Table 3.
Author | Year | Sample Size | Technique | Use Case | Biomarkers Candidates | Validated? | Statistical Details | Comments |
---|---|---|---|---|---|---|---|---|
Wang [50] | 2017 |
n = 3 subjects Cancer tissue: 3 Benign adjacent tissue: 3 |
MALDI-FTICR-MS | Diagnosis | differential metabolites were not mentioned | No | students t-test | coated tissue slice |
Huan [42] | 2016 | Training set: n = 16 Pca: 13; Benign: 12 Validation set 1: n = 18 Pca: 19; Benign: 17 Validation set 2: n = 12 Pca: 12; benign: 12 |
LC QTOF-MS | Diagnosis | adenosine monophosphate, spermidine, uracil, ophthalmic acid + HPO3, 2,3-diaminopropionic acid + HPO3 + 2 unknown metabolites = putative identification | Yes | OPLS-DA volcano plot | Tissue extracts from core biopsies after prostatectomy |
McDunn [44] | 2013 | Pca: 331 Benign: 178 (matched to 178 of the Pca samples) |
UHPLC-MS/MS GC-MS |
Staging | aggressive Pca:ADP, Glucose, 6-sialyl-N-actyllyctosamine, 2-hydroxypalmitate, 5,6 dihydrouracil, choline, fumarate, kynurenine, phophate, 2-hydrxoystearate, Ac-SDKP, choline phosphate, glycerol-3-phophate, n-acetylaspartate Gleason pattern progression:proline, malate, ADP-ribose, 6-sialyl-N-acetyllactosamineextracapsular extension:NAD+, N-acetylaspartate, putrescine, Glucose Tumor spread (regional lymph nodes/seminal vesicles):choline phosphate, Glycerol3-phophate, putrescine, 6-sialyl-N-acetyllactosamine |
No | paired t-testWilcoxon test linear regression | Tissue extract from OCT embedded tissue from prostatectomies |
Jung [47] | 2013 |
n = 95 matched cancer and benign adjacent tissue |
LC-MS/MS GC-MS |
Diagnosis Prognosis Biological recurrence |
Diagnosis of Pca:2-hdroxybehenic acid, crebronic acid, tricosanoic acid, glycerophophoethanolamine, isopentenyl pyrophosphate, 7-methylguanine, 2-aminoadipic acid, gluconic acid, maltotriose, tricosanoic acid Prediction of biological recurrence risk:2-aminoadipic acid, gluconic acid, maltotriose |
No | Wilcoxon paired test ROC analysis logistic regression Kaplan–Meier curves univariate and multivariate Cox regression | tissue extracts of punch biopsy from cryosections after prostatectomy |
Brown [51] | 2012 |
n = 8 matched cancer and benign adjacent tissue |
UHPLC-MS/MS GC-MS |
Diagnosis | > 40 metabolites not specified further | No | Welch’s two sample t-test hierachical clustering | tissue extracts from core biopsy after prostatectomy |
Selnæs [53] | 2012 |
n = 13 subjects 40 tissue samples |
HR-MAS-1H-MRS | Staging | CCS/C ratio (choline+creatine+spermine over citrate) | No | Spearman’s rank correlation Jonchheere– Terpstra test |
intact tissue from needle biopsy after prostatectomy |
Maxeiner [60] | 2010 | Pca with biological recurrence: 16 Pca without biological recurrence: 32 |
HR-MAS-1H-MRS | Prognosis | spermine, glutamine, myo-inositol, phophoryl choline, scylloinositol, glutamate | Yes | PCA student’s t-test Canonical analysis ANOVA ROC analysis | intact tissue from needle biopsy after prostatectomy;training and test set with identical case group but distinct control groups |
Sreekumar [28] | 2009 |
n = 42 tissue samples benign adjacent: 16 localized Pca: 12 metastatic Pca: 14 |
UHPLC-MS/MS GC-MS |
Diagnosis | sarcosine, uracil, kynurenine, glycerol-3-phophate, leucine, proline | Yes | Wilcoxon rank-sum test | tissue extracts from biopsy samplesonly sarcosine was analyzed in validation set |
Cacciatore [49] | 2017 | matched benign and Pca samples Training set: n = 8 Validation set: n = 4 |
UHPLC-MS/MS GC-MS |
Diagnosis | 32 metabolites reported; biomarkers included in the model not specified | Yes | Hierarchical clustering OSC-PLS | tissue extracts from tissue section after prostatectomyalso compared OCT-embedded and FFPE tissue as biospecimen |
