SUPPLEMENTARY MATERIAL FOR

Differential metabolic alterations and biomarkers between gastric cancer and

colorectal cancer: A Systematic Review and Meta-analysis

List of Supplementary Material

1. Supplementary Figures

Supplementary Figure 1. Workflow of the process of literature retrieval for the systematic review of metabolomics studies.

Supplementary Figure 2. Overall distribution of sample types, platforms, publication year, study design, and populations in the systematic review of metabolomics studies of gastric cancer and colorectal cancer.

Supplementary Figure 3. Visualization of the typical pathways in gastric cancer and colorectal cancer.

2. Supplementary Tables

Table S1. PRISMA Checklist of Items to Include When Reporting a Systematic Review Involving a Meta-analysis

Table S2. The characteristics of included metabolomics studies of gastric cancer

Table S3. The characteristics of included metabolomics studies of colorectal cancer in this systematic review

Table S4. Quality assessment of gastric cancer studies included in the systematic review

Table S5. Quality assessment of colorectal cancer studies included in the systematic review by

QUADOMICS

Table S6. Differential metabolites and the reported frequencies in previous metabolomics studies of gastric cancer

Table S7. Differential metabolites and the reported frequencies in previous metabolomics studies of colorectal cancer

Table S8. Pathway enrichment analyses based on the differential metabolites of gastric cancer

Table S9. Pathway enrichment analyses based on the differential metabolites of colorectal cancer 1. Supplementary Figures

Supplementary Figure legends

Supplementary Figure 1. Workflow of the process of literature retrieval for the systematic review of metabolomics studies. (A). Gastric cancer; (B). Colorectal cancer.

Supplementary Figure 2. Overall distribution of sample types, platforms, publication year, study design, and populations in the systematic review of metabolomics studies of gastric cancer and colorectal cancer. (A). Publication year; (B). Epidemiologic design; (C). Regions of subjects; (D).

Detection platforms and E. Specimen origins of the included studies.

Supplementary Figure 3. Visualization of the typical pathways in gastric cancer and colorectal cancer. Colorectal cancer (brown); Gastric cancer (blue).

SEARCH STRATEGY A Electronic literature search in Pubmed, Embase and Sciencedirect using combining terms(gastric/stomach + cancer/carcinoma/neoplasm/tumor)AND(metabolomics/metabonomics)AND(NMR/LC-MS/GC-MS/CE/MS) Total citations retrieved from search (n=648) Citations excluded due to duplication(n=198) Unique citations undergoing abstract review(n=450) Studies excluded following abstract review: cell lines or animal models(n=248); genomic(n=12); proteomics (n=78); review (n=22); others(eg. prediction models, techonology assessment and bromatology)(n=52)

Browsing backgrounds and methods after searching full-text(n=38) Studies excluded following full-text review:full-text unavailable(n=13);non-English(n=1) Studies included in this systematic review(n=24)

B SEARCH STRATEGY Electronic literature search in Pubmed,Embase and Sciencedirect using combining terms( colorectal/colon +cancer/ neoplasm/tumor/ carcinoma)AND(metabolomics/metabonomics)AND(NMR,GC-MS,LC-MS) Total citations retrieved from search(n=990) Citations excluded due to duplication(n=405) Unique citations undergoing abstract review(n=585)

Studies excluded for non-English papers(n=11), review (n=17), and abstracts only(n=47) - Browsing backgrounds and methods after searching full-text(n=510)

Additional studies identified Studies excluded following full-test review: cell from reference list and line, animal, and proteomics researches(n=341); review(n=7) others(eg. survival prediction and therapy evaluation(n=113) Studies included in this systematic review(n=65) Supplementary Figure 1 12 A

9

8

D 8 7 Cancer 7 6 CRC

Number GC Platform 5 6

3 5

2 4 Multi-platforms 1 Frequency 3 2006 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 Others Year 2 B Case-control Nested case-control Self-control

40 1 38 36 34 32 30 Tissue Urine Serum Gastric juice Plasma 28 26 Gastric cancer 24 Cancer 22 20 CRC 18 Number GC 16 14 12 10 8 6 4 2 E 24 0 23 CRC GC CRC GC CRC GC 22 Cancer 21 20

19 c Asia Europe North America 18 Platform 17 39 16 37 15 35 14 33 13 31 12 29 11 forms 27 Frequency 10 25 9 23 Cancer 8 Others 21 7 19 CRC 6 Number 17 GC 15 5 13 4 11 3 9 2 7 1 5 3 1 Tissue Serum Urine Feces Volatile Plasma

CRC GC CRC GC CRC GC Colorectal cancer Cancer Supplementary Figure 2 Supplementary Figure 3 2. Supplementary Tables

Table S1. PRISMA checklist of items to include when reporting a systematic review involving a meta-analysis

Reported Section/topic # Checklist item on page # TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. Page 1 ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, Page 2 participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. Page 3 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, Page 4 outcomes, and study design (PICOS). METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide Not registration information including registration number. available Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, Page 5 language, publication status) used as criteria for eligibility, giving rationale. Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify Page 4 additional studies) in the search and date last searched. Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be Page 4 repeated. Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, Page 4-5 included in the meta-analysis). Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes Page 5 for obtaining and confirming data from investigators. Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and Page 5 simplifications made. Risk of bias in individual 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was Page 5 studies done at the study or outcome level), and how this information is to be used in any data synthesis. Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). Page 5

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency Page 5-6 2 (e.g., I ) for each meta-analysis. Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective Page 5 reporting within studies). Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating Page 5-6 which were pre-specified. RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at Page 6 each stage, ideally with a flow diagram.

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and Page 6 provide the citations.

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Page 7 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each Page 7 intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. Page 6-7

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). Page 7 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). Page 7-9 DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to Page 9- key groups (e.g., healthcare providers, users, and policy makers). 13 Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of Page 13 identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. Page 14 FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the Page 15 systematic review.

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097 For more information, visit: www.prisma-statement.org. Table S2. The characteristics of included metabolomics studies of gastric cancer

Study Study Number of Subjects Match Sample Source Sample Platform Metabolites First Type or Not type Author[ref]year Zhang, H. [1] 2018 Case- LNM-positive GC Yes (80 the West China tissue 1H-NMR Isoleucine, Leucine, Valine, Lactate, Threonine, Alanine, control patients (n = 40), LNM- matche Hospital of Sichuan Citrulline, VLDL:-CH2-CH2-CH2O, N-acetyl glycoprotein, negative GC patients (n d) University O-acetyl glycoprotein, Acetic acid, Glutamine, D-ribose, = 40) Acetone, Lipid, -CH2-C=O, Pyruvate Succinate, Glutathione, and normal controls (n = Methylamine, Choline, PC(phosphochline), Trimethylamine-N- 40) oxide, Taurine, myo-Inositol, Glucose, Glycine, Lysine, Betaine, Serine, Uracil, Fumarate, Tyrosine, Hypoxanthine Liu, H.N. [2]2018 Case- 25 GC patients and 30 unclear Zhongshan Hospital, serum GC/MS Propanoic acid, 3-Trimethylsiloxymyristic acid, (-)- control HCs Fudan University Cholesterol, Silane, Tocopherol, Cyclopentasiloxane, Silanol, l- Threonine, Hexadecanoic acid, Octadecanoic acid, Glucose oxime, Hexadecane, D-Glucose, Heptacosane, Butanoic acid, Phosphoric acid, D-Mannose, D-Mannitol, D-Galactose, Undecane, Hentriacontane, Ethanamine, Tetratriacontane, Pentacosane, Heptasiloxane Corona, G. [3]2018 Case- the training set : unclear the Oncological serum AbsoluteIDQ Training set:C0, C14, C16, C18:1, C2, C3, C5-OH ,C3-DC-M, control 49 GC patients and 37 Gastroenterology, p180 Kit Cit, Creatinine, lle, total DMA, Thr, PC aa 32:2, PC aa 34:3, FDR Centro di Riferimento PC aa 34:4, PC aa 36:2, PC aa 36:6, PC aa 40:2, PC aa 40:3, validation set :22 GC and Oncologico, IRCCS- PC aa 42:0, PC aa 42:2, PC aa 42:6, PC ae 32:2, PC ae 34:2, 17 FDR National Cancer PC ae 34:3, PC ae 36:2, PC ae 36:3, PC ae 36:4, PC ae 38:0, Institute, Aviano, Italy PC ae 38:6, PC ae 40:1, PC ae 42:2, PC ae 42:3, PC ae 42:4, PC ae 44:6, SM 16:1, SM 24:0, SM(OH)22:1, SM(OH)22:2, SM(OH)24:1 Validation set: SM(OH)22:1, SM(OH)22:2, SM(OH)24:1, C2, C16 and C18:1, PC ae 40:1, PC ae 42:2 and PC ae 42:3 Lario, S. [4]2017 Case- 80 patients (19 NAG−, unclear Outpatients Plasma LC-MS Alanine, Asparagine, Citrulline, Erythro-lsoleucine, control 20 CAG+, 21 PLGC and Hexadecadienylcarnitine, Histidine, 20 GC) Hydroxytetradecadienylcarnitine, Lysine, Methionine, Methionine, Sulfoxide, N-Acetylornithine, N- Formylkynurenine, Octadecenoylcarnitine, Ornithine, PAGN, Sarcosine, Spermidine, Symmetric Dimethylarginine, Taurine, Tetradecanoylcarnitine, Threonine, Tryptophan, Xanthurenic Acid, 3-Indoleacetonitrile, Quinolinic acid, Aminophenol, 3-hydroxykynurenine, p- Tyrosine, m-Tyrosine, Serotonin, 5-hydroxytryptophan, o-Tyrosine, Kynurenine, Phenylalanine, N-Formylkynurenine, Hydroxyanthranillic acid, Tryptophan, Xanthurenic Acid, Tryptamine, Kynurenic acid, 5-Methoxytryptamine, 4-Chloro- kynurenine, Acetylserotonin, Phenylacetylglutamine, 6-Hydroxymelatonin, Indole-3-acetamide, Anthranilic acid, Formyl-N-acetyl-methoxykynurenine, Indolelactic acid, Melatonin, 3-Indoleacetic acid, Tryptophol Wang, H. [5] 2016 Self- 125 GC mucosa Yes (54 West China Hospital of tissue 1H-NMR VLDL: CH3-(CH2)n, Isoleucine, Leucine, Valine, β- control 54 normal mucosa matche Sichuan University hydroxybutyrate, Lactate, 2-Hydroxyisobutyric acid, Citrulline, d) VLDL: −CH2-CH2-CH2O, Acetate, N-Acetyl glycoprotein, O- Acetyl glycoprotein, D-ribose, Acetone, Lipid, -CH2-C=O, Acetoacetate, Acetoacetic acid, Glutamate, Succinate, Glutamine, Glutathione, Methylamine, Aspartate, Dimethylamine, Acetic acid, Phosphocreatine, Creatine, Ceatinine, Choline, PC TMAO, myo-Inositol, α-Glucose, Glycine, Glycerol, Dimethylglycine, Lysine, Glycolate, Serine, Uracil, Fumarate, 4-Hydroxyphenylactate, Tyrosine, Tryptophan, Phenyacetylglutamine, Adenine, Hypoxanthine, Formate Kuligowski, J. [6] Case- 33 GC No the Corporació Plasma UPLC/TOF- Tryptophan, Phenylacetylglutamine 2016 control 40 H.pylori-negative Sanitària Parc Taulí MS with non-active gastritis 38 H.pylori-positive with chronic active gastritis 32 precursor lesions of gastric cancer 5 peptic ulcer Jiang, H.P. [7] Case- 30 GC unclear Hubei Cancer Hospital Urine SPME/LC- N-Methyl-N-threonylcarbamoyladenosin, 5- 2016 control 30 esophagus cancer MS/MS Methylaminomethyluridine, N-Acetylcytidine, 6-Hydroxyl-1,6- 30 lymphoma dihydropurine ribonucleoside, N-Methyl-2- 30 healthy controls methylthioadenosine, 5-Methylaminomethyl-2-thiouridine,1- Ribosyl-N-acethlhistamine, Uracil-5-oxyacetic acid methylester, 7-Methyl-8-oxoguanosine, Ribosylpyridinonecarboxamide, 5-Carbamoylmethyl-2- thiouridine, N,N-Dimethylcytidine, 1-Ribosyl-N- propionylhistamine, n-Ribosylhistidine, 5- Hydroxymethylcytidine, Succinyladenosine, N,7- dimethylguanosine, 2-Hydroxyluridine, Isoguanosine, 3- Methylcytidine, N-methyladenosine, 1-Methylguanosine, 5- Methyluridine, Nicotinamide, riboside, Pseudouridine, Guanosine, 1-Methyl-N-ethylguanosine, beta-D-3- Ribofuranosyluric acid, 5- (Isopentenylaminomethyl)uridine,5,6-Dihydrouridine, Coformycin, 3-Hydroxychavicol 1-glucoside, 3-Methyluridine, 1-Methylinosine, Orotidine, 5-Methylcytidine, 5- Formylcytidine, Cytidine, N-Hydroxymethyladenosine, N,N- dimethylguanosine, 5-(Isopentenylaminomethyl)-2-thiouridine, 6-Methyluridine, 1-Methyl-N2-ethylguanosine, Xanthosine, 5- Methoxycarbonylmethyluridine, 1-Ribosyl-N-ω- valerylhistamine, Adenosine, N-methylguanosine, 5- Carbamoylmethyluridine, Isoinosine, 7-Methylguanosine, Urate-3-ribonucleoside, Inosine, N,N-Dimethyladenosine, 5'- Deoxyadenosine, 8-Oxo-Guanosine, 1-Ribosyl-N-ω- vbutyrylhistamine, 2-Methylthio-N-methyladenosine, 1- Methyladenosine, N2,N2,7-trimethylguanosine, N- isopentenyladenosine, N-threonylcarbamoyladenosine, 3-(3- Amino-3-caroxypropyl)-uridine, Uridine, 5'-Deoxy-5'- methylthioadensine, 1-(beta-D-Ribofuranosyl)-1,4- dihydronicotinamide, 2-Thiouridine, 4-((1H-imidazol-2- yl)methyl)phenol-1-glucoside Choi, J.M. [8] Case- 35 GC No Seoul St. Mary’s Serum LC-MS/MS Indole-3-lactic acid, Anthranilic acid, Kynurenic acid, 2016 control 17 gastritis Hospital Gastric juice Kynurenine, 3-Indoxyl-sulfate, Tryptophan, Anthranilic acid, Nicotinic acid, Kynurenic acid Chen, Y. [9] 2016 Case- Training set: Yes Ruijin Urine GC-MS Alanine, Glycine, Valine, Isoleucine, Serine, Threonine, control 47 GC, 47 controls hospital Proline, Methionine, Tyrosine, Tryptophan, Ethyl 2- methylacetoacetate, Levulinic acid, p-Cresol, Benzylmalonic Validation set: acid, 4-Hydroxybenzoic acid, Hippuric acid, Benzil 112 GC, 87 controls Chan, A.W. Case- 43 GC Yes Three Hospitals in Urine 1H-NMR 1-Methylnicotinamide, 2-Furoylglycine, 2-Hydroxyisobutyrate, [10]2016 control 40 benign gastric disease Edmonton, Canada 3-Hydroxyisobutyrate, 3-Indoxylsulfate, 5-Hydroxytryptophan, 40 healthy controls 6-Hydroxynicotinate, Alanine, Betaine, Chlorogenate, Citrate, Creatinine, Dimethylamine, Formate, Homovanillate, Indole-3- lactate, Methylguanidine, N-AcetylglutamineDerivative, N- Acetylserotonin, Pantothenate, Sucrose, Trimethylamine, N- oxide, Tropate, Tyrosine, cis-Aconitate, trans-Aconitate, β- Alanine, π-Methylhistidine Mokhtari, M. [11] Self- 48 gastric Yes Hospitals Urine URC kit 5-Hydroxyindoleacetic Acid 2015 control adenocarcinoma Affiliated to Shiraz 47 chronic gastritis University of Medical 50 normal controls Sciences Liang, Q. [12] 2015 Nest 13 GC No Hospital affiliated to Urine LC-MS 2-Oxoglutarate, Alanine, Succinic acid, Citric acid, case- 9 healthy controls Heilongjiang Glycocholic acid, Glycine, Hexadecanoic acid, Hippurate, L- control University of Chinese proline, 4-Deoxythreonic acid, Malic acid, Medicine Phenylacetylglycine, Urea, Uric acid, Pyrimidine, Taurine Training set: 1-Methylnicotinamide, 2-Oxobutyrate, 3-Aminoisobutyrate, 3- Urine: 50 GC, 50 Indoxylsulfate, 4-Hydroxyphenylacetate, Acetate, Acetone, 1H NMR Case- controls Urine Alanine, Arginine, Betaine, Formate, Glycine, Glycolate, Jung, J. [13] 2014 Yes KUMC HR-MAS control Tissue: Tissue Histidine, Hypoxanthine, Lactate, Leucine, Mannitol, NMR 30 GC mucosa Methionine, N-Methylhydantoin, O-Acetylcarnitine, 30 normal mucosa Phenylacetylglycine, Phenylalanine, Putrescine, Succinate, Taurine, Tyrosine, Valine, Lipid I, Lipid II, Valine, Leucine, Validation set: Isoleucine, Lactate, Alanine, Lysine, Glutamate, Glutamine, Urine: 23 GC, 31 Acetate, Choline, Phosphocholine, Taurine, Creatine, Tyrosine, controls Phenylalanine, Inosine, Formate Lactic acid, Arginine, Leucine, Isoleucine, Valine, Citric acid, Case- 26 GC Shanghai Sixth Chen, J. [14]2014 No Urine MRB/CE-MS Histidine, Methionine, Serine, Aspartate, Malic acid, Succinate, control 14 healthy controls People’s Hospital Isoleucine, Valine Ribulose, Threonate,Gluconic acid, Uridine, A,b- Dihydroxyisobutyric acid, alpha-Hydroxytriazolam, N- acetylaspartate, Deoxyribose, Xanthosine, 2-Furoic acid, 4- Hydroxy-3-methoxymandelic acid, Salicyluric acid, Tryptophan, Midazolam, N-Valeryl acetic acid, Salicylic acid, 3-Methyladipic acid, 3-Hydroxyphenylacetate, β- Zhang, Y. [15] Case- 25 GC The Second Hospital of No Urine LC/QTOF-MS ureidoisobutyric acid, 3,4-Dihydroxyphenylpropionic acid, 2013 control 17 controls Jilin University Diflunisal, Sebacic acid, 3-Hydroxyphenylacetate, Dihydroxymelphalan, 3,4,5-Trimethoxybenzoic acid, Bis(p- fluorophenyl)methanol, Ethynylestradiol 3-sulfate, 3- Methylindole, Sebacic acid, Rimiterol, Androsterone glucuronide, Hydroxyibuprofen, Megestrol, Ethisterone

