutarylcarnitine, decanoylcarnitine, and dihydrolipoyl dehydrogenase (pyruvate dehydrogenase complex)
Peng et al., 2014 [34]	China and Canada	285	? Male and female	? BCa: 68±14^a ? Control: 61±5^a	? LC-MS	Urine	135	? 150 o- Hernia: 82; o- UTI or HU: 68	? 5-hydroxyindoleacetic acid, phosphoethanolamine, and pyroglutamic acid	? Uridine and histamine
Wittmann et al, 2014 [36]	USA	440	? Male and female	? BCa: mean 67.4 ? Control: mean 64.2	? UHPLC-MS/MS- GC-MS	Urine	95	? Non-BCa Pts: 345	? Lactate, acetylcarnitine, palmitoyl sphingomyelin, adipate, Trp, gluconate, Ile, Val, Leu, phosphocholine, choline, aspartate, beta-hydroxypyruvate, and guanine	? 3-hydroxyphenylaceate, fructose, pyridoxate, succinate, xanthurenate, itaconate, 2-methylbutyrylglycine, pyruvic acid, citrate, tyramine, guanidinoacetate, anserine, gamma-aminobutyrate, creatine, adenosine, and ethanolamine
Shen et al., 2015 [37]	China	44	? Male and female	? BCa: 65.14±13.27^a ? Control: 53.76 ±19.47^a	? UPLC-HRMS	Urine	23	? HC: 21	? Nicotinuric acid, Asp, Gly, Trp, and trehalose	? Gly, Cys, Ala, Lys, inosinic acid, and ureidosuccinic acid
Zhou et al., 2016 [38]	China	140	? Male and female	? BCa: 66±12.6^a ? Control: 65.6±6.8^a	? GC-MS-SIM	Plasma	92	? HC: 48	? Hypotaurine, uridine, malic acid, fumaric acid, creatinine, ribose, glycolic acid, gluconic acid, kynurenine, erythritol, ribonic acid, and serine	? Hippuric acid, hypoxanthine, lactose, xylitol, eicosenoic acid, and glyoxylic acid
Shao et al., 2017 [40]	China	122	? Male and female	? BCa: 68.2±14.5^a ? Control: 64.6±13.2^a	? UPLCTOF-MS	Urine	87	? Hernia: 65	? Imidazoleacetic acid	? NR
Tan et al., 2017 [39]	China	172	? Male and female	? NR	? UHPLC-Q-TOFMS	Serum	120	? HC: 52	? 5-aminoimidazole ribonucleotide, hypoxanthine, inosine, acetyl-N-formyl-5-methoxykynurenamine, Indoleacetic acid, glycocholic acid, phytosphingosine, sphinganine, and linolenyl carnitine	? 3-hydroxyoctanoyl carnitine and 3-hydroxydecanoyl carnitine
Cheng et al, 2018 [42]	China	284	? Male and female	? BCa: 62.2±13.2^a ? Control: 59.5±11.2^a	? LC-HRMS	Urine	167	? HC: 117	? Dopamine 4-sulfate, doxazosin, dihydroferulic acid 4-O-glucuronide, ofloxacin, 15-dehydro-prostaglandin E1(1-), 4-(ethoxymethyl) phenol, ovalicin, flunisolide, (Z)-13-hexadecenoic acid, and alpha-ionol O-[arabinosyl-(1->6)-glucoside]	? Aspartyl-histidine, tyrosyl-methionine, 3-hydroxy-carbofuran, 1,2-dehydrosalsolinol, ecabet, gossyvertin, avocadyne 4-acetate, 13-hydroxy-9-methoxy-10-oxo-11-octadecenoic acid, fluoxymesterone, and 1-acetoxy-2-hydroxy-16-heptadecen-4-one
Yumba Mpanga et al., 2018 [41]	Poland	80	? Male and female	? BCa: median 62; ? Control: median 60	? RP-HPLC-QQQ/MS	Urine	40	? HC: 40	? Trimethyllysine, Tau, citrulline, acetyllysine, glucuronic acid, gluconic acid, N-acetylneuraminic acid, pseudouridine, xanthine, uridine, 7-methylguanine, aconitic acid, and Trp	? 3,7-dimethyluric acid, 2-furoyglycine, 1,7-dimethylxanthine, and hippuric acid
Wei et al., 2019 [44]	China	30	? NR	? NR	? HS-GC-MS	Blood	15	? HC: 15	? Formaldehyde, acetaldehyde, propanal, butanal, pentanal, hexanal, and heptanal	? NR