Sandsmark [54] | 2017 |
n = 41 subjects Pca: 95 benign adjacent: 34 |
HR-MAS-1H-MRS | Diagnosis | Pca with high vs. Pca with low/intermediate NCWP-EMT score: spermine and citratePca with low vs. Pca with high NCWP-EMT score taurine, phosphoethanolamine | No | t-test | intact tissue from prostatectomiesmain focus: alterations in non-canonical WNT signaling pathway (NCWP) and EMT in Pcajoint gene expression and metabolomic analyses; targeted analysis of 23 metabolites; metabolomics was performed only on the main cohort |
Hansen [55] | 2016 |
n = 41 subjects Pca: 95 benign adjacent: 34 |
HR-MAS MRS | Staging | citrate, spermine (correlated with presence ERG translocation) | Yes | unsupervised multivariate analysis PLS-DA | gene expression analysis and TMPRSS2-ERG as marker for disease aggressiveness;intact tissue from tissue slices collected from prostatectomies; analyzed metabolic alterations in PCA patients positive for TMPRSS2-ERG/high ERG gene fusion; targeted analysis of 23 metabolites |
Meller [57] | 2016 |
n = 106 subjects matched cancer and benign adjacent tissue ERG-positive Pca: 27 ERG-negative Pca: 23 |
GC-MS LC-MS |
Staging Prognosis Biological recurrence |
Gleason score:pantothenic acid, maltose, fructose-6-phosphate, gluconic acid, cholesterol ERG status:maltotriose, gluconic acid, citrate, cis-aconitate, spermine, putrescine, cerebronic acid, 2-hydroxybehenic acid, tricosanoic acid, Biological relapse:tyrosine and tryptophan |
No | ANOVA PCA | tissue extracts of punch biopsy from cryosections after prostatectomy |
Ren [43] | 2016 | Training set:25 paired PCa and adjacent benign Validation set:51 paired Pca and adjacent benign 16 BPH |
LC-MS | Diagnosis | sphingosine, citicoline, choline, pantothenic acid, carnitine C4-OH, GPC, NAD, phenylacetyl-glutamine, carnitine C14:2 | Yes | PCA PLS-DA Signrank Wilcoxon signed rank two-sides test (biomarker analysis) | joint transciptomics and metabolomics to identify altered metabolic pathways in PCA tissue;tissue extracts from prostatectomies |
Liu [46] | 2015 |
n = 42 tissue samples benign adjacent: 16 localized Pca: 12 metastatic Pca: 14 |
n.a. | Diagnosis | Proline, Cholesterol, sarcosine, spermidine, spermine, Putrescine, 4-Acetamidobutanoate | Yes | DRW-GM + logistic regression | joint analysis of genomic and metabolomic data and pathway topology using directed random walk on a global gene-metabolite pathway graph;used dataset established by Sreekumar et al. 2009 |
Priolo [48] | 2014 | Discovery set: Pca: 61; benign: 25 Validation set: Pca: 40; benign: 16 |
UHPLC-MS/MS GC-MS |
Diagnosis Tumour subtyping |
MYC-driven Pca:Oleic acid, arachidonic acid, docosahexaenoic acidsAKT1-driven Pca:2-aminoadipic acid, creatine | Yes | Mann–Whitney test | metabolomic profiling of tumors driven by MYC and AKT1 oncogenes;extracts of frozen tissue from prostatectomy;metabolomic profiling in cell lines, mice and human tissue; validation of selected markers in human tissue samples |
Keshari [58] | 2011 |
n = 49 tissue samples high-grade Pca: 13 low-grade Pca: 22 benign: 14 |
1-D and 2-D HR-MAS Spectroscopy |
Staging | Benign vs. Pca tissue: choline, phosphocholine, glycerophosphocholine, phosphoethanolamine, glycerophosphoethanolamine, citrate, polyamineslow-grade vs. high-grade Pca:phosphocholine, glycerophosphocholine | No | Student’s t-test | intact tissue from core biopsies after prostatectomy;targeted analysis of phospholipid metabolites |
Shuster [45] | 2011 | Pca: 14 benign: 14 |