l-Glutamine, l-Valine, Sarcosine, Hexanedioic acid, 9,12- Octadecadienoic acid, 9-Octadecenoic acid, trans-13- the Sixth Affiliated Octadecenoic acid, Nonahexacontanoic acid, Cholesta-3,5- Case- 30 GC Hospital of Sun Yat- Song, H. [16]2012 Yes Serum GC-MS diene, Cholesterol, pentafluoropropionate, Cholesterol, control 30 healthy controls sen Cholest-5-en-3-ol, Fumaric acid, 2-O-Mesyl arabinose, University Hexadecanenitrile, Benzeneacetonitrile, 2-Amino-4-hydroxy- pteridinone, 1,2,4-Benzenetricarboxylic acid 11 GC 3-Hydroxypropionic acid, Pyruvic acid, 3-Hydroxyisobutyric Case- 15 esophageal cancer Kobe University Ikeda, A. [17]2012 No Serum GC-MS acid, Octanoic acid, Phosphoric acid control 12 colorectal cancer Hospital 12 healthy controls 9 preoperative GC 13 postoperative GC 19 chronic superficial The First Urate, Ornithine, 1-Monohexadecanoylglycerol, Case- gastritis Affiliated Hospital of Pyroglutamate, 11-Eicosenoic acid, Glutamate, γ-Tocopherol, Yu, L. [18] 2011 No Plasma GC/TOF-MS control 13 chronic atrophic Nanjing Medical Asparagine, 2-Hydroxybutyrate, Azelaic acid, Creatinine, gastritis University Threonate 10 intestinal metaplasia 15 dysplasia Fumaric acid, Valeric acid, α-ketoglutaric acid, Xylonic acid, The Sixth Affiliated 9-Hexadecenoic acid, 3-Hydroxybutanoic acid, Hexadecanoic Self- 30 GC mucosa Song, H. [19] 2011 Yes Hospital, Sun Yat-sen Tissue GC-MS acid, Benzenepropanoic acid, Octadecanoic acid, cis-Vaccenic control 30 normal mucosa University acid, Arachidonic acid, 1-Phenanthrene-carboxylic acid, 9- Octadecenamide, Squalene 199 GC 985 controls 200 lung cancer 996 controls Hospital Threonine, Asparagine, Glutanine, Alanine, Citrulline, Valine, Miyagi, Y. [20] Case- 199 colorectal cancer HPLC/ESI- Yes Cancer center Plasma Methionine, Isoleucine, Leucine, Tyrosine, Phenylalanine, 2011 control 995 controls MS Medical institutes Histidine, Tryptophan, Lysine, Arginine 198 breast cancer 976 controls 134 prostate cancer 666 controls Heptanedioic acid, Propanoic acid, Phenanthrenol, Butanetriol, L-Valine, Acetamide, L-Isoleucine, Serine, Butenoic acid, Self- 18 GC mucosa Oxazolethione, Naphthalene, L-Glutamine, Phosphoserine, L- Wu, H. [21]2010 Yes Zhongshan Hospital Tissue GC-MS control 18 normal mucosa Altrose, L-Mannofuranose, Galactofuranoside, myo-Inositol, D-Ribofuranose, L-Cysteine, Hypoxanthine, L-Tyrosine, Phenanthrenol, Butanoic acid Cai, Z. [22] 2010 Self- 65 GC mucosa Yes The First Tissue GC/TOF-MS Hydroxyacetic Acid, 2-Aminobutyric acid, 3- control 65 normal mucosa Affiliated Hospital of Aminoisobutanoic acid, Valine, 2-Hydroxy-4-methyl-pentanoic Zhengzhou University acid, Isoleucine, Proline,Uracil, 3,4-Dihydroxy-2(3H)- (Henan, China) Furanone, Threonine, Thymine, Nicotinamide, Dihydrouracil, Aspartic acid, Pyroglutamic acid, GABA, Cysteine, Glutamic acid, Dodecanoic acid, Asparagine, Putrescine, Glycerol, Phosphate, Cadaverine, Tetradecanoic acid, Ascorbic acid, Gluconic acid, Xanthine, Palmitelaidic acid, Palmitic acid, N- Acetyl-glucosamine, Kynurenine, Linoleic acid, Stearic acid, Arachidonic acid, Inosine, 1-Palmitoyl-Glycerol, Sucrose, Cholesterol, Fructose 6-Phosphate, Fructose 1,6-Diphosphate, Glyceraldehyde 3-Phosphate, Pyruvic acid, Lactic acid, Fumaric acid, Isocitric acid Proline, Arginine, Putrescine, Phenylalanine, 4-Aminobutyrate, 12 GC mucosa Valine, Tyrosine, β-Alanine, Hydroxyproline, Asparagine, 12 normal mucosa Institution Review Alanine, NADPH, Gluconate, Serine, Cystathionine, Cysteine, Hirayama, A. [23] Self- 16 colorectal cancer Yes Board of the National Tissue CE/TOF-MS Tryptophan, Leucine, Lysine, Threonine, Glutamate, 2- 2009 control mucosa Cancer Center Aminobutyrate, Histidine, Carnosine, γ-Glu-Cys, Glycine, 16 normal mucosa Spermidine, Guanine, Isoleucine, Hypoxanthine, SAH, Adenine, SAM, Methionine Buszewski, B. [24] Case- 5 GC mucosa University Surgical SPME/GC- Yes Tissue Ethanol, Butane, Carbon disulfide, 1-Propanol, 2-Butanone 2008 control 5 normal mucosa Clinic in Torun MS References: 1. Zhang H, Cui L, Liu W, Wang Z, Ye Y, Li X et al. (1)H NMR metabolic profiling of gastric cancer patients with lymph node metastasis. Metabolomics : Official journal of the Metabolomic Society 2018; 14(4): 47; e-pub ahead of print 2018/03/16; doi 10.1007/s11306-018-1344-x. 2. Liu HN, Wu H, Tseng YJ, Chen YJ, Zhang DY, Zhu L et al. Serum microRNA signatures and metabolomics have high diagnostic value in gastric cancer. BMC cancer 2018; 18(1): 415; e-pub ahead of print 2018/04/15; doi 10.1186/s12885-018-4343-4. 3. Corona G, Cannizzaro R, Miolo G, Caggiari L, De Zorzi M, Repetto O et al. Use of Metabolomics as a Complementary Omic Approach to Implement Risk Criteria for First-Degree Relatives of Gastric Cancer Patients. International journal of molecular sciences 2018; 19(3); e-pub ahead of print 2018/03/10; doi 10.3390/ijms19030750. 4. Lario S, Ramirez-Lazaro MJ, Sanjuan-Herraez D, Brunet-Vega A, Pericay C, Gombau L et al. Plasma sample based analysis of gastric cancer progression using targeted metabolomics. Scientific reports 2017; 7(1): 17774; e-pub ahead of print 2017/12/21; doi 10.1038/s41598-017-17921-x. 5. Wang H, Zhang H, Deng P, Liu C, Li D, Jie H et al. Tissue metabolic profiling of human gastric cancer assessed by (1)H NMR. BMC cancer 2016; 16: 371; e-pub ahead of print 2016/07/01; doi 10.1186/s12885- 016-2356-4. 6. Kuligowski J, Sanjuan-Herraez D, Vazquez-Sanchez MA, Brunet-Vega A, Pericay C, Ramirez-Lazaro MJ et al. Metabolomic Analysis of Gastric Cancer Progression within the Correa's Cascade Using Ultraperformance Liquid Chromatography-Mass Spectrometry. Journal of proteome research 2016; 15(8): 2729-2738; e-pub ahead of print 2016/07/08; doi 10.1021/acs.jproteome.6b00281. 7. Jiang HP, Chu JM, Lan MD, Liu P, Yang N, Zheng F et al. Comprehensive profiling of ribonucleosides modification by affinity zirconium oxide-silica composite monolithic column online solid-phase microextraction - Mass spectrometry analysis. Journal of chromatography A 2016; 1462: 90-99; e-pub ahead of print 2016/08/09; doi 10.1016/j.chroma.2016.07.086. 8. Choi JM, Park WS, Song KY, Lee HJ, Jung BH. Development of simultaneous analysis of tryptophan metabolites in serum and gastric juice - an investigation towards establishing a biomarker test for gastric cancer diagnosis. Biomedical chromatography : BMC 2016; 30(12): 1963-1974; e-pub ahead of print 2016/05/31; doi 10.1002/bmc.3773. 9. Chen Y, Zhang J, Guo L, Liu L, Wen J, Xu L et al. A characteristic biosignature for discrimination of gastric cancer from healthy population by high throughput GC-MS analysis. Oncotarget 2016; 7(52): 87496- 87510; e-pub ahead of print 2016/09/03; doi 10.18632/oncotarget.11754. 10. Chan AW, Mercier P, Schiller D, Bailey R, Robbins S, Eurich DT et al. (1)H-NMR urinary metabolomic profiling for diagnosis of gastric cancer. British journal of cancer 2016; 114(1): 59-62; e-pub ahead of print 2015/12/10; doi 10.1038/bjc.2015.414. 11. Mokhtari M, Rezaei A, Ghasemi A. Determination of urinary 5-hydroxyindoleacetic acid as a metabolomics in gastric cancer. Journal of gastrointestinal cancer 2015; 46(2): 138-142; e-pub ahead of print 2015/03/13; doi 10.1007/s12029-015-9700-9. 12. Liang Q, Wang C, Li B. Metabolomic Analysis Using Liquid Chromatography/Mass Spectrometry for Gastric Cancer. Applied biochemistry and biotechnology 2015; 176(8): 2170-2184; e-pub ahead of print 2015/06/20; doi 10.1007/s12010-015-1706-z. 13. Jung J, Jung Y, Bang EJ, Cho SI, Jang YJ, Kwak JM et al. Noninvasive diagnosis and evaluation of curative surgery for gastric cancer by using NMR-based metabolomic profiling. Annals of surgical oncology 2014; 21 Suppl 4: S736-742; e-pub ahead of print 2014/08/06; doi 10.1245/s10434-014-3886-0. 14. Chen JL, Fan J, Lu XJ. CE-MS based on moving reaction boundary method for urinary metabolomic analysis of gastric cancer patients. Electrophoresis 2014; 35(7): 1032-1039; e-pub ahead of print 2013/08/01; doi 10.1002/elps.201300243. 15. Zhang Y, Ren H, Jiang Y, Gao YF, Liu SY. Urinary metabonomics of stomach cancer assessed by rapid resolution liquid chromatography/time-of-fight mass spectrometry. Chinese medical journal 2013; 126(10): 1930-1933; e-pub ahead of print 2013/05/16. 16. Song H, Peng JS, Dong-Sheng Y, Yang ZL, Liu HL, Zeng YK et al. Serum metabolic profiling of human gastric cancer based on gas chromatography/mass spectrometry. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 2012; 45(1): 78-85; e-pub ahead of print 2011/11/30. 17. Ikeda A, Nishiumi S, Shinohara M, Yoshie T, Hatano N, Okuno T et al. Serum metabolomics as a novel diagnostic approach for gastrointestinal cancer. Biomedical chromatography : BMC 2012; 26(5): 548- 558; e-pub ahead of print 2011/07/21; doi 10.1002/bmc.1671. 18. Yu L, Aa J, Xu J, Sun M, Qian S, Cheng L et al. Metabolomic phenotype of gastric cancer and precancerous stages based on gas chromatography time-of-flight mass spectrometry. Journal of gastroenterology and hepatology 2011; 26(8): 1290-1297; e-pub ahead of print 2011/03/30; doi 10.1111/j.1440-1746.2011.06724.x. 19. Song H, Wang L, Liu HL, Wu XB, Wang HS, Liu ZH et al. Tissue metabolomic fingerprinting reveals metabolic disorders associated with human gastric cancer morbidity. Oncology reports 2011; 26(2): 431- 438; e-pub ahead of print 2011/05/14; doi 10.3892/or.2011.1302. 20. Miyagi Y, Higashiyama M, Gochi A, Akaike M, Ishikawa T, Miura T et al. Plasma free amino acid profiling of five types of cancer patients and its application for early detection. PloS one 2011; 6(9): e24143; e-pub ahead of print 2011/09/15; doi 10.1371/journal.pone.0024143. 21. Wu H, Xue R, Tang Z, Deng C, Liu T, Zeng H et al. Metabolomic investigation of gastric cancer tissue using gas chromatography/mass spectrometry. Anal Bioanal Chem 2010; 396(4): 1385-1395; e-pub ahead of print 2009/12/17; doi 10.1007/s00216-009-3317-4. 22. Cai Z, Zhao JS, Li JJ, Peng DN, Wang XY, Chen TL et al. A combined proteomics and metabolomics profiling of gastric cardia cancer reveals characteristic dysregulations in glucose metabolism. Molecular & cellular proteomics : MCP 2010; 9(12): 2617-2628; e-pub ahead of print 2010/08/12; doi 10.1074/mcp.M110.000661. 23. Hirayama A, Kami K, Sugimoto M, Sugawara M, Toki N, Onozuka H et al. Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer research 2009; 69(11): 4918-4925; e-pub ahead of print 2009/05/22; doi 10.1158/0008-5472.Can-08-4806. 24. Buszewski B, Ulanowska A, Ligor T, Jackowski M, Klodzinska E, Szeliga J. Identification of volatile organic compounds secreted from cancer tissues and bacterial cultures. Journal of chromatography B, Analytical technologies in the biomedical and life sciences 2008; 868(1-2): 88-94; e-pub ahead of print 2008/05/21; doi 10.1016/j.jchromb.2008.04.038 Table S3. The characteristics of included metabolomics studies of colorectal cancer in this systematic review