Jacyna et al, 2019 [43]	Poland	48	? Male	? NR	? HPLC-TOF/MS, GC-QQQ/MS, and HNMR	Urine	24	? HC: 24	? 2-deoxy-ribonic acid, diacetylspermine, meso-erythritol, Gln, lactic acid, pentanedioic acid, phenylacetylglutamine, propanoic acid, threonic acid, Tyr, uric acid, and uridine	? S-adenosylmethionine, benzenediol, glycolic acid, hippuric acid, and pipecolic acid
Loras et al., 2019 [45]	Spain	34	? Male and female	? NR	? H-NMR	Tissue and urine	21	? Non-BCa Pts: 13	? Ala, Gln, glutamate, Tau, Pro, Gly, Thr, Phe, Val, Lys, methanol, creanine, choline, glycerol, glycerophosphocholine, phosphocholine, citrate, succinate, hippuric acid, lactic acid, Tau, and sucrose	? Ala, Gln, glutamate, Tau, Pro, Gly, Thr, Phe, Val, Lys, methanol, creanine, choline, glycerol, glycerophosphocholine, phosphocholine, citrate, succinate, hippuric acid, lactic acid, Tau, and sucrose
Lin et al, 2021 [46]	China	124	? Male and female	? BCa: 67.4±13.5^a ? Control: 65±12^a	? GC-MS	Urine	63	? Hernia: 61	? Desaminotyrosine, erythritol, d-ribose, ribitol, d-fructose, d-mannose, and d-galactose	? NR
Luczykowski et al, 2021 [47]	Poland	48	? Male and female	? BCa: 65±12^a ? Control: 64±10.4^a	? LC-MS	Urine	24	? HC: 24	? 2-acetyl-1-alkyl-sn-glycero-3, phosphocholine, and adenine	? 3-dehydroxycarnitine, 3-methylxanthine, 4-hydroxycinnamic acid, 5-hydroxyindoleacetic acid, benzoic acid, carnosine, epinephrine, hippuric acid, histidine, isoniazid, n-acetyl-Phe, p-aminobenzoic acid, retinol, theophylline, gluconic acid, and indolelactic acid
Pinto et al., 2021 [48]	Portugal	109	? Male and female	? BCa: 68.9±10.6^a ? Control: 51±5.2^a	? HS-SPME-GC-MS	Urine	53	? Non-BCa Pts: 56	? 2-methylnonane, 2,4-dimethylheptane, 2,6-dimethylnonane, 1-methylnaphthalene, 2-methylnaphthalene, 1,2,4-trimethylbenzene, and p-cresol	? 2-furaldehyde, 2-methylbutanal, formaldehyde, hexanal, 2-butanone, 4-heptanone, carvone, piperitone, and 1,5-dimethyl-6,8-dioxabicycloctane
Li et al, 2022 [49]	China	95	? Male and female	? BCa: 65.8±3.5^a ? Control: 61±4.1^a	? LC-MS	Urine	57	? Non-BCa Pts: 38	? Isoleucyl-Phe, choline, 1-methylhistidine, n-undecanoylglycine, linoleyl carnitine, adenosine-monophosphate, niacinamide, phenylalanyl-asparagine, and Tau	? Mesobilirubinogen, 2-hydroxycaproic acid, urobilin, 6-hydroxyhexanoic acid, cytidine, dihydrotestosterone, histidine, flavin mononucleotide, valyl-serine, 4-acetamidobutanoic acid, (5R)-5-hydroxyhexanoic acid, adenosine, arginine, 1,11-undeanedicarboxylic acid, ubiquinone-2, butenylcarnitine, sebacic acid, and alanyl-tyrosine
Jacyna et al., 2022 [50]	Poland	48	? Male and female	? 69.6±5.6^a	? HPLC-TOF/MS, GC-QqQ/MS and H-NMR	Urine	24	? HC: 24	? Benzenediol, 2-deoxy-ribonic acid, diacetylspermine, meso-erythritol, Gln, hippuric acid, lactic acid, pentanedioic acid, phenylacetylglutamine, pipecolic acid, propanoic acid, threonic acid, Tyr, uric acid, and uridine	? Benzenediol, 2-deoxy-ribonic acid, diacetylspermine, meso-erythritol, Gln, hippuric acid, lactic acid, pentanedioic acid, phenylacetylglutamine, pipecolic acid, propanoic acid, threonic acid, Tyr, uric acid, and uridine

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