GC-MSLC-MS/MS | Diagnosis | cysteine, dihomo-linoleate, docosapentaenoate, N-acetylaspartate, N-acetylglucosamine, uracil, xanthine, and 1-stearoylglycerophophoinositol;uracil, kynurenine, glycerol-3-phosphate, leucine, proline; choline, lactate, alanine citrate, putrescine, spermidine, spermine | No | matched paired t-test | tissue extracts from needle biopsies after prostatectomy;description of the mPREF methodreplicated metabolites previously published by Sreekumar et al. 2009 and various in vivo studies |
Zhang [59] | 2014 | untreated patients: benign: 58; indolent Pca: 5; aggressive Pca: 8 radiation-treated patients: benign: 32; indolent Pca: 7 (relapse); aggressive Pca: 12 (relapse) |
1-D and 2-D HR-MAS Spectroscopy |
Staging Diagnosis |
aggressive vs. indolent Pca:choline, phosphocholine, glycerophosphocholine, [choline + phosphocholine + glycerophosphocholine] to creatine ratio, (lactate; only in untreated)benign vs. Pca (untreated):citrate, polyamines, lactate, glutamate, alanine | No | linear mixed-effects model Wilcoxon Rank Sum Test Kruskal–Wallis Test | intact tissue from core biopsies |
Giskeødegård [52] | 2013 |
n = 158 tissue samples from 48 subjects benign: 47v low-grade Pca: 30 high-grade Pca: 81 |
HR-MAS 1H MRS |
Staging | Pca vs. benign: citrate, taurine, creatine, glycerohpophocholine, phosphocholine, choline, glycinelow-grade vs. high-grade Pca:spermine, citrate, CCP/C ratio | No | Linear mixed models PLS-DA models | intact tissue from biopsies |
Jentzmik [56] | 2011 |
n = 92 Matched PCa and adjacent benign tissue |
GC-MS | Staging | sarcosine | No | Mann–Whitney U test Wilcoxon test Spearman rank correlation Kaplan–Meier curve Cox proportional hazards regression analysis log rank test ROC analysis |
target analysis of sarcosine as biomarker for disease progression tissue extracts from punch biopsies of tissue sections collected after prostatectomy |
Thysell [29] | 2010 | Discovery set: bone metastases: 14 (hormone-naive Pca: 7; CRPC 7) adjacent normal bone: 10 Validation set:bone metastases: 13(6 Pca, 7 other cancers) normal bone: 11 Primary tumour: with metastases: 7 w/o metastases: 6benign: 17 |
GC-TOFMS | Staging | Bone tissue: metastases vs. normal: Cholesterol, myo-inositol-1-phosphate, citrate, fumarate, glycerol-3-phosphate, amino aicds Primary tumour: metastatic PCa vs. benign tissue and non-metastatic PCa:malate, dehydroascrobic acid, urea, hypoxanthine, asparagine, threonine, fumarate, linoleic acid |
Yes | OPLS-DA Mann–Whitney U-test | tissue extracts from fresh-frozen biopsies of bone metastases and from biopsies of primary Pca and benign prostateall patients were selected to have hihg-risk tumours (i.e., presence of bone metastases, locally advanced tumour or poorly differnitated cancer)validation set available only for bone metastatic tissueblood plasma samples from men who underwent prostate biopsies were also analyzed |
ADT: androgen deprivation therapy; ANOVA: one-way analysis of variance; BPH: benign prostate hyperplasia; GC: gas chromatography; (HP/UP)LC: (high performance/ultra performance) liquid chromatography; MALDI-FTICR: matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry imaging; MRS: magnetic resonance spectroscopy; MS: mass spectrometry; MS/MS tandem mass spectrometry; (HR-MAS) NMR: (high resolution - magic angle spinning) nuclear magnetic resonance; OPLS-DA: orthogonal projections to latent structures-discriminant analysis; (Q)TOF: (quadrupole) time of flight; PCa: prostate cancer; PCA: principal component analysis; PLS(R)-DA: partial least squares (regression)-discriminant analysis; ROC: receiver-operating characteristic.