Study Study Number of Subjects Match or Not Sample Source Sample Country Platform Metabolites First Author[ref]year Type Le Gall, G.[1]2018 Case- The first set of samples:20 CRC Age and sex Addenbrookes stool UK 1HNMR Cholate, Taurine, Glutamine, β-Alanine, Glucose control patients and matched Hospital Lithodeoxycholate, Xylose, Deoxycholate, study 20 healthy controls Ormithine, Glycerol, Guanosine, Isoleucine, The second of samples: 30 CRC Methanol, Galactose, 4-Aminohippurate, Isovalerate, patients and 30 healthy Hexose-phosphate, Phenylacetate, Isobutyrate, Valerate individuals Hu, X. Q.[2]2018 Case- Fifty healthy control (HC) and 70 NA the Official Plasma China((Sh GC-MS Aminomalonic acid, D-Aspartic acid, Terephthalic acid, control CRC patients Ethics ang hai Ormithine, D-Galactose, Uric acid, D-Tryptophan, study Committee in University Cholesterol, 1,2-Ethanediamine, L-Alanine, Urea, Glycerol, Shuguang ) Glycine, Creatinine, Palmitic acid, L-Proline, 1,2,3- Hospital Propanetricarboxylic acid, D-Galactose, 2-Indolecarboxylic acid Bian, X.[3]2018 Case- 20 healthy human and 20 NA hospital serum China(Sun UHPLC-Q- 11(S)-HETE, 12(S)-HEPE, 12(S)-HETE, 12(S)-HPETE, control CRC patients Yat-sen TOF/MS 13(S)-HPODE, 15(S)-HEPE, study University 15(S)-HETE, 15(S)-HETrE, 15(S)-HPETE, 5(S)-HEPE, ) 5(S)-HETE, 5(S)-HPETE, 6-keto-PGF1α, 8(S)-HETE, 9(S)-HPODE, Alanine, Arginine, Asparagine, Butyric acid, Chenodeoxycholic acid, Cholic acid, Deoxycholic acid, Fumaric acid, Glutamine, Glutarate, Glycine, Glycochenodeoxylic acid, Glycocholic acid, Histidine, Isobutyric acid, Isoleucine, Isovaleric acid, Lactic acid, Leucine, Lithocholic acid, Lysine, Malic acid, Methionine, PGE1, PGF2α, Proline, Propionic acid, Serine, Succinic acid, Threonine, Tryptophan, Tyrosine, Ursodeoxycholic acid, Valeric acid,Valine, α-KG Djukovic, D. [4]2018 Case- Serum samples were obtained Age and gender Hospital Serum United LC-MS 2'-deoxyuridine, Arginine, Dimethylglycine, Glutamic acid, control from patients undergoing either matched States Glutamine, Glyceraldehyde, Glycochenodeoxycholate, study colonoscopy for CRC screening (Purdue Glycocholate, Hippuric acid, Histidine, or CRC surgery after overnight University Hydroxyproline/Aminolevulinate, Linolenic acid, Lysine, fasting and identical bowel and Methionine, N-Acetyl-glycine, Uridine preparation prior to their Indiana procedure. University Samples were collected from School of CRC patients (n=66), polyp Medicine) patients (n=76), and healthy controls (n=92). Farshidfar, F. [5]2018 Case- Samples were collected from Age and gender Hospital Serum Canada FIA-MS / C10:1, C16, C16:1, C16:1-OH, C18:1, C18:2, C3, C3:1, control CRC patients (N=62), adenoma matched (Universit MS C3-OH, Gln, lysoPC a C24:0, lysoPC a C26:0, lysoPC a study (N=31), and controls (N=81). y of C26:1, lysoPC a C28:0, lysoPC a C6:0, Met, Orn, PC aa Training set: 32 CRC and 21 Calgary, C24:0, PC aa C26:0, PC aa C40:1, PC aa C40:2, PC aa disease-free controls. Foothills C40:3, PC aa C42:2, PC aa C42:4, PC aa C42:5, PC ae Validation set: 28 CRC and 20 Medical C30:1, PC ae C30:2, PC ae C36:1, PC ae C36:5, PC ae healthy controls. Center) C38:1, PC ae C38:2, PC ae C38:3, PC ae C38:6, PC ae Colorectal cancer patients were C40:1, PC ae C40:2, PC ae C40:3, PC ae C40:4, PC ae diagnosed at the Foothills C40:5, PC ae C42:1, PC ae C42:2, PC ae C42:3, PC ae Medical Center. Disease-free C42:4, PC ae C42:5, PC ae C44:3, Ser, SM C22:3, Trp, Val controls consisted of individuals who underwent screening colonoscopy and were found not to have CRC or adenoma. Shu, X. [6]2018 Nested Samples were collected from Matched Population Plasma China GC- MG(0:0/18:3/0:0), PE(20:0/18:2), Tetracosanoic acid, case - female 122 pairs (case/control) (matched to the (Shanghai TOFMS PE(22:6/p-18:1), PE(p-16:0/20:4), PC(22:6/18:0), 5,6:8,9- control and male 123 pairs (case/control). case on age (± 2 Women’s UPLC- diepoxyergost-22-ene-3,7beta-diol, PE(22:6/16:0), PE(p- study years), sex, date Health QTOF/MS 18:0/18:2), PS(18:0/18:0), PE(o-18:1/20:4), 2,3- of sample Study epoxymenaquinone, Butenylcarnitine, PE(18:3/18:0), collection (± 30 (SWHS) PC(18:3/16:0), PE(p-16:0/18:1), PC(16:0/16:0), Ethyl 4- days), time of and the (methylthio)butyrate, 13'-carboxy-alpha-tocopherol, N- sample Shanghai undecylbenzenesulfonic acid, 2-dodecylbenzenesulfonic collection Men’s acid, 4-hydroxy-5-(dihydroxyphenyl)-valeric acid-o- (morning or Health methyl-o-sulphate, Coumarin, 3-aminobenzoic acid, 2- afternoon), time Study methyl-4-phenyl-2-butyl 2-methylpropanoate, Benzoic interval after (SMHS)) acid, Selenocystine, Isoputreanine, Glutamyl-glutamate, last meal (± 2 Homocarnosine, 2-keto-glutaramic acid, Picolinic acid, 4- hours), recent amino-1-piperidinecarboxylic acid, 2-acetyl-5- antibiotic use methylpyridine, 1-deoxy-d-xylulose 5-phosphate (yes or no), and menopausal status (for women)) Venalainen, M.K. Case- Samples were collected from 116 NA. Hospital Urine Singapore LC-MS/MS N1,N12-diacetylspermine [7]2018 control patients including 57 patients (Seinajoki study with CRC (38 colonic, 19 rectal), Central 13 with IBD, 12 with adenoma, Hospital and 34 healthy controls (19 from patients scheduled for hernia Kuopio repair and 15 for laparoscopic University cholecystectomy) Hospital) Chen, C. [8]2017 Case- Samples were collected from NA. Hospital Serum United LC-MSMS 2′-Deoxyuridine, Alanine, Alpha-ketoglutaric acid, control CRC patients (n=36), polyp States Aminolevulinate, Aspartic acid, Cystathionine, study patients (n=39), and healthy (Purdue Epinephrine, glucose-1,6-bisphosphate, Glutamine, controls (n=83). University Glyceraldehyde, Hippuric acid, Histidine, Hydroxyproline, All consenting participants and Linoleic acid, Linolenic acid, Lysine, Methionine, Orotate, undergoing colonoscopy or CRC Indiana Phenylalanine, Xanthine, Xanthosine surgery were evaluated. University School of Medicine) Guertin, K.A. [9]2017 Nested Samples were collected from Age matched Population Serum Finland LC-MSMS choline case - ATBC Study. All identified (The control colorectal cancer cases (n=644) Alpha study and an equivalent number of Tocophero controls. l, Beta Incident colorectal cancer cases Carotene in ATBC were identified by the Cancer Finnish Cancer Registry. Prevention (ATBC) Study) Jing, Y. [10]2017 Case- Samples were collected from 81 Non matched Hospital Dried China AB Sciex 3-hydroxyisovalerylcarnitine, alanine, arginine, asparagine, control polyp patients (47 men and 34 blood (The First 4000 QTrap aspartate, butyrylcarnitine, C18:1, cisovalerylcarnitine, study women) and 85 CRC patients (50 spot Affiliated systerm citrulline, glutarylcarnitine, methionine, myristoylcarnitine, men and 35 women). Hospital octadecanoylcarnitine, octanoylcarnitine, ornithine, Polyps and CRC were identified of Jinzhou palmitoylcarnitine, phenylalanine, propionylcarnitine, by colonoscopy and confirmed by Medical tyrosine, valine histology. University. ) Kinross, J. [11]2017 Self- Samples were collected from 18 Paired tissue Hospital Tissue United NMR Acetate, Alanine, Creatine, Formate, control tumor tissue and at 5 cm and 10 Kingdom Glycerophosphorylcholine, Glycine, Iso-butyrate, Lactate, study cm away from the tumor. (St Mary’s Leucine, Phosphocholine, Scylloinositol, Taurine, Valine Patients with histologically Hospital confirmed invasive malignancy (London, or high-grade dysplasia of the UK)) colon, having either open or laparoscopic surgery without the use of bowel preparation. Mika, A. [12]2017 Case- Blood samples were collected Non matched Hospital Serum, Poland GC-MS 14:0, 14:1, 16:0, 16:1, 18:0, 18:1, 18:3n-3, 20:0, 20:4n-6, control from 19 patients with stage I-III for blood; tissue (Medical 20:5n-3, 22:0, 22:1, 22:6n-3, 24:0, 24:1, 26:0 study CRC and 17 healthy volunteers Paired tissue University (10 male/7 female), tissue of samples were collected from 19 Gdansk) patients with stage I-III CRC Ning, W. [13]2017 Self- Fresh CRC tissues and their Paired tissue Hospital Tissue China GC‐ Alanine, Aspartic acid, Glucose, Glutamic acid, Glycine, control matched adjacent nontumor (China- TOF/MS Hypoxanthine, Inositol, Isoleucine, Lactic acid, Leucine, study tissues (located more than 5cm Japan Mannose, Methionine, Norleucine, O‐ from the tumor) were collected Friendship phosphorylethanolamine, Oxo‐proline, Palmitic acid, from 20 CRC patients. Hospital) Phenylalanine, Phosphate, Proline, Serine, Threonine, Tyrosine, Uracil, Valine Nishiumi, S. [14]2017 Case- Samples were collected from 282 Matched Hospital Plasma Japan GC/QqQM 2-aminobutyric acid, 2-ketoglutaric acid, 3- control colorectal cancer patients and 291 (gender, age, (National S hydroxyisovaleric acid, Arabinose, Arabitol, Cysteine, study healthy volunteers. and the year of Cancer Elaidic acid, Fructose, Fumaric acid, Glycolic acid, Patients who were diagnosed blood Center Isocitric acid, Lactic acid, Leucine, Lysine, Malic acid, with stage 0, I or II colorectal collection) Hospital) Maltose, meso-erythritol, Ornithine, Palmitoleic acid, cancer at the National Cancer Proline, Pyruvic acid, Sorbose, Sucrose, Threitol, Center Hospital; were Tryptophan, Uric acid, Valine, Xylitol, Xylose histologically confirmed to have adenocarcinoma. The control plasma samples were obtained from healthy individuals who underwent cancer screening at the Research Center for Cancer Prevention and Screening. Shen, S. [15]2017 Case- Samples were collected from 25 NA. Hospital plasma China LC- 5M(38:8), Cer(36:1), Cer(44:5), DG((40:7), DG(37:1), control CRC patients (aged 31–80 years) (Affiliated QToF/MS DG(38:6), FFA(20:1), FFA(20:2), FFA(22:4), FFA(ZZ:2), study and 10 healthy controls. Hospital GalCer(33:2), GalCer(34:1), GalCer(36:4), GalCer(41:2), The CRC patients were of GalCer(42:2), GalCer(42:3), GluCer(42:3), LacCer(35:1), categorized according to Guangdon LacCer(38:1), LacCer(40:1), LacCer(40:2), LacCer(40:4), histopathological features and g Medical LacCer(42:4), LPC(14:0), LPC(18:2), LPC(18:3), confirmed by University LPC(20:3), LPS(20:4), PC(32:2), PC(34:3), PC(34:4), immunohistochemistry. ) PC(40:5), PC(O-34:3), PC(O-35:4), PC(O-40:5), PE(32:1), PE(34:1), PE(36:4), PE(36:5), PE(38:2), PE(38:6), PE(40:6), PE(40:7), PE(42:1), PE(O-34:1), PE(O-34:2), PE(O-34:3), PE(O-36:2), PE(O-36:3), PE(O-36:5), PE(O- 38:3), PE(O-38:5), PE(O-38:6), PE(O-40:3), PEIO-36:4), pG(34:0), PS(37:2), SM(32:2), SM(37:1), SM(42:2), SM(44:2), TG(52:1), TG(52:2), TG(56:6) Uchiyama, K. [16]2017 Case- Samples were collected from Age and gender Hospital Serum Japan CE-TOFMS 10-Hydroxydecanoic acid, 2-Aminoisobutyric acid, 2- control CRC patients (n=56), colonic matched (Hospital Hydroxybutyric acid, 2-Oxoisovaleric acid, 3- study adenoma patients (n=59), and of the Hydroxybutyric acid, 3-Indoxylsulfuric acid, 3- healthy controls (n=60) Kyoto Methylhistidine, 4-Pyridoxic acid, ADMA, Ala, Arg, Asn, Prefectural Benzoic acid, beta-Ala, Betaine, Cholic acid, Choline, cis- University Aconitic acid, Citric acid, Citrulline, Cystine, Decanoic of acid, Diethanolamine, Dyphylline, Ethanolamine, Medicine) Ethanolamine phosphate, Gln, Gluconic acid, Glucuronic acid, Glu-Gly/Gly-Glu, Gly, Glycerol 3-phosphate, Gly- Thr/Ser-Ala, Hippuric acid, His, Homovanillic acid, Hydroxyproline, IndolE-3-acetic acid, Isethionic acid, Isobutyric acid, Isocitric acid, Isovaleric acid, Kynurenine, Lauric acid, Lys, Met, Mucic acid, N2- Phenylacetylglutamine, O-Acetylcarnitine, Octanoic acid, Octanoylcarnitine, Ornithine, Pelargonic acid, Perillic acid, Phe, Pipecolic acid, Pro, Sarcosine, S-Methylcysteine, Stachydrine, Succinic acid, Taurine, Thr, Threonic acid, Trimethylamine N-oxide, Trp, Tyr, Uric acid, Uridine, Val Wang, X. [17]2017 Case- Samples were collected from the NA. Hospital Stool China GC-MS Aspartic acid, Cholesterol derivatives, Elaidic acid, control 15 patients with colorectal cancer (Third Glutamic acid, Glycerin, Glycerin, Glycine, Leucine, study (nine males and six females) and Hospital Linoleic acid, Monoacyl glycerol, Myristic acid, Oleic acid, 12 healthy control individuals Affiliated Pantothenic acid, Phenylacetic acid, Phenylalanine, Proline, of Propionic acid, Serine, Ursodesoxycholic acid, Valine Nanchang University ) Wang, Z. [18]2017 Case- Samples were collected from Age and gender Hospital Urine China NMR Acetoacetate, Alanine, Asparagine, Choline, cis-Aconitate, control CRC patients (n=55) and healthy matched (Second Creatinine, Cysteine, Dimethyl sulfone, Glutamine, study controls (n=40). Affiliated Guanidoacetate, Hippurate, Homocysteine, Isocitrate, Patients did not receive any Hospital Methylamine, Phenylalanine, trans-Aconitate neoadjuvant chemotherapy or of Shantou radiation therapy prior to sample University collection. Healthy controls were age- and gender-matched Medical patients, and had no declared College) history of cancer or gastrointestinal symptoms. Zhang, L.J. [19]2017 Case- Samples were collected from 25 Non matched Hospital Serum China UPLC- 12-keto-LTB4, 13-HODE, 13-HpODE, 13-KODE, 19- control CRC patients and 10 healthy (Affiliated MS/MS HETE, 9-HODE, 9-HpODE, 9-KODE study volunteers. Hospital of GuangDon g Medical University ) Yan, L. [20] 2016 Case- Samples were collected from 68 Non matched Hospital Feces China 1H NMR Acetate, Alanine, Butyrate, Dimethylglycine, Glucose, control cancer patients and 32 healthy (Second Glutamate, Glutamine, Isoleucine, Lactate, Leucine, study controls. affiliated proline, Propionate, succinate, Valine The CRC patients were hospital of diagnosed by microscopy, biopsy, Shantou or surgical resection. University Medical College) Gao, P.[21] 2016 Self- Set 1: 11 cancer and Set 1: paired Hospital Tissue China CE–MS Betaine, Choline, Cysteine, Glutathione, Glycine, control corresponding paracancerous tissue (Dalian Methionine, S-adenosylhomocysteine, S- study tissues Set 2: Non- University adenosylmethionine, Sarcosine, Serine, Taurine, Threonine Set 2: 22 cancer samples and 10 matched Affiliated advanced adenoma samples Xinhua Hospital) Yuan, T.[22] 2016 Self- CRC tumors including 16 colon Paired tissue Hospital Tissue China HR MAS Lipid, Lactate, Leucine, Valine, Isoleucine, Alanine, control cancer and 34 rectal cancer (Zhongnan NMR and Glutamine, Glutamate, Aspartate, Aspargine, Cysteine, study together with the corresponding Hospital GC- Glycine, Tyrosine, Phenylalanine, Choline, PC/GPC, PE, adjacent non-involved tissues of Wuhan FID/MS Scyllo-inositol, GSH, Taurine, Uracil, Cytosine, (ANIT) were collected from 50 University Isocytosine, Inosine, C20:1n9, C20:2n6, C18:3n3, CRC patients。 ) C18:1n9, C18:2n6, UFA, MUFA, PUFA, n6, n3, ToFA Crotti, S. [23] 2016 Case- For the untargeted lipidomic Non matched Hospital Plasma Italy (First GC-MS Decanoic acid, Dodecanoic acid, Hexanoic acid , Octanoic control approach, samples were collected Surgical acid study from 15 CRC patients and 15 Clinic of healthy subjects who underwent Padua colonoscopy and for whom a Hospital) negative result was attained. For the targeted analysis, plasma samples from 48 CRC patients at surgery. Control plasma samples were obtained from 20 healthy subjects who underwent colonoscopy but for whom no pathological affliction was found。 Farshidfar, F. [24] 2016 Nested Samples were collected from 320 Age and gender Population Serum Canada GC-MS 2-Monostearoylglycerol, Alanine, Arabinose, Butanoic case- cancer patients, 31 adenomas, matched (Forzani acid, 2-hydroxy-, Butanoic acid, 3-hydroxy-, Citric acid, and 254 healthy controls. and Cystine, D-Ribose 5-phosphate, Ethylene glycol, di-TMS, control Disease-free controls consisted of MacPhail Fructose, Glyceric acid, Glycerol, Glycerol-3-phosphate, study healthy individuals who had a Colon Glyceryl palmitate, Glycine, Hexadecanoic acid, Inositol, normal screening colonoscopy. Cancer myo-, Isoleucine, Lactic acid, Linoleic acid, Lysine, Screening Malonic acid, Bis TMS, Nonane, Palmitic acid, Centre at Phenylalanine, Stearic acid, trimethylsilyl ester, Threonic the acid, Threonine, allo-, Tyrosine University of Calgary) Sinha, R. [25]2016 Case- Samples were collected from 69 Gender and Hospital Feces United HPLC- Palmitoyl_Sphingomyelin, p_Hydroxybenzaldhyde, control cancer patients, 114 controls. BMI matched States GC/MS-MS Conjugated linoleic acid, p_Aminobenzoate, study Newly diagnosed cases with (National Alpha_Tocopherol adenocarcinoma of the colon or Cancer rectum were recruited prior to Institute) surgery and treatment. Controls were the patients awaiting elective surgery for non- oncologic, nongastrointestinal conditions at these hospitals during the same period. Zhang, H. [26]2016 Self- Samples were collected from 125 Paired tissue Hospital Tissue China NMR 2‑Hydroxyisovaleric acid, Acetate, Acetic acid, control CRC patients and a total of 166 (West Acetoacetate, Adenine, Alanine, α‑ketoglutarate, Arginine, study surgical specimens. Among them, China β‑hydroxybutyrate, Creatine, Creatinine, Dimethylamine, 41 normal control tissues were Hospital DMG, Formate, Glucose, Glutamine, Glutathione, extracted at least 5-10 cm away of Sichuan Glycolate, GPC, Isoleucine, Lactate, Leucine, Lipid from the edge of a tumor from University ‑CH2‑C=O, Lipid ‑CH2‑CH=CH, Lysine, Methylamine, the same sample, thus 82 cases ) myo‑inositol, O‑acetyl glycoprotein, PC, Phosphocreatine, included matched tumor and Sarcosine, Serine, Succinate, Taurine, Threonine, Thymine, normal control tissues. TMA, Trimethylamine‑N‑oxide, Tryptophan, Uracil, The pathological diagnosis of Valine, VLDL: ‑CH2‑CH2‑CH2O CRC was confirmed using routine histopathological H&E stained specimens. Amal, H. [27] 2016 Case- Samples were collected from 65 Non matched Hospital Breath Latvia GC-MS 4- methyl octane, Acetone, Ethanol, Ethyl acetate control cancer patients, 22 adenomas and (Riga East study 122 controls. University Control group was defined as hospital or patients without adenocarcinoma Digestive or adenomatous polyps. Diseases Centre GASTRO (Riga, Latvia)) Williams, M.D. [28] 2015 Self- Samples included 9 tumor and 9 Paired tissue Hospital Tissue United UPLC- 1,3-Bisphosphogylcerate, 12-Ketodeoxycholic acid, 2,3- control adjacent non-malignant tissue States TWIMMS Diphosphoglyceric acid, 3＇AMP, 5-Aminoimidazole study (Providenc ribonucleotide, 5-Methylcytidine, 7-Ketodeoxycholic acid, e Regional AMP, Arginine, Ascorbic acid, Asparaginyl-Glutamine, Cancer Carnitine, Citicoline, CL(18:1/18:1/20:4/18:2), CMP, CoA- Center, [4'-phosphopantetheinel], CPA(18:0/0:0), Sacred Cysteineglutathione disulfide, Cytidine, Galactinol, Heart Ganglioside GM1(d18:0/12:0), Glanglioside Hospital, GM2(d18:1/18:1), Glutathione, Glutathione[M+K], Spokane) Glycerylphosphorylethanolamine, Hypoxanthine, Inosine, LPA(0:0/18:0), L-Thyronine, LysoPC(14:0), LysoPC(16:0)[M+K], LysoPC(18:1)[M+H], LysoPC(18:1)[M+K], LysoPC(18:1)[M+Na], LysoPE(0:0/20:4), Malic acid, Me-FapyGua, N5-formyl- THF, N-acetylneuraminate, N-Succinyl-L,L-2,6- diaminopimelate, Palmitic amide, PC(14:1/22:1), PC(18:1/16:0), p-Cresol sulfate, PGP(16:1/22:6), PIP(16:0/18:0), PS(14:1/14:0), Ribonic acid, Serinyl- Methionine, Succinyladenosine, Taurine, Threoninyl- Aspartate, Threoninyl-Serine, UDP-D-Xylose, UMP, Uridine diphosphate glucose, Uridine diphosphate-N- acetylglucosamine, Xanthine Zamani, Z. [29] 2014 Case- Samples were collected from 33 NA Hospital Serum Iran (Amir NMR 3-Hydroxybutyric acid, 3-Hydroxyisovaleric acid, 5- control CRC patients and 33 individuals Alam Methylcytidine, 7-Ketocholesterol, Beta-leucine, study without colon cancer. Hospital, Cholesterol, Glycine, Glycocholic acid, L-fucose, L- Patients were diagnosed with Tehran) palmitoylcarnitine, Orotidine, Pyridoxamine, Pyridoxine, cancer by colonoscopy and S-adenosylhomocysteine, Taurocholic acid biopsy. Cross, A.J.[30] 2014 Nested Samples were collected from 254 Age, gender, Population Serum United UPLC- Leucyl-leucine, Fumarate, 10-undecenoate (11:1n1), case- first primary incident colorectal and smoking States MS/MS Xanthine, Stearate, Glycochenodeoxycholate, Andro control cancers (International status matched (The GC-MS steroid monosulfate 2, Alpha-tocopherol, 17- study Classification of Diseases for Prostate, methylstearate, Palmitate, Eicosenoate (20:1n9 or 11), Oncology10, ICD-0-3 codes: Lung, Margarate, Dihomo-linoleate (20:2n6), Dihomo-linolenate, C180-189, C199, C209, C260) Colorectal, Cyclo(phe-phe), Octadecanedioate, Docosapentaenoate, N- Controls (254) were free from and acetylserine, 13-methylmyristic acid, Leucylalanine, any cancer at the time the Ovarian Methyl palmitate (15 or 2), 2-hydroxystearate, Scyllo- matched case was diagnosed. cancer inositol, Pentadecanoate, 2-hydroxypalmitate, Stearidonate screening (18:4n3), Glutaroyl carnitine, Glycerate, N- (PLCO) acetylneuraminate, Phenol sulfate, Myristate, Pantothenate, trial, Taurochenodeoxycholate, Pyridoxate, Glycocholate, which is a Taurolithocholate-3-sulfate, Taurodeoxycholate, large Glycylvaline, Glycoursodeoxycholate, Pyroglutamine, randomize Glycolate-hydroxyacetate, Pyroglutamylglycine, d Glycolithocholate sulfate, N-acetylalanine, 1-palmitoyl controlled glycerophosphoethanolamine, Succinate, 2- trial to test hydroxybutyrate (AHB) the efficacy of screening methods for each of these 4 cancers) Goedert, J.J. [31] 2014 Case- Samples were collected from 48 Gender and Hospital Feces United HPLC- 2-Hydroxyacetaminophen sulfate, 3-Cystein-S-YL- control cancer patients and 102 controls BMI matched States GC/MS-MS acetaminophen, 3-Dehydrocarnitine, 4-Acetamidophenol, study (contemporaneous patients (Three Alanyl-histidine, Alanyl-leucine, Alanyl-tryptophan, α- awaiting elective surgery for non- Washingto Glutamyl-valine, α-Tocopherol, Cis-Urocanate, Conjugated oncologic, non-gastrointestinal n DC area linoleate-18-2N7, γ-Tocopherol, Heme, Histidine, Histidyl- conditions). hospitals) alanine, Histidyl-glycine, Histidyl-phenylalanine, Leucyl- Only newly diagnosed, glutamate, Leucyl-serine, Leucyl-tryptophan, Mandelate, histologically confirmed cases of N-2-Furoyl-glycine, PABA, p- adenocarcinoma of the colon or Acetamidophenylglucuronide, Palmitoyl-sphingomyelin, p- rectum were retained. Hydroxybenzaldehyde, Prolyl-alanine, Pterin, Pyro- glutamyl-glycine, Sitostanol, Tryptophyl-glycine, Tyrosyl- glutamine, Valyl-aspartate, Valyl-histidine Bae, S.[32] 2014 Nested Participants were selected from Matched Population Plasma United LC-MS/MS Betaine, Choline, TMAO case- the WHI-OS cohort. A total of (matched on age States control 835 colorectal cancer patients and (±3 years), (WHI-OS study 835 controls were finally race/ethnicity, is a included. timing of prospectiv baseline blood e cohort draw (±6 study months), designed enrollment date to (±1 year), and investigate baseline the hysterectomy predictors status.) and causes of morbidity and mortality in postmenop ausal women) Wang, C.[33] 2014 Case- Samples were collected from 20 Non matched Hospital Breath China GC/MS 2,21-Dimethyldecane, 21-Methylpropanoate, 41-Ethyl-111- control cancer patients and 20 healthy gas (First octyn1-31-ol, 61-t1-Butyl-12,2,9,91-tetramethyl-13,51- study individuals Affiliated decadien-171-yne, Cyclohexanone, Cyclooctylmethanol, Hospital Dodecane 31-hydroxy-12,4,41-trimethylpentyl, of Harbin Ethylaniline, Trans-121-Dodecen-111-ol Medical University ) Wang, C. [34] 2014 Case- Samples were collected from 16 Non matched Hospital Blood v China GC/MS 1,1,4,4-Tetramethyl-2,5-dimethylene-cyclohexane, 6-t- control CRC patients and 20 healthy olatile (First Butyl-2,2,9,9-tetramethyl-3,5-decadien-7-yne, study volunteers compou Affiliated ethylhexanol, Phenyl methylcarbamate nds Hospital of Harbin Medical University ) Mirnezami, R.[35] 2014 Self- Samples were retrieved from the Paired tissue Hospital Tissue United HR-MAS Acetate, Alanine, alpha-glucose, beta-glucose, Creatine - control center of tumor (n=44) and from Kingdom NMR CH2-, Creatine -CH3, Glycerophosphorylcholine(GPC), study healthy mucosa 5cm from the (St Mary’s Glycine, Isoglutamine, Lactate -CH-, Lactate -CH3, tumor margin (n=44) Hospital, Leucine, Lipids/triglycerides, Scyllo-inositol, Taurine - London) CH2-NH, Taurine CH2SO3, Valine Qiu, Y. [36] 2014 Self- A total of 55 patients contributed Paired tissue Hospital Tissue China and GC– 2-Aminoadipate, 2-Aminobutyrate, 3-Methy-3- control paired samples and the other 30 the United TOFMS hydrpoxybutyrate, 4-Aminobutyrate, 5-Oxoproline, AMP, study patients contributed colorectal States Ascorbate, Asparagine, Aspartate, b-Alanine, Cystein, cancer tissue only. (Fudan Galactose, Glucose, Glutamate, Glyceraldehyde, Glycerate, In addition, three validation University Glycerol, Glycine, Homocysteine, Hypotaurine, batches of samples were collected Shanghai Hypoxanthine, Kynurenine, Lactate, Laurate, from Cancer Hospital affiliated Cancer Methioninamide, Myo-inositol, Myristate, Nicotinamide, with the Chinese Academy of Center) Ornithine, Palmitoleate, Phosphate, Putrescine, Spermidine, Medical Sciences (Beijing, Uracil, Xylose China; n=23, paired tissue samples with two batches of nontumor tissues located 5 and 2–5 cm from the edge of the tumor, respectively), the Second Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China; n= 65, paired tissue samples), and the City of Hope Comprehensive Cancer Center (Duarte,CA; n=20,pairedtissuesamples). Phua, L.C. [37] 2014 Case- Fecal samples were collected Non matched Hospital Fecal/ Singapore GC/TOFMS 3-phosphoglycerate, Citric acid, Creatinine, Fructose , control from 11 cancer patients and 10 for fecal. Tissue (Singapore Galactose, Glucose, Inosine, Linoleic acid, Nicotinic acid, study healthy subjects. Matched tumor Paired tissue General Proline, Uracil, Uridine Self- and normal mucosa were Hospital) control collected from 8 out of the 11 study CRC patients. Matched normal mucosa samples were obtained from excised tissue at least 5 cm away from the edges of the tumor. Jiménez, B. [38] 2013 Self- Samples were retrieved from Paired tissue Hospital Tissue United HR-MAS Acetate, Alanine, β-Glucose, Choline, Creatine, Formate, control tumor (n=22) and adjacent Kingdom NMR Iso-butyrate, Iso-glutamine, Lactate, Leucine, study normal colorectal mucosa 5 to 10 (St Mary’s Lipids/Triglycerides, Phenylalanine, Phosphocholine, cm from the tumor margin Hospital Scyllo-inositol, Taurine, Tyrosine, Valine (n=23). (London, There were 19 matched paired UK)) samples, 3 additional tumor samples and 4 additional off- tumor samples. Kim, S. [39] 2013 Self- Samples were collected from 9 Paired tissue Hospital Tissue Korea HR-MAS 2-Hydroxybutyrate, Acetoacetate, Arginine, Aspartate, control cancer patients. Tissue was (Jeju NMR Carnitine, Ethylmalonate, Glutamate, Glutathione, study divided into normal and cancer National Glycine, Isoleucine, Leucine, Malonate, Myo-inositol, N- samples according to biopsy. University Acetylglutamine, O-Phosphocholine, Proline, Taurine, Hospital) Uracil Li, F. [40]2013 Case - Samples were collected from 52 Matched Hospital Serum China DI-ESI(±)- eicosatrienoic acid, hexadecanedioic acid, LPA(16:0), control CRC patients and 52 healthy (Peking FTICR MS LPA(18:0), LPC(16:0), myristic acid, octadecanoic acid, study controls. Union oleamide, palmitic amide The healthy controls were Medical selected by routine clinical Hospital, examination and the subjects Heze with any clinically diagnosed Municipal acute or chronic disease were Hospital) excluded. Weir, T.L. [41] 2013 Case- Stool samples were collected Non matched Hospital Feces United GC-MS Alanine, Aspartic acid, Benzeneacetic Acid, Cholesterol control from healthy individuals (n=11) States derivative, Elaidic acid, Glutamate, Glycerol, Glycine, study and recently diagnosed colon (Universit Leucine, Linoleic acid, Lysine, Monooleoylglycerol, cancer patients (n=10) prior to y of Myristic Acid, Oleic acid, Pantothenic acid, Phenylalanine, surgery for colonic resection. Colorado Proline, Propionic acid, Serine, Threonine, Stool samples were provided for Health- Ursodeoxycholic acid, Valine analyses prior to administration Poudre of any preoperative antibiotics or Valley bowel preparation. Hospital in Fort Collins, CO.) Tan, B.[42] 2013 Case- Learning group: 62 samples from Age and gender Hospital Serum China GC−TOFM 12a-hydroxy-3-oxocholadienic acid, 2-aminobutanoic acid, control cancer patients and 62 from matched (Ruijin Sand 2-hydroxy-3-methylpentanoic acid, 2-hydroxybutyric acid, study healthy subjects. Hospital UPLC−QT 2-oxobutanoic acid, 3,4,5-trimethoxycinnamic acid, 3- Validation group: 39 samples affiliated OFMS oxodecanoic acid, 4-hydroxyproline, 4-hydroxystyrene, 5- from cancer patients and 40 from with hydroxytryptamine, 6-phosphogluconic acid, acetyl healthy subjects (Healthy Shanghai carnitine, adenine, alanine, allantoic acid, allisoleucine, controls with inflammatory Jiao Tong allyl isothiocyanate, alpha-aminoadipic acid, asparagine, conditions or gastrointestinal University aspartate, benzaldehyde, beta-aspartylserine, beta- tract disorders were excluded). School of hydroxybutyrate, carnitine (18:1), chenodeoxycholic acid, Medicine) cholic acid, cis-aconitate, CPA(18:0/0:0), creatinine, cystine, decanoyl carnitine, elaidic acid, erythrotetrofuranose, fumaratea, glutamate, glyceric acid, glycerol, glycolaldehyde, histidine, hydroquinone, indoleacrylic acid, indoxyl, indoxyl sulfate, inositol, linolic acid, LPA(18:0/0:0), LysoPC(14:0), LysoPC(16:1(9Z)), LysoPC(20:0), LysoPC(P-18:1(9Z)), methionine, N-acetyl- 5-hydroxytryptamine, octenedioate, oleamide, oleic acid, ornithine, palmitic acida, phenol, phenylalanine, proline betaine, pyruvate, ribitol, serine, sphinganine, tetrahydrogestrinone, threitol, trihydroxycoprostanoic acid, trimethylamine N-oxide, tryptophan, ubiquinone, urea, xanthosine Nishiumi, S. [43] 2012 Case- Training set: samples were Age and gender Hospital Serum Japan GC/MS 2-hydroxy-butyrate, Arabinose, Asparagine, Aspartic acid, control collected from 60 CRC patients matched (Kobe b-alanine, Citrulline, Creatinine, Cystamine, Cystine, study and 60 healthy volunteers. University Glucosamine_2, Glucuronate_1, Glutamic acid, Inositol, Validation set: samples were Graduate Isoleucine, Kynurenine, Lactitol, meso-erythritol, Nonanoic collected from 59 CRC patients School of acid(C9), O-phosphoethanolamine, Ornithine, Palmitoleate, and 63 healthy volunteers. Medicine) Phosphate, p-hydroxybenzoic acid, Pyroglutamic acid, The patients were diagnosed by Pyruvate, Ribulose, Xylitol microscopy, biopsy, or surgical resection and classified using the sixth edition of the International Union Against Cancer classification (UICC). The serum samples from the healthy volunteers were obtained from Kobe University Hospital and two other facilities. In Kobe University Hospital, it was confirmed that there is no abnormality of blood tests, endoscopic examinations, diagnostic imaging, and/or medical interview. At two other facilities, healthy volunteers were selected via health checks including blood tests, endoscopic examinations, diagnostic imaging, and/or medical interviews. Chen, J.L.[44] 2012 Case- Urine samples were collected Non matched Hospital Urine China CE-ESI-MS Arginine, Aspartate, Citric acid, Histidine, Isoleucine, control from 20 CRC patients (aged 37 to (Shanghai Lactic acid, Leucine, Malic acid, Methionine, Serine, study 87 years old) and 14 healthy Sixth Succinate, Valine volunteers (female/male, 6/8, People’s aged 50 to 86 years old, and the Hospital, median age was 68 years old) Shanghai from Shanghai Sixth People’s Jiaotong Hospital. University ) Cheng, Y.[45] 2012 Case- Training set 1: samples were Age and gender Hospital Urine China GC- 2-Aminobutyrate, 2-Hydroxyestradiol, 4-Aminohippurate, control collected from 61 cancer patients matched (Ruijin TOFMS 4-Hydroxybutyrate, 5-Hydroxy-tryptophan, Acetyl- study and 62 healthy controls Hospital And UPLC- carnitine, Alanine, Arabitol, Citrate, Creatinine, Fumarate, Testing set 2: samples were (Shanghai, QTOFMS Glucuronate, Hippurate, Histidinol, Homovanillate, collected from 40 cancer patients China).) Hydroxyacetate, Indole, Indoleacetate, Kynurenate, and 41 healthy controls Myristate, N-Acetyl-L-lysine, p-Cresol, Phenol, Putrescine, Patients were categorized Pyridoxal (Vitamin B6), Pyruvate, Sorbose, Threonate, according to histopathological Trimethylamine N-oxide, Tryptophan, Tyrosine, Uracil, features and stages according to Urea, Uridine, Xylose TNM classification of malignant tumors. Mal, M.[46] 2012 Self- Matched tumor and normal Paired tissue Hospital Tissue United GC×GC/TO 11-eicosenoic acid, 1-methyl-hydantoin, 1- control tissues (n=63) obtained from 31 States FMS monooleoylglycerol, Aminomalonic acid, Arachidonic study patients (Singapore acid, β-alanine, Cholesterol, D-galactose, D-glucose, D- General mannose, Fumarate, Glycerol, Glycine, Lactateb, L-alanine, Hospital) L-arabinose, L-aspartic acid, Lignoceric acid, Linolenic acid, L-isoleucine, L-leucine, L-methionine, L- phenylalanine, L-proline, L-serine, L-threonine, L-valine, Malate, Maleic acid, Margaric acid, Myristic acid, Oleic acid, Oxalate, Palmitic acid, Pantothenic acid, Pentadecanoic acid, Phosphate, Picolinic acid, Ribitol, Squalene, Stearic acid, Succinate, Uracil, Uridine Ma, Y.[47] 2012 Case- Samples were collected from 30 Age matched Population Serum China GC/MS 1-Deoxyglucose, 3-Hydroxybutyric, Glycine, L-Threonine, control CRC patients and 30 healthy (Sixth L-Valine, Ribitol study blood donors and 20 fetuses. People’s Control blood samples were Hospital obtained from healthy blood Affiliated donors in Shanghai. The age to range of the donors matched with Shanghai those of the patients and the JiaoTong donors participated in strict University screening and a follow-up visit. ) Fetal blood samples were obtained from the Department of gynecology and obstetrics. Bertini, I. [48] 2012 Case- Training set: samples were Non matched Population Serum Denmark 1H NMR 3-hydroxybutyrate, Acetate, Alanine, Citrate, Creatine, control collected from 45 CRC patients (Three Formate, Glutamine, Glycerol, Lactate, Leucine, Lipid (- study and 96 healthy individuals. hospitals CH2-OCOR), N-acetyl signal of glycoproteins, Peptide Validation set: samples were in NHs, Phelylalanine, Proline, Pyruvate, Tyrosine, Valine collected from 108 CRC patients Denmark) and 43 healthy individuals. Serum samples were collected from a cohort of 181 Danish patients with mCRC resistant to 5-FU, oxaliplatin, and irinotecan. Serum samples of controls were collected from Danish healthy blood donors and 43 healthy subjects. Ong, E.S.[49] 2010 Self- Colonic tissues including tumor, Paired tissue Hospital Tissue Singapore GC/MS Acetylcarnitine, Adenosine, Adenosine monophosphate, control polyps and adjacent mucosa were (Singapore LC/MS/MS Arachidicacid(C20:0), Arachidonicacid(C20:4), study obtained from 26 CRC patients. General Behenicacid(C22:0), Betaine, beta-Sitosterol, Carnitine, Tumor specimens, polyps and Hospital) Cholesterol, Choline, Citramalicacid, Deoxycholicaicd, adjacent normal-appearing Elaidiccarnitine, Glucose, Glutamate, Glycerol 1-(9- tissues at least 8 cm away were octadecenoate), Glycerol 1-palmitate, Glycerol 1-stearate, collected from the same Glycerol 2-palmitate, Glycerophosphocholine, patients undergoing colorectal Hypoxanthine, Inosine, Inositolmonophosphate, resection according to procedure Lauricacid(C12:0), Linoleicacid(C18:2), LPC C16:0, LPC reported earlier. C18:0, LPC C18:1, LPC C18:2, LPC C20:4, Lysine, Margaricacid(C17:0), Methionine, myo-Inositol, Myristamide, Myristicacid(C14:0), Oleamide, Oleamide, Oleic acid(C18:1), Palmitamide, Palmiticacid(C16:0), Palmitoylcarnitine, Phenylalanine, Phosphoric acid, Proline, Stearamide, Stearicacid(C18:0), Tyrosine, Uric acid, Uridine, Vitamin C, Xanthine Ma, Y.[50] 2010 Self- Samples were collected from 30 Matched Hospital Serum China GC/MS 11-cis-octadecenoic acid, 1-Deoxyglucose, 2-hydroxy- control colorectal cancer patients pre- (The Sixth 1,2,3-propanetricarboxylic acid, 3-Hydroxybutyric acid, 3- study operatively and post-operatively. People’s Hydroxy-proline, 5-oxo-L-proline, 9,12-octadecadienoic The preoperative blood samples Hospital acid, Aminomalonic acid, Arachidonic acid, Butanedioic were drawn at 7 O’clock on the Affiliated acid, Cholesterol, D-maltose, D-turanose, Glycerol, second day before to Glycine, Hexadecanoic acid, L-alanine, L-isoleucine, L- hospitalization, and the Shanghai proline, L-threonine, L-tyrosine, L-valine, Malic acid, postoperative blood samples were Jiao Tong Monostearin, Myo-inositol, Octadecanoic acid, drawn in 2 h after surgery. University Palmitelaidic acid, Phenylalanine, Phosphoric acid, Ribitol, During or within 2 h after ) Serine, Threonine, Trans-9-octadecenoic acid, Tryptophan surgery, the patients were not given any blood transfusion or other transfusion. The diagnosis of CRC was confirmed in all cases by histopathologic examination and immunohistochemistry. Tessem, M.B.[51] 2010 Self- Fresh frozen colon tissue samples Paired tissue Hospital Tissue Norway HR-MAS beta-glucose, choline, creatine, control (n=63) from two hospitals in NMR glycerophosphorylcholine(GPC), glycine, lactate, myo- study Norway were obtained from 31 inositol, PC , scyllo-inositol, taurine newly diagnosed cancer patients (mean age: 73 years (range: 48- 93), 16 women and 15 men). Two samples were collected from each patient; one from the tumor area and the other from normal mucosa. Wang, W.[52] 2010 Case- Samples were collected from 50 Matched Hospital Urine China UPLC Q- 1-methyladenosine, 2,2-dimethylguanosine, control cancer, 34 benign colorectal (Ruijin TOFMS Acetylcarnitine, Acylcarnitine (C13:0), Acylcarnitine study tumor (23 of ademona and 11 of Hospital, SPE-HPLC (C9:0), Acylcarnitine (C9-OH), Aspartylysine, other diseases) and 34 healthy Shanghai C11H20O4N2, Cytidine, Leucylproline, N6- volunteers. Jiaotong methyladenosine, Phenylacetylglutamine, Prolylleucine, University Pseudouridine, Uridine School of Medicine) Shureiqi, I. [53]2010 Case- A total of 125 patients divided NA. Hospital Tissue United LC-MS/MS 13S-hydroxyoctadecadienoic acid control into three groups: 49 subjects States study with normal colon, 36 with (Gastroint colonic polyps, and 40 with estinal colorectal cancer. clinics at The colorectal cancer group The patients’ biopsies were obtained university from the colorectal cancers and of Texas from normal-appearing mucosa at M. D. least 10 cm from the cancer. Anderson Cancer Center and other hospitals within the Texas Medical Center) Qi u, Y. [54] 2010 Case- Samples were collected from 60 Age matched Hospital Urine China GC-MS 2-hydroxyhippurate, 3-methyl-histidine, 5- control CRC patients and 63 healthy (Cancer hydroxyindoleacetate, 5-hydroxytryptophan, 5-oxoproline, study volunteers. Hospital, Citrate, Glutamate, Histidine, Isocitrate, N-acetyl-aspartate, All the CRC patients were Shanghai p-cresol, Phenylacetate, Phenylacetylglutamine, p- diagnosed with different Medical hydroxyphenylacetate, Succinate, Tryptophan histopathological features and College, Fudan stages according to recent TNM University classification. ) Chae, Y.K. [55] 2010 Self- Cancerous and normal tissues Paired tissue Hospital Tissue Korea NMR choline, glucose, glutamate, glycerol, malate, taurine control were obtained from 12 patients (4 study men, 8 women, mean age: 67.75 years, age range: 41 - 85 years) with histologically proven colorectal cancers. Chan, E.C.Y.[56] 2009 Self- Matched CRC and normal Paired tissue Hospital Tissue Singapore HR-MAS 11,14-Eicosadienoic acid, 11-Eicosenoic acid, 1- control mucosae (n=63) were obtained (Singapore NMR and Hexadecanol, 1-Monooleoylglycerol, 1-O- study from the 31 CRC patients during General GC/MS Heptadecylglycerol, 2-Hydroxy-3-methylvalerate, surgery. Among these subjects, Hospital) Arachidonic acid, ChoCC, Cholesterol, D-Galactosed, D- one patient provided two Glucosed, D-Mannosed, Fumarate, Glucose, Glycine, matched pairs of tissues. Lactate, Lactate, L-Glycine, Lipids, L-Phenylalanine, L- None of the patients received Proline, Malate, Marganic acid, Oleic acid, Palmitic acid, neoadjuvant chemotherapy or PC, PE, PEG, Phosphate, Propyl octadecanoate, Scyllo- radiotherapy prior to surgical inositol, Stearic acid, Taurine, Uridine excision. Qi u, Y. [57] 2009 Case- Samples were collected from 64 Non matched Hospital Serum China GC- 2-hydroxybutanoic acid, 2-Piperidinecarboxylic acid, 3- control cancer patients and 65 healthy (Cancer TOFMS/UP hydroxybutanoic acid, 4-hydroxyproline, Arginine, study individuals. Hospital, LC−QTOF Carnitine, Citrulline, Dopamine, Glutamic acid, Glycerol The clinical diagnosis and Shanghai MS phosphate, Hippurate, Lactate, Leucine, Lysine, Malic acid, pathological reports of all the Medical Myristic acid, Nervonic acid, Nicotinamide, Oleamide, patients were obtained from the College, Oleic acid, Ornithine, Palmitic acid, Phenylalanine, Proline, hospital. The healthy volunteers, Fudan Pyruvate, Pyruvic acid, Threonic acid, Threonine, ages 42-69 years, were selected University Tryptophan, Tyrosine, Urea, Uridine, Valine by a routine physical examination ) and any subjects with inflammatory conditions or gastrointestinal tract disorders were excluded. Righi, V. [58] 2009 Self- Samples of 23 subjects, Paired tissue Hospital Tissue Italy HR-MAS Ac, choline-containing compounds, creatine, Glu plus Gln, control including14 tumor and 14 normal NMR glucose, Lac, lipids, polyols (Myo and Scy) (scyllo-inositol, study tissues were obtained from 14 myo-inositol), Tau. colorectal cancer patients; 9 normal tissues were obtained from 9 healthy individuals. Hirayama, A.[59] 2009 Self- Tumor and surrounding grossly Paired tissue Hospital Tissue Japan CE-TOFMS 2-aminobutyrate, 4-aminobutyrate, adenine, Alanine, control normal-appearing tissues were arginine, asparagine, aspartate, beta-alanine, beta-Glu-cys, study obtained from 16 colon cancer citrate, Citrulline, cystathionine, cysteine, cystine, F1,6DP, patients. F6P, fumarate, G1P, gluconate, Glutamate, Glycerol-3P, Glycine, GMP, GSH, histidine, Hydroxyproline, hypotaurine, hypoxanthine, Isoleucine, lactate, Leucine, lysine, malate, methionine, NADPH, ophthalmate, phenylalanine, proline, putrescine, pyruvate, S7P, SAH, SAM, serine, spermidine, spermine, succinate, taurine, threonine, tryptophan, tyrosine, valine Hsu, W.Y.[60] 2009 Case- Patients with colorectal cancer Non matched Population Urine China LC-MS/MS 8-hydroxy-2′-deoxyguanosine, adenosine, cytidine, N2,N2- control (n=26) were collected at the (China dimethylguanine, uridine study CMUH. All control subjects Medical (n=18) were healthy people who University had undergone a routine annual Hospital) health examination. Mal, M.[61] 2009 Case- Tumor and normal tissue (n=12) Paired tissue Hospital Tissue Singapore GC/MS 1-O-Heptadecylglycerol, Creatinine enol (enolic form), D- control were obtained from 6 patients. (Singapore Galactose, D-Glucose, D-Mannose, Lactate, L-Glycine, study Another 6 pairs of tumor and General Malate, Marganic acid, Palmitic acid, Propyl normal tissue were obtained from Hospital) octadecanoate, Stearic acid method validation. Monleón, D. [62] 2009 Case- Samples were collected from 21 Non matched Hospital Feces Spain (The NMR Acetate , Butyrate, Cysteine, Leucine, Proline control CRC patients and 11 healthy Instituto study individuals. Valencian A full-length colonoscopy o de established the diagnosis in every Oncologia patient and healthy control. All ) stool samples were collected before surgery or endoscopic examination, with no bowel preparation. Piotto, M.[63] 2008 Self- Cancerous and normal tissues Paired tissue Hospital Tissue France NMR Acetate, Alanine, alpha-Glucose, Arginine, Ascorbic acid, control were obtained from 44 patients. (Tumor Asparagine, Aspartic acid, beta-Glucose, Choline, Creatine, study For 4 patients, only the healthy or bank of Ethanol, Fatty acids , Glutamate, Glutamine, Glycerol, the tumoral biopsy was available. the Glycerophosphocholine, Glycine, Isoleucine, Lactate, All patients underwent a surgical University Leucine, Lysine, Methionine, Myo-Inositol, Phenylalanine, resection of the primary lesion Hospitals Phosphoethanolamine, Phosphorylcholine, Proline, Scyllo- and a radical lymphadenectomy. of Inositol, Serine, Succinic acid, Taurine, Threonine, Neither neo-adjuvant Strasbourg Tyrosine, Valine chemotherapy nor radiotherapy , France.) was performed prior to the operation. Denkert, C. [64] 2008 Self- In total, 27 primary colon Paired tissue Hospital Tissue Germany GC-TOF 1,4-benzenedi carboxylic acid, 2-amino-2- control carcinomas and 18 normal (hydroxymethyl)-1,3-propanediol, 4-hydroxyproline, study mucosa samples. For 15 cases adenosine, adipic acid, arachidonic acid, arginine, paired samples of caner tissue asparagine, azelaic acid, benzoate, beta-alanine(minor), and normal tissue were available. capric acid, cholesterol, citraconate, creatinine, cysteine, fructose, galactonate gamma-lactone, glutamate, glutamine, glutarate, glycerol, glycine, glycolate, heptadecanoic acid 2, homoserine, hypoxanthine, inositol stereoisomer, isoleucine, leucine, lysine minor, malonate, methionine, N- actylglycine, octanedioic acid, oleic acid, palmitic acid, parabanic acid, Pelargonic acid, phenylalanine, phosphothreonine, pimelate, proline, serine, threonine, uracil, valine Tadano, T. [65]2006 Case- Serum samples were collected Non matched Hospital Feces, Japan GC-MS Allolithocholic acid control from 22 healthy adults and 20 serum study cancer patients. Feces Samples were collected from 20 healthy adults and 20 cancer patients Reference: 1.Le Gall G, Guttula K, Kellingray L, Tett AJ, Ten Hoopen R, Kemsley KE et al. Metabolite quantification of faecal extracts from colorectal cancer patients and healthy controls. Oncotarget 2018; 9(70): 33278- 33289; e-pub ahead of print 2018/10/04; doi 10.18632/oncotarget.26022. 2. Hu XQ, Wei B, Song YN, Ji Q, Li Q, Luo YQ et al. Plasma metabolic profiling on postoperative colorectal cancer patients with different traditional Chinese medicine syndromes. Complementary Therapies in Medicine (Article) 2018; 36: 14-19; doi 10.1016/j.ctim.2017.11.006. 3. Bian X, Li N, Tan B, Sun B, Guo MQ, Huang G et al. Polarity-Tuning Derivatization-LC-MS Approach for Probing Global Carboxyl-Containing Metabolites in Colorectal Cancer. Analytical chemistry 2018; 90(19): 11210-11215; e-pub ahead of print 2018/09/08; doi 10.1021/acs.analchem.8b01873. 4. Djukovic D, Zhang J, Raftery D. Colorectal Cancer Detection Using Targeted LC-MS Metabolic Profiling. Methods in molecular biology (Clifton, NJ) 2018; 1765: 229-240; e-pub ahead of print 2018/03/29; doi 10.1007/978-1-4939-7765-9_15. 5. Farshidfar F, Kopciuk KA, Hilsden R, McGregor SE, Mazurak VC, Buie WD et al. A quantitative multimodal metabolomic assay for colorectal cancer. BMC cancer 2018; 18(1): 26; e-pub ahead of print 2018/01/06; doi 10.1186/s12885-017-3923-z. 6. Shu X, Xiang YB, Rothman N, Yu D, Li HL, Yang G et al. Prospective study of blood metabolites associated with colorectal cancer risk. International journal of cancer 2018; e-pub ahead of print 2018/02/27; doi 10.1002/ijc.31341. 7. Venalainen MK, Roine AN, Hakkinen MR, Vepsalainen JJ, Kumpulainen PS, Kiviniemi MS et al. Altered Polyamine Profiles in Colorectal Cancer. Anticancer research 2018; 38(6): 3601-3607; e-pub ahead of print 2018/06/01; doi 10.21873/anticanres.12634. 8. Chen C, Nagana Gowda GA, Zhu J, Deng L, Gu H, Chiorean EG et al. Altered metabolite levels and correlations in patients with colorectal cancer and polyps detected using seemingly unrelated regression analysis. Metabolomics (Article) 2017; 13(11); doi 10.1007/s11306-017-1265-0. 9. Guertin KA, Li XS, Graubard BI, Albanes D, Weinstein SJ, Goedert JJ et al. Serum Trimethylamine N-oxide, Carnitine, Choline, and Betaine in Relation to Colorectal Cancer Risk in the Alpha Tocopherol, Beta Carotene Cancer Prevention Study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2017; 26(6): 945-952; e-pub ahead of print 2017/01/13; doi 10.1158/1055-9965.Epi-16-0948. 10. Jing Y, Wu X, Gao P, Fang Z, Wu J, Wang Q et al. Rapid differentiating colorectal cancer and colorectal polyp using dried blood spot mass spectrometry metabolomic approach. IUBMB life 2017; 69(5): 347-354; e-pub ahead of print 2017/03/23; doi 10.1002/iub.1617. 11. Kinross J, Mirnezami R, Alexander J, Brown R, Scott A, Galea D et al. A prospective analysis of mucosal microbiome-metabonome interactions in colorectal cancer using a combined MAS 1HNMR and metataxonomic strategy. Scientific reports 2017; 7(1): 8979; e-pub ahead of print 2017/08/23; doi 10.1038/s41598-017-08150-3. 12. Mika A, Kobiela J, Czumaj A, Chmielewski M, Stepnowski P, Sledzinski T. Hyper-Elongation in Colorectal Cancer Tissue - Cerotic Acid is a Potential Novel Serum Metabolic Marker of Colorectal Malignancies. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2017; 41(2): 722-730; e-pub ahead of print 2017/02/20; doi 10.1159/000458431. 13. Ning W, Li H, Meng F, Cheng J, Song X, Zhang G et al. Identification of differential metabolic characteristics between tumor and normal tissue from colorectal cancer patients by gas chromatography-mass spectrometry. Biomedical chromatography : BMC 2017; 31(11); e-pub ahead of print 2017/05/06; doi 10.1002/bmc.3999. 14. Nishiumi S, Kobayashi T, Kawana S, Unno Y, Sakai T, Okamoto K et al. Investigations in the possibility of early detection of colorectal cancer by gas chromatography/triple-quadrupole mass spectrometry. Oncotarget 2017; 8(10): 17115-17126; e-pub ahead of print 2017/02/10; doi 10.18632/oncotarget.15081. 15. Shen S, Yang L, Li L, Bai Y, Cai C, Liu H. A plasma lipidomics strategy reveals perturbed lipid metabolic pathways and potential lipid biomarkers of human colorectal cancer. Journal of Chromatography B 2017; 1068-1069: 41-48; doi https://doi.org/10.1016/j.jchromb.2017.10.004. 16. Uchiyama K, Yagi N, Mizushima K, Higashimura Y, Hirai Y, Okayama T et al. Serum metabolomics analysis for early detection of colorectal cancer. Journal of gastroenterology 2017; 52(6): 677-694; e- pub ahead of print 2016/09/22; doi 10.1007/s00535-016-1261-6. 17. Wang X, Wang J, Rao B, Deng L. Gut flora profiling and fecal metabolite composition of colorectal cancer patients and healthy individuals. Experimental and therapeutic medicine 2017; 13(6): 2848-2854; e-pub ahead of print 2017/06/08; doi 10.3892/etm.2017.4367. 18. Wang Z, Lin Y, Liang J, Huang Y, Ma C, Liu X et al. NMR-based metabolomic techniques identify potential urinary biomarkers for early colorectal cancer detection. Oncotarget 2017; 8(62): 105819- 105831; e-pub ahead of print 2017/12/30; doi 10.18632/oncotarget.22402. 19. Zhang LJ, Chen B, Zhang JJ, Li J, Yang Q, Zhong QS et al. Serum polyunsaturated fatty acid metabolites as useful tool for screening potential biomarker of colorectal cancer. Prostaglandins Leukot Essent Fatty Acids 2017; 120: 25-31; e-pub ahead of print 2017/05/19; doi 10.1016/j.plefa.2017.04.003. 20. Yan L, Ma C, Liu C, Wang Z, Yang J, Liu X et al. NMR-based fecal metabolomics fingerprinting as predictors of earlier diagnosis in patients with colorectal cancer. Oncotarget 2016; 7(20): 29454-29464. 21. Gao P, Zhou C, Zhao L, Zhang G, Zhang Y. Tissue amino acid profile could be used to differentiate advanced adenoma from colorectal cancer. Journal of Pharmaceutical & Biomedical Analysis 2016; 118: 349-355. 22. Yuan T, Xu T, Huang J, Zhang L, Xu S, Xiong B et al. Tissue Metabonomic Phenotyping for Diagnosis and Prognosis of Human Colorectal Cancer. Scientific reports 2016; 6: 20790. 23. Crotti S, Agnoletto E, Cancemi G, Di Marco V, Traldi P, Pucciarelli S et al. Altered plasma levels of decanoic acid in colorectal cancer as a new diagnostic biomarker. Analytical and bioanalytical chemistry 2016; 408(23): 6321-6328; e-pub ahead of print 2016/07/06; doi 10.1007/s00216-016-9743-1. 24. Farshidfar F, Weljie AM, Kopciuk KA, Hilsden R, McGregor SE, Buie WD et al. A validated metabolomic signature for colorectal cancer: exploration of the clinical value of metabolomics. British journal of cancer 2016; 115(7): 848-857; e-pub ahead of print 2016/08/26; doi 10.1038/bjc.2016.243. 25. Sinha R, Ahn J, Sampson JN, Shi J, Yu G, Xiong X et al. Fecal Microbiota, Fecal Metabolome, and Colorectal Cancer Interrelations. PloS one (Article) 2016; 11(3): e0152126; doi 10.1371/journal.pone.0152126. 26. Zhang H, Qiao L, Li X, Wan Y, Yang L, Wang H. Tissue metabolic profiling of lymph node metastasis of colorectal cancer assessed by 1H NMR. Oncology reports 2016; 36(6): 3436-3448; e-pub ahead of print 2016/10/18; doi 10.3892/or.2016.5175. 27. Amal H, Leja M, Funka K, Lasina I, Skapars R, Sivins A et al. Breath testing as potential colorectal cancer screening tool. International journal of cancer 2016; 138(1): 229-236. 28. Williams MD, Zhang X, Park JJ, Siems WF, Gang DR, Resar LM et al. Characterizing metabolic changes in human colorectal cancer. Analytical & Bioanalytical Chemistry 2015; 407(16): 4581-4595. 29. Zamani Z, Arjmand M, Vahabi F, Hosseini SME, Fazeli SM, Iravani A et al. A Metabolic Study on Colon Cancer Using 1H Nuclear Magnetic Resonance Spectroscopy. Biochemistry Research International 2014; 2014(2): 348712. 30. Cross AJ, Moore SC, Boca S, Huang WY, Xiong X, Stolzenberg‐Solomon R et al. A prospective study of serum metabolites and colorectal cancer risk. Cancer 2014; 120(19): 3049-3057. 31. Goedert JJ, Sampson JN, Moore SC, Xiao Q, Xiong X, Hayes RB et al. Fecal metabolomics: assay performance and association with colorectal cancer. Carcinogenesis 2014; 35(9): 2089. 32. Bae S, Ulrich CM, Neuhouser ML, Malysheva O, Bailey LB, Xiao L et al. Plasma choline metabolites and colorectal cancer risk in the Women's Health Initiative Observational Study. Cancer Research 2014; 74(24): 7442. 33. Wang C, Ke C, Wang X, Chi C, Guo L, Luo S et al. Noninvasive detection of colorectal cancer by analysis of exhaled breath. Analytical & Bioanalytical Chemistry 2014; 406(19): 4757-4763. 34. Wang C, Li P, Lian A, Sun B, Wang X, Guo L et al. Blood volatile compounds as biomarkers for colorectal cancer. Cancer Biology & Therapy 2014; 15(2): 200-206. 35. Mirnezami R, Jiménez B, Li JV, Kinross JM, Veselkov K, Goldin RD et al. Rapid diagnosis and staging of colorectal cancer via high-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy of intact tissue biopsies. Annals of Surgery 2014; 259(6): 1138-1149. 36. Qiu Y, Cai G, Zhou B, Li D, Zhao A, Xie G et al. A distinct metabolic signature of human colorectal cancer with prognostic potential. Clinical Cancer Research An Official Journal of the American Association for Cancer Research 2014; 20(8): 2136. 37. Phua LC, Xiu PC, Koh PK, Cheah PY, Han KH, Chan ECY. Non-invasive fecal metabonomic detection of colorectal cancer. Cancer Biology & Therapy 2014; 15(4): 389-397. 38. Jiménez B, Mirnezami R, Kinross J, Cloarec O, Keun HC, Holmes E et al. 1H HR-MAS NMR spectroscopy of tumor-induced local metabolic "field-effects" enables colorectal cancer staging and prognostication. Journal of Proteome Research 2013; 12(2): 959. 39. Kim S, Lee S, Maeng YH, Chang WY, Jin WH, Kim S. Study of Metabolic Profiling Changes in Colorectal Cancer Tissues Using 1D 1 H HR-MAS NMR Spectroscopy. Bulletin of the Korean Chemical Society 2013; 34(5): 1467-1472. 40. Li F, Qin X, Chen H, Qiu L, Guo Y, Liu H et al. Lipid profiling for early diagnosis and progression of colorectal cancer using direct-infusion electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry. Rapid Commun Mass Spectrom 2013; 27(1): 24-34; e-pub ahead of print 2012/12/15; doi 10.1002/rcm.6420. 41. Weir TL, Manter DK, Sheflin AM, Barnett BA, Heuberger AL, Ryan EP. Stool microbiome and metabolome differences between colorectal cancer patients and healthy adults. Plos One 2013; 8(8): e70803. 42. Tan B, Qiu Y, Xia Z, Chen T, Xie G, Yu C et al. Metabonomics Identifies Serum Metabolite Markers of Colorectal Cancer. Journal of Proteome Research 2013; 12(6): 3000. 43. Nishiumi S, Kobayashi T, Ikeda A, Yoshie T, Kibi M, Izumi Y et al. A Novel Serum Metabolomics-Based Diagnostic Approach for Colorectal Cancer. Plos One 2012; 7(7): e40459. 44. Chen JL, Fan J, Yan LS, Guo HQ, Xiong JJ, Ren Y et al. Urine Metabolite Profiling of Human Colorectal Cancer by Capillary Electrophoresis Mass Spectrometry Based on MRB. Gastroenterology Research and Practice,2012,(2012-12-02) 2012; 2012(6): 125890. 45. Cheng Y, Xie G, Chen T, Qiu Y, Zou X, Zheng M et al. Distinct urinary metabolic profile of human colorectal cancer. Journal of Proteome Research 2012; 11(2): 1354-1363. 46. Mal M, Koh PK, Cheah PY, Chan EC. Metabotyping of human colorectal cancer using two-dimensional gas chromatography mass spectrometry. Analytical & Bioanalytical Chemistry 2012; 403(2): 483- 493. 47. Ma Y, Zhang P, Wang F, Liu W, Yang J, Qin H. An integrated proteomics and metabolomics approach for defining oncofetal biomarkers in the colorectal cancer. Annals of Surgery 2012; 255(4): 720. 48. Bertini I, Cacciatore S, Jensen BV, Schou JV, Johansen JS, Kruhøffer M et al. Metabolomic NMR fingerprinting to identify and predict survival of patients with metastatic colorectal cancer. Cancer Research 2012; 72(1): 356. 49. Ong ES, Zou L, Li S, Cheah PY, Eu KW, Ong CN. Metabolic profiling in colorectal cancer reveals signature metabolic shifts during tumorigenesis. Molecular & Cellular Proteomics Mcp 2010. 50. Ma Y, Liu W, Peng J, Huang L, Zhang P, Zhao X et al. A pilot study of gas chromatograph/mass spectrometry-based serum metabolic profiling of colorectal cancer after operation. Molecular Biology Reports 2010; 37(3): 1403-1411. 51. Tessem MB, Selnæs KM, Sjursen W, Tranø G, Giskeødegård GF, Bathen TF et al. Discrimination of Patients with Microsatellite Instability Colon Cancer using 1H HR MAS MR Spectroscopy and Chemometric Analysis. Journal of Proteome Research 2010; 9(7): 3664-3670. 52. Wang W, Feng B, Li X, Yin P, Gao P, Zhao X et al. Urinary metabolic profiling of colorectal carcinoma based on online affinity solid phase extraction-high performance liquid chromatography and ultra performance liquid chromatography-mass spectrometry. Molecular Biosystems 2010; 6(10): 1947-1955. 53. Shureiqi I, Chen D, Day RS, Zuo X, Hochman FL, Ross WA et al. Profiling lipoxygenase metabolism in specific steps of colorectal tumorigenesis. Cancer Prev Res (Phila) 2010; 3(7): 829-838; e-pub ahead of print 2010/06/24; doi 10.1158/1940-6207.CAPR-09-0110. 54. Qiu Y, Cai G, Su M, Chen T, Liu Y, Xu Y et al. Urinary metabonomic study on colorectal cancer. Journal of Proteome Research 2010; 9(3): 1627. 55. Chae YK, Kang WY, Kim SH, Jong E, Joo JK, Han BW et al. Combining Information of Common Metabolites Reveals Global Differences between Colorectal Cancerous and Normal Tissues. Bulletin- Korean Chemical Society 2010(2). 56. Chan ECY, Koh PK, Mal M, Cheah PY, Kong WE, Backshall A et al. Metabolic Profiling of Human Colorectal Cancer Using High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HR- MAS NMR) Spectroscopy and Gas Chromatography Mass Spectrometry (GC/MS). Journal of Proteome Research 2009; 8(1): 352-361. 57. Qiu Y, Cai G, Su M, Chen T, Zheng X, Xu Y et al. Serum Metabolite Profiling of Human Colorectal Cancer Using GC−TOFMS and UPLC−QTOFMS. Journal of Proteome Research 2009; 8(10): 4844. 58. Righi V, Durante C, Cocchi M, Calabrese C, Di FG, Lecce F et al. Discrimination of healthy and neoplastic human colon tissues by ex vivo HR-MAS NMR spectroscopy and chemometric analyses. Journal of Proteome Research 2009; 8(4): 1859. 59. Hirayama A, Kami K, Sugimoto M, Sugawara M, Toki N, Onozuka H et al. Quantitative Metabolome Profiling of Colon and Stomach Cancer Microenvironment by Capillary Electrophoresis Time-of- Flight Mass Spectrometry. Cancer Research 2009; 69(11): 4918-4925. 60. Hsu WY, Chen TL, Lin WD, Tsai FJ, Tsai Y, Lin CT et al. Analysis of urinary nucleosides as potential tumor markers in human colorectal cancer by high performance liquid chromatography/electrospray ionization tandem mass spectrometry. Clinica Chimica Acta 2009; 412(19-20): 1861. 61. Mal M, Koh PK, Cheah PY, Chan ECY. Development and validation of a gas chromatography/mass spectrometry method for the metabolic profiling of human colon tissue. Rapid Communications in Mass Spectrometry 2009; 23(4): 487–494. 62. Monleón D, Morales JM, Barrasa A, López JA, Vázquez C, Celda B. Metabolite profiling of fecal water extracts from human colorectal cancer. Nmr in Biomedicine 2009; 22(3): 342-348. 63. Piotto M, Moussallieh FM, Dillmann B, Imperiale A, Neuville A, Brigand C et al. Metabolic characterization of primary human colorectal cancers using high resolution magic angle spinning 1 H magnetic resonance spectroscopy. Metabolomics 2008; 5(3): 292-301. 64. Denkert C, Budczies J, Weichert W, Wohlgemuth G, Scholz M, Kind T et al. Metabolite profiling of human colon carcinoma – deregulation of TCA cycle and amino acid turnover. Molecular Cancer 2008; 7(1): 72. 65. Tadano T, Kanoh M, Matsumoto M, Sakamoto K, Kamano T. Studies of serum and feces bile acids determination by gas chromatography-mass spectrometry. Rinsho byori The Japanese journal of clinical pathology 2006; 54(2): 103-110; e-pub ahead of print 2006/03/22

Table S4. Quality assessment of gastric cancer studies included in the systematic review by QUADOMICS

Item First author Year 1 2 3 4a 4b 5 6 7 8 9 10 11 12 13 14 15 16 Zhang, H.[1]2018 Y N/A Y Y Y Y Y Y Y Y Y ? N Y N/A N N Liu, H.N.[2]2018 Y N/A Y Y Y Y Y Y Y Y Y ? N Y N/A N N Corona, G.[3]2018 Y N/A Y Y N Y Y Y N Y Y ? N Y N/A N Y Lario, S.[4]2017 Y N/A Y Y Y Y Y Y N Y Y Y N Y N/A N N Wang, H. [5]2016 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Kuligowski, J. [6]2016 Y N/A Y Y Y Y Y Y N Y Y Y N Y N/A N N Jiang, H.P. [7]2016 Y N/A Y Y Y Y Y Y N Y Y ? N Y N/A N N Choi, J.M.[8]2016 Y N/A Y Y Y Y Y Y ? Y Y Y N Y N/A N N Chen, Y. [9]2016 Y N/A Y Y Y Y Y Y N Y Y Y N Y N/A N Y Chan, A.W [10]2016 Y N/A Y Y Y Y Y Y N Y Y Y N Y N/A N N Mokhtari, M. [11]2015 Y N/A Y Y Y Y Y Y ? Y Y Y N Y N/A N N Liang, Q. [12]2015 Y N/A Y N N Y Y Y N Y Y ? N Y N/A N N Jung, J. [13]2014 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N Y Chen, J. [14]2014 Y N/A Y Y Y Y Y Y N Y Y Y N Y N/A N N Zhang, Y. [15]2013 Y N/A Y N N Y Y Y N Y Y ? N Y N/A N N Song, H. [16]2012 Y N/A Y Y Y Y Y Y N Y Y Y N Y N/A N N Ikeda, A. [17]2012 Y N/A Y Y Y Y Y Y N Y Y Y N Y N/A N N Yu, L. [18]2011 Y N/A Y Y Y Y Y Y N Y Y Y N Y N/A N N Song, H. [19]2011 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N Y Miyagi, Y.[20]2011 Y N/A Y Y Y Y Y Y N Y Y Y N Y N/A N N Wu, H. [21]2010 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Cai, Z.[22]2010 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N Y Hirayama, A. [23]2009 Y N/A Y Y Y Y Y Y Y Y Y ? N Y N/A N N Buszewski, B. [24]2008 Y N/A Y Y N Y Y Y Y Y Y ? N Y N/A N N YES% 100 0 100 91.67 83.33 100 100 100 37.5 100 100 66.67 0 100 0 0 20.83 NO% 0 0 0 8.33 16.67 0 0 0 54.17 0 0 0 100 0 0 100 79.17 UC% 0 0 0 0 0 0 0 0 8.33 0 0 33.33 0 0 0 0 0 N/A% 0 100 0 0 0 0 0 0 0 0 0 0 0 0 100 0 0 Note, the reference numbers are the same as in Supplementary Table 1. Index: Y=criteria achieved, N=criteria not achieved, ?=Unclear, N/A=not applicable. Item 1. Were selection criteria clearly described? 2. Was the spectrum of patients’ representative of patients who will receive the test in practice? 3. Was the type of sample fully described? 4. Were the procedures and timing of biological sample collection with respect to clinical factors described with enough detail? 4a. Clinical and physiological factors; 4b. Diagnostic and treatment procedures. 5. Were handling and pre-analytical procedures reported in sufficient detail and similar for the whole sample? And, if differences in procedures were reported, was their effect on the results assessed? 6. Is the time period between the reference standard and the index test short enough to reasonably guarantee that the target condition did not change between the two tests? 7. Is the reference standard likely to correctly classify the target condition? 8. Did the whole sample or a random selection of the sample receive verification using a reference standard of diagnosis? 9. Did patients receive the same reference standard regardless of the result of the index test? 10. Was the execution of the index test described in sufficient detail to permit replication of the test? 11. Was the execution of the reference standard described in sufficient detail to permit its replication? 12. Were the index test results interpreted without knowledge of the results of the reference standard? 13. Were the reference standard results interpreted without knowledge of the results of the index test? 14. Were the same clinical data available when test results were interpreted as would be available when the test is used in practice? 15. Were uninterpretable/intermediate test results reported? 16. Is it likely that the presence of over-fitting was avoided

Table S5. Quality assessment of colorectal cancer studies included in the systematic review by QUADOMICS

Item First author Year 1 2 3 4a 4b 5 6 7 8 9 10 11 12 13 14 15 16 Le Gall, G. [1]2018 Y N/A Y Y N Y Y Y N Y Y Y N Y N/A N Y Hu, X.Q. [2]2018 Y N/A Y Y Y Y Y Y N Y Y ? N Y N/A N N Bian, X. [3]2018 Y N/A Y Y N Y Y Y Y Y N ? N Y N/A N N Djukovic, D. [4]2018 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Farshidfar, F. [5]2018 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N Y Shu, X.[6]2018 Y N/A Y Y N Y Y Y ? ? Y ? N Y N/A N N Venalainen, M.K. [7]2018 Y N/A Y Y Y Y Y Y ? Y Y ? N Y N/A N N Chen, C. [8]2017 Y N/A Y N Y Y Y Y Y Y Y Y N Y N/A N N Guertin, K.A.[9]2017 Y N/A Y Y N Y Y Y ? Y Y ? N Y N/A N N Jing, Y.[10]2017 Y N/A Y Y N Y Y Y Y Y Y Y N Y N/A N N Kinross, J.[11]2017 Y N/A Y Y Y Y Y Y Y Y N Y N Y N/A N N Mika, A.[12]2017 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Ning, W.[13]2017 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Nishiumi, S.[14]2017 Y N/A Y Y N Y Y Y Y Y Y Y N Y N/A N N Shen, S.[15]2017 Y N/A Y Y N Y Y Y N Y Y Y N Y N/A N N Uchiyama, K.[16]2017 Y N/A Y Y N Y Y Y N Y Y Y N Y N/A N N Wang, X.[17]2017 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Wang, Z.[18]2017 Y N/A Y Y Y Y Y Y N Y Y Y N Y N/A N N Zhang, L.J.[19]2017 Y N/A Y Y Y Y Y Y N Y Y Y N Y N/A N N Yan, L.[20]2016 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Gao, P.[21]2016 Y N/A Y N N Y Y Y Y Y Y N N Y N/A N Y Yuan, T.[22]2016 Y N/A Y Y N Y Y Y Y Y Y Y N Y N/A N N Crotti, S.[23]2016 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N Y Farshidfar, F.[24]2016 Y N/A Y Y N Y Y Y Y Y Y Y N Y N/A N N Sinha, R.[25]2016 Y N/A Y Y Y Y Y Y ? Y N ? N Y N/A N N Zhang, H.[26]2016 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Amal, H.[27]2016 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Williams, M.D.[28]2015 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Zamani, Z.[29]2014 Y N/A Y N N Y Y Y ? Y Y Y N Y N/A N N Cross, A.J.[30]2014 Y N/A Y Y Y Y Y Y Y Y N Y N Y N/A N N Goedert, J.J.[31]2014 Y N/A Y Y Y Y Y Y ? Y N Y N Y N/A N N Bae, S.[32]2014 Y N/A Y Y Y Y Y Y Y Y Y ? N Y N/A N N Wang, C.[33]2014 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Wang, C.[34] 2014 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Mirnezami, R.[35]2014 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Qiu, Y.[36]2014 Y N/A Y Y Y Y Y Y Y Y Y ? N Y N/A N N Phua, L.C.[37]2014 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Jiménez, B.[38]2013 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Kim, S.[39]2013 Y N/A Y N N Y Y Y Y Y Y Y N Y N/A N N Li, F.[40]2013 Y N/A Y Y ? Y Y Y ? Y Y Y N Y N/A N N Weir, T.L.[41]2013 Y N/A Y Y Y Y Y Y N Y Y ? N Y N/A N N Tan, B.[42]2013 Y N/A Y Y Y Y Y Y ? Y Y ? N Y N/A N Y Nishiumi, S.[43]2012 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N Y Chen, J.L.[44]2012 Y N/A Y Y Y Y Y Y N Y Y Y N Y N/A N N Cheng, Y.[45]2012 Y N/A Y Y Y Y Y Y ? Y Y Y N Y N/A N Y Mal, M.[46]2012 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Ma, Y.[47]2012 Y N/A Y N N Y Y Y Y Y Y ? N Y N/A N N Bertini, I.[48]2012 Y N/A Y ? Y Y Y Y N Y Y ? N Y N/A N Y Ong, E.S.[49]2010 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Ma, Y.[50]2010 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Tessem, M.B.[51]2010 Y N/A Y Y N Y Y Y Y Y Y ? N Y N/A N N Wang, W.[52]2010 Y N/A Y N N Y Y Y N Y Y ? N Y N/A N N Shureiqi, I.[53]2010 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Qiu, Y.[54]2010 Y N/A Y Y Y Y Y Y N Y Y Y N Y N/A N N Chae, Y.K.[55]2010 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Chan, E.C.Y.[56]2009 Y N/A Y Y Y Y Y Y Y Y Y ? N Y N/A N N Qiu, Y.[57]2009 Y N/A Y Y N Y Y Y N Y Y ? N Y N/A N N Righi, V.[58]2009 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Hirayama, A.[59]2009 Y N/A Y Y N Y Y Y Y Y Y N N Y N/A N N Hsu, W.Y.[60]2009 Y N/A Y Y Y Y Y Y ? Y Y ? N Y N/A N N Mal, M.[61]2009 Y N/A Y N N Y Y Y Y Y Y ? N Y N/A N N Monleón, D.[62]2009 Y N/A Y N Y Y Y Y Y Y Y ? N Y N/A N N Piotto, M.[63]2008 Y N/A Y Y Y Y Y Y Y Y Y Y N Y N/A N N Denkert, C.[64]2008 Y N/A Y Y N Y Y Y Y Y Y Y N Y N/A N N Tadano, T.[65]2006 Y N/A Y N N Y Y Y ? Y Y ? N Y N/A N N YES% 100 0 100 84.62 66.15 100 100 100 64.62 98.46 92.31 66.15 0 100 0 0 12.31 NO% 0 0 0 13.85 32.31 0 0 0 18.46 0 7.69 3.08 100 0 0 10 87.69 0 UC% 0 0 0 1.53 1.54 0 0 0 16.92 1.54 0 30.77 0 0 0 0 0 N/A% 0 100 0 0 0 0 0 0 0 0 0 0 0 0 100 0 0 Note, the reference numbers are the same as in Supplementary Table 2. Index: Y=criteria achieved, N=criteria not achieved, ?=Unclear, N/A=not applicable. Item 1. Were selection criteria clearly described? 2. Was the spectrum of patients’ representative of patients who will receive the test in practice? 3. Was the type of sample fully described? 4. Were the procedures and timing of biological sample collection with respect to clinical factors described with enough detail? 4a. Clinical and physiological factors; 4b. Diagnostic and treatment procedures. 5. Were handling and pre-analytical procedures reported in sufficient detail and similar for the whole sample? And, if differences in procedures were reported, was their effect on the results assessed? 6. Is the time period between the reference standard and the index test short enough to reasonably guarantee that the target condition did not change between the two tests? 7. Is the reference standard likely to correctly classify the target condition? 8. Did the whole sample or a random selection of the sample receive verification using a reference standard of diagnosis? 9. Did patients receive the same reference standard regardless of the result of the index test? 10. Was the execution of the index test described in sufficient detail to permit replication of the test? 11. Was the execution of the reference standard described in sufficient detail to permit its replication? 12. Were the index test results interpreted without knowledge of the results of the reference standard? 13. Were the reference standard results interpreted without knowledge of the results of the index test? 14. Were the same clinical data available when test results were interpreted as would be available when the test is used in practice? 15. Were uninterpretable/intermediate test results reported? 16. Is it likely that the presence of over-fitting was avoided

Table S6. Differential metabolites and the reported frequencies in previous metabolomics studies of gastric cancer

Metabolite Name HMDB ID Frequency Metabolite Name HMDB ID Frequency Tyrosine HMDB0000158 11 Propanoic acid HMDB0000237 1 Valine HMDB0000883 11 Squalene HMDB0000256 1 Isoleucine HMDB0000172 9 Serotonin HMDB0000259 1 Tryptophan HMDB0000929 9 Thymine HMDB0000262 1 Alanine HMDB0000161 8 D-ribose HMDB0000283 1 Methionine HMDB0000696 7 4-Hydroxy-3-methoxymandelic acid HMDB0000291 1 Leucine HMDB0000687 6 Xanthine HMDB0000292 1 Glycine HMDB0000123 5 Urea HMDB0000294 1 Phenylalanine HMDB0000159 5 9-Octadecenoic acid HMDB0000297 1 Threonine HMDB0000167 5 Tryptamine HMDB0000303 1 Asparagine HMDB0000168 5 3-Hydroxybutanoic acid HMDB0000357 1 Histidine HMDB0000177 5 3,4-Dihydroxyphenylpropionic acid HMDB0000423 1 Lysine HMDB0000182 5 Hexanedioic acid HMDB0000448 1 Serine HMDB0000187 5 3-Methylindole HMDB0000466 1 Lactate HMDB0000190 5 2-Butanone HMDB0000474 1 Taurine HMDB0000251 5 5,6-Dihydrouridine HMDB0000497 1 Glutamate HMDB0003339 5 4-Hydroxybenzoic acid HMDB0000500 1 Acetate HMDB0000042 4 3-Methyladipic acid HMDB0000555 1 Fumaric acid HMDB0000134 4 2-Furoic acid HMDB0000617 1 Formate HMDB0000142 4 Dodecanoic acid HMDB0000638 1 Hypoxanthine HMDB0000157 4 3-Hydroxypropionic acid HMDB0000700 1 Proline HMDB0000162 4 Levulinic acid HMDB0000720 1 Succinate HMDB0000254 4 Hydroxyproline HMDB0000725 1 Arginine HMDB0000517 4 2-Hydroxyisobutyric acid HMDB0000729 1 Cholesterol HMDB0000067 3 3-hydroxykynurenine HMDB0000732 1 Citrate HMDB0000094 3 5-Hydroxyindoleacetic Acid HMDB0000763 1 Glycolate HMDB0000115 3 Mannitol HMDB0000765 1 Aspartic acid HMDB0000191 3 Pseudouridine HMDB0000767 1 Inosine HMDB0000195 3 Azelaic acid HMDB0000784 1 Palmitic acid HMDB0000220 3 Orotidine HMDB0000788 1 L-Cysteine HMDB0000574 3 Octanoic acid HMDB0000791 1 Gluconic acid HMDB0000625 3 2-Amino-4-hydroxy-pteridinone HMDB0000802 1 Glutamine HMDB0000641 3 Tetradecanoic acid HMDB0000806 1 Indolelactic acid HMDB0000671 3 N-acetylaspartate HMDB0000812 1 Kynurenine HMDB0000684 3 1-Propanol HMDB0000820 1 Kynurenic acid HMDB0000715 3 Salicyluric acid HMDB0000840 1 Phenylacetylglycine HMDB0000821 3 Nicotinamide riboside HMDB0000855 1 Citrulline HMDB0000904 3 Heptanedioic acid HMDB0000857 1 Anthranilic acid HMDB0001123 3 5-Methyluridine HMDB0000884 1 Putrescine HMDB0001414 3 Valeric acid HMDB0000892 1 Phenylacetylglutamine HMDB0006344 3 Succinyladenosine HMDB0000912 1 4-Hydroxyphenylacetate HMDB0000020 2 SAH HMDB0000939 1 Adenine HMDB0000034 2 trans-Aconitate HMDB0000958 1 Betaine HMDB0000043 2 5-Methylcytidine HMDB0000982 1 β-Alanine HMDB0000056 2 SAM HMDB0000988 1 Acetoacetate HMDB0000060 2 γ-Glu-Cys HMDB0001049 1 Creatine HMDB0000064 2 Fructose 1,6-Diphosphate HMDB0001058 1 Dimethylamine HMDB0000087 2 7-Methylguanosine HMDB0001107 1 Choline HMDB0000097 2 Glyceraldehyde 3-Phosphate HMDB0001112 1 GABA HMDB0000112 2 Aminophenol HMDB0001169 1 Malic acid HMDB0000156 2 Melatonin HMDB0001389 1 α-ketoglutaric acid HMDB0000208 2 Nicotinamide HMDB0001406 1 myo-Inositol HMDB0000211 2 Nicotinic acid HMDB0001488 1 Ornithine HMDB0000214 2 γ-Tocopherol HMDB0001492 1 Pyruvic acid HMDB0000243 2 Phosphocreatine HMDB0001511 1 Sucrose HMDB0000258 2 Methylguanidine HMDB0001522 1 Pyroglutamic acid HMDB0000267 2 1-Methylguanosine HMDB0001563 1 Sarcosine HMDB0000271 2 p-Cresol HMDB0001858 1 Urate HMDB0000289 2 Salicylic acid HMDB0001895 1 Uridine HMDB0000296 2 5'-Deoxyadenosine HMDB0001983 1 Xanthosine HMDB0000299 2 β-ureidoisobutyric acid HMDB0002031 1 Uracil HMDB0000300 2 n-Ribosylhistidine HMDB0002089 1 3-Hydroxyphenylacetate HMDB0000440 2 9-Octadecenamide HMDB0002117 1 2-Aminobutyric acid HMDB0000452 2 Phosphoric acid HMDB0002142 1 5-Hydroxytryptophan HMDB0000472 2 11-Eicosenoic acid HMDB0002231 1 Creatinine HMDB0000562 2 Cadaverine HMDB0002322 1 Linoleic acid HMDB0000673 2 4-Deoxythreonic acid HMDB0002453 1 3-Indoxylsulfate HMDB0000682 2 A,b-Dihydroxyisobutyric acid HMDB0002601 1 1-Methylnicotinamide HMDB0000699 2 6-Hydroxynicotinate HMDB0002658 1 Hippuric acid HMDB0000714 2 1-Methylinosine HMDB0002721 1 Sebacic acid HMDB0000792 2 Androsterone glucuronide HMDB0002829 1 Stearic acid HMDB0000827 2 Chlorogenate HMDB0003164 1 Xanthurenic Acid HMDB0000881 2 Deoxyribose HMDB0003224 1 Trimethylamine N-oxide HMDB0000925 2 9-Hexadecenoic acid HMDB0003229 1 Threonate HMDB0000943 2 1-Methyladenosine HMDB0003331 1 Arachidonic acid HMDB0001043 2 Symmetric Dimethylarginine HMDB0003334 1 N-Formylkynurenine HMDB0001200 2 α-Glucose HMDB0003345 1 Acetylserotonin HMDB0001238 2 N-Acetylornithine HMDB0003357 1 Spermidine HMDB0001257 2 Pyrimidine HMDB0003361 1 Phosphocholine HMDB0001565 2 Ribulose HMDB0003371 1 Acetone HMDB0001659 2 Tryptophol HMDB0003447 1 3-Aminoisobutyrate HMDB0003911 2 N-Methylhydantoin HMDB0003646 1 beta-D-3-Ribofuranosyluric acid HMDB0029920 2 N-methyladenosine HMDB0004044 1 2-Oxobutyrate HMDB0000005 1 6-Hydroxymelatonin HMDB0004081 1 2-Hydroxybutyrate HMDB0000008 1 5-Methoxytryptamine HMDB0004095 1 3-Hydroxyisobutyric acid HMDB0000023 1 Formyl-N-acetyl-methoxykynurenine HMDB0004259 1 Carnosine HMDB0000033 1 3-Methyluridine HMDB0004813 1 Butanoic acid HMDB0000039 1 N-methylguanosine HMDB0005862 1 Ascorbic acid HMDB0000044 1 N-Acetylcytidine HMDB0005923 1 Adenosine HMDB0000050 1 o-Tyrosine HMDB0006050 1 cis-Aconitate HMDB0000072 1 3-Indoleacetonitrile HMDB0006524 1 Dihydrouracil HMDB0000076 1 Butenoic acid HMDB0010720 1 Cytidine HMDB0000089 1 1-(beta-D-Ribofuranosyl)-1,4- HMDB0011648 1 dihydronicotinamide Dimethylglycine HMDB0000092 1 Lipid II HMDB0012306 1 Cystathionine HMDB0000099 1 Palmitelaidic acid HMDB0012328 1 Ethanol HMDB0000108 1 Hexadecadienylcarnitine HMDB0013334 1 Fructose 6-Phosphate HMDB0000124 1 Megestrol HMDB0014495 1 Glutathione HMDB0000125 1 Midazolam HMDB0014821 1 Glycerol phosphate HMDB0000126 1 Diflunisal HMDB0014999 1 Glycerol HMDB0000131 1 Indole-3-acetamide HMDB0029739 1 Guanine HMDB0000132 1 Naphthalene HMDB0029751 1 Guanosine HMDB0000133 1 1-Palmitoyl-Glycerol HMDB0031074 1 Glycocholic acid HMDB0000138 1 Hydroxyanthranillic acid HMDB0031188 1 Methylamine HMDB0000164 1 Erythro-lsoleucine HMDB0031275 1 Isocitric acid HMDB0000193 1 Acetamide HMDB0031645 1 3-Indoleacetic acid HMDB0000197 1 Benzeneacetonitrile HMDB0034171 1 O-Acetylcarnitine HMDB0000201 1 Carbon disulfide HMDB0036574 1 Pantothenate HMDB0000210 1 trans-13-Octadecenoic acid HMDB0041480 1 N-Acetyl glucosamine HMDB0000215 1 Xylonic acid HMDB0060256 1 NADPH HMDB0000221 1 alpha-Hydroxytriazolam HMDB0061053 1 Quinolinic acid HMDB0000232 1 Octadecenoylcarnitine HMDB0094687 1 cis-Vaccenic acid HMDB0240219 1

Table S7. Differential metabolites and the reported frequencies in previous metabolomics studies of colorectal cancer

Metabolite Name HMDB ID Frequency Metabolite Name HMDB ID Frequency Glycine HMDB0000123 24 Kynurenic acid HMDB0000715 1 L-Valine HMDB0000883 23 5-Hydroxyindoleacetic acid HMDB0000763 1 L-Alanine HMDB0000161 22 Pseudouridine HMDB0000767 1 L-Lactic acid HMDB0000190 22 Azelaic acid HMDB0000784 1 L-Phenylalanine HMDB0000159 20 Orotidine HMDB0000788 1 L-Proline HMDB0000162 20 Pterin HMDB0000802 1 L-Leucine HMDB0000687 20 N-Acetyl-L-aspartic acid HMDB0000812 1 L-Glutamic acid HMDB0000148 17 Salicyluric acid HMDB0000840 1 Taurine HMDB0000251 16 Pimelic acid HMDB0000857 1 Palmitic acid HMDB0000220 15 Succinyladenosine HMDB0000912 1 L-Methionine HMDB0000696 15 trans-Aconitic acid HMDB0000958 1 Glycerol HMDB0000131 14 N-Acetylserotonin HMDB0001238 1 L-Tyrosine HMDB0000158 14 Nicotinic acid HMDB0001488 1 L-Threonine HMDB0000167 14 Gamma-Tocopherol HMDB0001492 1 L-Isoleucine HMDB0000172 14 Phosphocreatine HMDB0001511 1 L-Serine HMDB0000187 14 Acetone HMDB0001659 1 L-Aspartic acid HMDB0000191 14 11Z-Eicosenoic acid HMDB0002231 1 D-Glucose HMDB0000122 13 1-Methyladenosine HMDB0003331 1 L-Lysine HMDB0000182 12 N-Methylhydantoin HMDB0003646 1 L-Arginine HMDB0000517 12 N6-Methyladenosine HMDB0004044 1 L-Glutamine HMDB0000641 12 Palmitelaidic acid HMDB0012328 1 Choline HMDB0000097 11 cis-Vaccenic acid HMDB0240219 1 L-Asparagine HMDB0000168 11 Citraconic acid HMDB0000634 1 myo-Inositol HMDB0000211 11 Galactaric acid HMDB0000639 1 Succinic acid HMDB0000254 11 Decanoylcarnitine HMDB0000651 1 L-Tryptophan HMDB0000929 11 Cysteineglutathione disulfide HMDB0000656 1 Acetic acid HMDB0000042 10 L-Thyronine HMDB0000667 1 Uridine HMDB0000296 10 Hexadecanedioic acid HMDB0000672 1 Myristic acid HMDB0000806 10 Mandelic acid HMDB0000703 1 Citric acid HMDB0000094 9 Glycoursodeoxycholic acid HMDB0000708 1 L-Histidine HMDB0000177 9 4-Hydroxybutyric acid HMDB0000710 1 Uracil HMDB0000300 9 L-Homoserine HMDB0000719 1 3-Hydroxybutyric acid HMDB0000357 9 Indoleacrylic acid HMDB0000734 1 Creatine HMDB0000064 8 Indole HMDB0000738 1 Fumaric acid HMDB0000134 8 Homocarnosine HMDB0000745 1 Ornithine HMDB0000214 8 Lithocholic acid HMDB0000761 1 Pyruvic acid HMDB0000243 8 N-Acetyl-L-alanine HMDB0000766 1 Creatinine HMDB0000562 8 Octadecanedioic acid HMDB0000782 1 L-Cysteine HMDB0000574 8 3-Phosphoglyceric acid HMDB0000807 1 Linoleic acid HMDB0000673 8 Stearoylcarnitine HMDB0000848 1 Stearic acid HMDB0000827 8 Beta-Sitosterol HMDB0000852 1 Oleic acid HMDB0000207 8 Ribonic acid HMDB0000867 1 scyllo-Inositol HMDB0006088 8 Suberic acid HMDB0000893 1 2-Hydroxybutyric acid HMDB0000008 7 Taurodeoxycholic acid HMDB0000896 1 Cholesterol HMDB0000067 7 Trimethylamine HMDB0000906 1 Glutathione HMDB0000125 7 Taurochenodesoxycholic acid HMDB0000951 1 L-Alpha-aminobutyric acid HMDB0000452 7 UDP-D-Xylose HMDB0001018 1 D-Galactose HMDB0000143 7 Coenzyme Q10 HMDB0001072 1 L-Palmitoylcarnitine HMDB0000222 7 PGF2 HMDB0001139 1 Beta-Alanine HMDB0000056 6 5-Aminolevulinic acid HMDB0001149 1 Hypoxanthine HMDB0000157 6 Allantoic acid HMDB0001209 1 Hippuric acid HMDB0000714 6 1-Deoxy-D-xylulose 5-phosphate HMDB0001213 1 4-Hydroxyproline HMDB0000725 6 Coumarin HMDB0001218 1 Arachidonic acid HMDB0001043 6 5-Aminoimidazole ribonucleotide HMDB0001235 1 Glycerophosphocholine HMDB0000086 6 Spermine HMDB0001256 1 Malic acid HMDB0000744 6 Glyceric acid 1,3-biphosphate HMDB0001270 1 Alpha-Linolenic acid HMDB0001388 6 2,3-Diphosphoglyceric acid HMDB0001294 1 L-Malic acid HMDB0000156 5 6-Phosphogluconic acid HMDB0001316 1 L-Acetylcarnitine HMDB0000201 5 Guanosine monophosphate HMDB0001397 1 Pyroglutamic acid HMDB0000267 5 Citicoline HMDB0001413 1 Citrulline HMDB0000904 5 Pyridoxamine HMDB0001431 1 Trimethylamine N-oxide HMDB0000925 5 PGE1 HMDB0001442 1 Oleamide HMDB0002117 5 Asymmetric dimethylarginine HMDB0001539 1 L-Cystine HMDB0000192 5 Pyridoxal HMDB0001545 1 Elaidic acid HMDB0000573 5 D-Ribose 5-phosphate HMDB0001548 1 Phosphate HMDB0001429 5 2-Keto-glutaramic acid HMDB0001552 1 Isobutyric acid HMDB0001873 5 N5-Formyl-THF HMDB0001562 1 Betaine HMDB0000043 4 Glucose 1-phosphate HMDB0001586 1 Ascorbic acid HMDB0000044 4 L-Norleucine HMDB0001645 1 Glycolic acid HMDB0000115 4 Acetaminophen HMDB0001859 1 Glycocholic acid HMDB0000138 4 Methanol HMDB0001875 1 Formic acid HMDB0000142 4 m-Aminobenzoic acid HMDB0001891 1 Isocitric acid HMDB0000193 4 2-Aminoisobutyric acid HMDB0001906 1 Inosine HMDB0000195 4 Docosapentaenoic acid (22n-6) HMDB0001976 1 Pantothenic acid HMDB0000210 4 Eicosapentaenoic acid HMDB0001999 1 Propionic acid HMDB0000237 4 Myristoleic acid HMDB0002000 1 Uric acid HMDB0000289 4 Butyrylcarnitine HMDB0002013 1 Xanthine HMDB0000292 4 Erucic acid HMDB0002068 1 Urea HMDB0000294 4 Methylcysteine HMDB0002108 1 Dodecanoic acid HMDB0000638 4 3-Hydroxy-L-proline HMDB0002113 1 Threonic acid HMDB0000943 4 Trihydroxycoprostanoic acid HMDB0002163 1 Phosphorylcholine HMDB0001565 4 N1,N12-Diacetylspermine HMDB0002172 1 Palmitoleic acid HMDB0003229 4 Docosahexaenoic acid HMDB0002183 1 L-Carnitine HMDB0000062 4 2-Indolecarboxylic acid HMDB0002285 1 Cytidine monophosphate HMDB0000095 4 Oxalic acid HMDB0002329 1 D-Xylose HMDB0000098 4 Hexacosanoic acid HMDB0002356 1 Glyceric acid HMDB0000139 4 Hydroquinone HMDB0002434 1 Phenylacetate HMDB0000209 4 3,4,5-Trimethoxycinnamic acid HMDB0002511 1 Ribitol HMDB0000508 4 Taurolithocholic acid 3-sulfate HMDB0002580 1 Beta-D-Glucose HMDB0000516 4 Sulfolithocholylglycine HMDB0002639 1 Cholic acid HMDB0000619 4 8,11,14-Eicosatrienoic acid HMDB0002925 1 L-Arabinose HMDB0000646 4 N-Acetylserine HMDB0002931 1 D-Fructose HMDB0000660 4 Inositol phosphate HMDB0002985 1 Heptadecanoic acid HMDB0002259 4 Heme HMDB0003178 1 Adenine HMDB0000034 3 Cyclohexanone HMDB0003315 1 Butyric acid HMDB0000039 3 8-Hydroxy-deoxyguanosine HMDB0003333 1 Adenosine HMDB0000050 3 Glycolaldehyde HMDB0003344 1 Acetoacetic acid HMDB0000060 3 1-Hexadecanol HMDB0003424 1 cis-Aconitic acid HMDB0000072 3 L-Histidinol HMDB0003431 1 Cytidine HMDB0000089 3 Alpha-D-Glucose 1,6-bisphosphate HMDB0003514 1 Dimethylglycine HMDB0000092 3 3'-AMP HMDB0003540 1 Glycerol 3-phosphate HMDB0000126 3 Beta-Leucine HMDB0003640 1 Oxoglutaric acid HMDB0000208 3 15(S)-HETE HMDB0003876 1 Sarcosine HMDB0000271 3 2-Hydroxyethanesulfonate HMDB0003903 1 L-Kynurenine HMDB0000684 3 L-Allothreonine HMDB0004041 1 S-Adenosylhomocysteine HMDB0000939 3 4-Hydroxystyrene HMDB0004072 1 Putrescine HMDB0001414 3 Indoxyl HMDB0004094 1 Alpha-N-Phenylacetyl-L-glutamine HMDB0006344 3 Selenocystine HMDB0004122 1 Adenosine monophosphate HMDB0000045 3 12-Keto-leukotriene B4 HMDB0004234 1 D-Mannose HMDB0000169 3 12(S)-HPETE HMDB0004243 1 Capric acid HMDB0000511 3 15(S)-HPETE HMDB0004244 1 Deoxycholate HMDB0000626 3 Diethanolamine HMDB0004437 1 Isovalerate HMDB0000718 3 Perillic acid HMDB0004586 1 Pelargonic acid HMDB0000847 3 Tetrahydrogestrinone HMDB0004626 1 Glyceraldehyde HMDB0001051 3 13-OxoODE HMDB0004668 1 Aminomalonic acid HMDB0001147 3 9-OxoODE HMDB0004669 1 Benzoic acid HMDB0001870 3 N2,N2-Dimethylguanosine HMDB0004824 1 Alpha-Tocopherol HMDB0001893 3 Dimethyl sulfone HMDB0004983 1 Tetracosanoic acid HMDB0002003 3 Aspartylysine HMDB0004985 1 LysoPC(14:0) HMDB0010379 3 9E,11E-Octadecadienoic acid HMDB0005047 1 LysoPC(16:0) HMDB0010382 3 Tetradecanoylcarnitine HMDB0005066 1 Palmitic amide HMDB0012273 3 Ophthalmic acid HMDB0005765 1 Monooleoylglycerol HMDB0094684 3 Galactinol HMDB0005826 1 L-Cystathionine HMDB0000099 2 Allyl isothiocyanate HMDB0005843 1 Ethanol HMDB0000108 2 Isoputreanine HMDB0006009 1 Gamma-Aminobutyric acid HMDB0000112 2 N-Acetylglutamine HMDB0006029 1 Methylamine HMDB0000164 2 Benzaldehyde HMDB0006115 1 Indoleacetic acid HMDB0000197 2 Elaidic carnitine HMDB0006464 1 Xanthosine HMDB0000299 2 D-Aspartic acid HMDB0006483 1 Gluconic acid HMDB0000625 2 Stearidonic acid HMDB0006547 1 Indoxyl sulfate HMDB0000682 2 9(S)-HPODE HMDB0006940 1 L-Octanoylcarnitine HMDB0000791 2 LysoPA(0:0/18:0) HMDB0007850 1 Valerate HMDB0000892 2 LysoPA(18:0/0:0) HMDB0007854 1 5-Methylcytidine HMDB0000982 2 PC(14:1(9Z)/22:1(13Z)) HMDB0007920 1 Spermidine HMDB0001257 2 PC(18:3(6Z,9Z,12Z)/16:0) HMDB0008166 1 Niacinamide HMDB0001406 2 PC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/18:0) HMDB0008727 1 p-Cresol HMDB0001858 2 PE(18:3(6Z,9Z,12Z)/18:0) HMDB0009123 1 Phosphoric acid HMDB0002142 2 PE(20:0/18:2(9Z,12Z)) HMDB0009225 1 Alpha-D-Glucose HMDB0003345 2 PE(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/16:0) HMDB0009682 1 Glycerol 1-hexadecanoate HMDB0031074 2 PIP(16:0/18:0) HMDB0009923 1 Octadecenoylcarnitine HMDB0094687 2 15(S)-HEPE HMDB0010209 1 Deoxyuridine HMDB0000012 2 9-HODE HMDB0010223 1 4-Pyridoxic acid HMDB0000017 2 Acetaminophen glucuronide HMDB0010316 1 Pipecolic acid HMDB0000070 2 LysoPC(16:1(9Z)) HMDB0010383 1 Homovanillic acid HMDB0000118 2 LysoPC(18:0) HMDB0010384 1 D-Glucuronic acid HMDB0000127 2 LysoPC(18:3(6Z,9Z,12Z)) HMDB0010387 1 D-Maltose HMDB0000163 2 LysoPC(20:0) HMDB0010390 1 O-Phosphoethanolamine HMDB0000224 2 LysoPC(20:3(5Z,8Z,11Z)) HMDB0010393 1 Phenol HMDB0000228 2 LysoPC(24:0) HMDB0010405 1 N-Acetylneuraminic acid HMDB0000230 2 LysoPC(P-18:1(9Z)) HMDB0010408 1 Propionylcarnitine HMDB0000317 2 3-Oxodecanoic acid HMDB0010724 1 3-Methylhistidine HMDB0000824 2 5(S)-HETE HMDB0011134 1 Caprylic acid HMDB0000482 2 5(S)-HPETE HMDB0011135 1 Aminoadipic acid HMDB0000510 2 19(S)-HETE HMDB0011136 1 Chenodeoxycholic acid HMDB0000518 2 L-beta-aspartyl-L-serine HMDB0011168 1 Acetylglycine HMDB0000532 2 Leucylproline HMDB0011175 1 D-Arabitol HMDB0000568 2 O-Phosphothreonine HMDB0011185 1 Glycochenodeoxycholate HMDB0000637 2 PE(P-16:0/18:1(9Z)) HMDB0011342 1 Glutarate HMDB0000661 2 PE(P-16:0/20:4(5Z,8Z,11Z,14Z)) HMDB0011352 1 Malonic acid HMDB0000691 2 Glyceryl 2-palmitate HMDB0011533 1 Homocysteine HMDB0000742 2 Glyceryl 2-stearate HMDB0011535 1 3-Hydroxyisovaleric acid HMDB0000754 2 p-Cresol sulfate HMDB0011635 1 2-Hydroxy-3-methylpentanoic acid HMDB0000479 2 2,6-Diamino-4-hydroxy-5-N- HMDB0011657 1 methylformamidopyrimidine Pentadecanoic acid HMDB0000826 2 Turanose HMDB0011740 1 Behenic acid HMDB0000944 2 3-Dehydrocarnitine HMDB0012154 1 Ursodeoxycholic acid HMDB0000946 2 N-Succinyl-L,L-2,6-diaminopimelate HMDB0012267 1 Hypotaurine HMDB0000965 2 PS(14:1(9Z)/14:0) HMDB0012341 1 S-Adenosylmethionine HMDB0001185 2 PS(18:0/18:0) HMDB0012378 1 L-Sorbose HMDB0001266 2 13'-Carboxy-alpha-tocopherol HMDB0012555 1 p-Aminobenzoic acid HMDB0001392 2 Propenoylcarnitine HMDB0013124 1 4-Aminohippuric acid HMDB0001867 2 Hydroxypropionylcarnitine HMDB0013125 1 Arachidic acid HMDB0002212 2 Butenylcarnitine HMDB0013126 1 Picolinic acid HMDB0002243 2 9-Hexadecenoylcarnitine HMDB0013207 1 Nervonic acid HMDB0002368 2 PC(o-16:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)) HMDB0013409 1 Terephthalic acid HMDB0002428 2 PC(o-16:1(9Z)/14:1(9Z)) HMDB0013410 1 1,5-Anhydrosorbitol HMDB0002712 2 PC(o-16:1(9Z)/18:2(9Z,12Z)) HMDB0013413 1 LysoPC(18:1(9Z)) HMDB0002815 2 PC(o-16:1(9Z)/20:4(8Z,11Z,14Z,17Z)) HMDB0013415 1 D-Xylitol HMDB0002917 2 PC(o-18:1(9Z)/22:0) HMDB0013433 1 Erythritol HMDB0002994 2 PC(o-18:2(9Z,12Z)/22:0) HMDB0013437 1 13(S)-HPODE HMDB0003871 2 PC(o-18:2(9Z,12Z)/24:0) HMDB0013438 1 D-Threitol HMDB0004136 2 PC(o-20:0/20:4(8Z,11Z,14Z,17Z)) HMDB0013442 1 D-Tryptophan HMDB0013609 1 PC(o-22:1(13Z)/20:4(8Z,11Z,14Z,17Z)) HMDB0013451 1 Proline betaine HMDB0004827 2 13S-hydroxyoctadecadienoic acid HMDB0004667 2 Eicosadienoic acid HMDB0005060 2 PC(o-20:1(11Z)/20:4(8Z,11Z,14Z,17Z)) HMDB0013444 2 CPA(18:0/0:0) HMDB0007004 2 Alanyl-Histidine HMDB0028689 1 LysoPC(18:2(9Z,12Z)) HMDB0010386 2 Alanyl-Leucine HMDB0028691 1 4-Hydroxybenzaldehyde HMDB0011718 2 Alanyl-Tryptophan HMDB0028698 1 Glutarylcarnitine HMDB0013130 2 Asparaginyl-Glutamine HMDB0028729 1 Dyphylline HMDB0014789 1 Glutaminylglutamic acid HMDB0028796 1 11-Eicosenoic acid HMDB0034296 2 Glutamylglutamic acid HMDB0028818 1 2-Ketobutyric acid HMDB0000005 1 Glutamylvaline HMDB0028832 1 p-Hydroxyphenylacetic acid HMDB0000020 1 Glycyl-Valine HMDB0028854 1 Dimethylamine HMDB0000087 1 Leucyl-Alanine HMDB0028922 1 Fructose 6-phosphate HMDB0000124 1 Leucyl-Glutamate HMDB0028928 1 Guanosine HMDB0000133 1 Leucyl-Leucine HMDB0028933 1 NADPH HMDB0000221 1 Leucyl-Serine HMDB0028938 1 Squalene HMDB0000256 1 Leucyl-Tryptophan HMDB0028940 1 Sucrose HMDB0000258 1 Prolyl-Alanine HMDB0029010 1 Serotonin HMDB0000259 1 Serylmethionine HMDB0029045 1 Thymine HMDB0000262 1 Threoninyl-Aspartate HMDB0029057 1 Adipic acid HMDB0000448 1 Threoninyl-Serine HMDB0029070 1 4-Hydroxybenzoic acid HMDB0000500 1 Tryptophyl-Glycine HMDB0029083 1 Alpha-ketoisovaleric acid HMDB0000019 1 Tyrosyl-Glutamine HMDB0029103 1 Taurocholic acid HMDB0000036 1 Valyl-Aspartate HMDB0029123 1 Epinephrine HMDB0000068 1 Valyl-Histidine HMDB0029129 1 Dopamine HMDB0000073 1 lysoPC(26:0) HMDB0029205 1 Nonane HMDB0029595 1 12a-Hydroxy-3-oxocholadienic acid HMDB0000385 1 Guanidoacetic acid HMDB0000128 1 lysoPC(6:0) HMDB0029207 1 Ethanolamine HMDB0000149 1 lysoPC(26:1(5Z)) HMDB0029220 1 L-Fucose HMDB0000174 1 Glycerylphosphorylethanolamine HMDB0000114 1 Maleic acid HMDB0000176 1 2-Dodecylbenzenesulfonic acid HMDB0031031 1 Orotic acid HMDB0000226 1 Glycerol 1-octadecanoate HMDB0031075 1 Pyridoxine HMDB0000239 1 1,2,3-Propanetricarboxylic acid HMDB0031193 1 Sphinganine HMDB0000269 1 Ethyl acetate HMDB0031217 1 Uridine diphosphate glucose HMDB0000286 1 1,2-Ethanediamine HMDB0031225 1 Uridine 5'-monophosphate HMDB0000288 1 xi-2-Ethyl-1-hexanol HMDB0031231 1 12-Ketodeoxycholic acid HMDB0000328 1 N-Undecylbenzenesulfonic acid HMDB0032549 1 Uridinediphosphate-N-acetylglucosamine HMDB0000290 1 5,6:8,9-Diepoxyergost-22-ene-3,7beta-diol HMDB0033647 1 2-Hydroxyestradiol HMDB0000338 1 Octadecanamide HMDB0034146 1 3-Hydroxymethylglutaric acid HMDB0000355 1 Ethyl 4-(methylthio)butyrate HMDB0037620 1 Allolithocholic acid HMDB0000381 1 Dmpec 2-methylpropanoate HMDB0037640 1 lysoPC(28:0) HMDB0029206 1 2-Acetyl-5-methylpyridine HMDB0040222 1 7-Ketodeoxycholic acid HMDB0000391 1 2-Hydroxy-3-methylbutyric acid HMDB0000407 1 Lactitol HMDB0040937 1 4-Hydroxy-5-(dihydroxyphenyl)-valeric acid-O- HMDB0059977 1 methyl-O-sulphate

Table S8. Pathway enrichment analyses based on the differential

metabolites of gastric cancer

Pathway name Total Hits P-value FDR Impact Tissue Aminoacyl-tRNA biosynthesis 75 19 1.09E-10 8.7E-09 0.16902 Alanine, aspartate and glutamate metabolism 24 9 3.08E-07 9.48E-06 0.67996 Nitrogen metabolism 39 11 3.89E-07 9.48E-06 0.0083 Glycine, serine and threonine metabolism 48 12 4.74E-07 9.48E-06 0.47867 Glutathione metabolism 38 10 2.76E-06 4.29E-05 0.42474 Arginine and proline metabolism 77 14 3.22E-06 4.29E-05 0.45397 beta-Alanine metabolism 28 8 1.51E-05 0.000173 0.36975 Pantothenate and CoA biosynthesis 27 7 0.000106 0.000955 0.09288 Cysteine and methionine metabolism 56 10 0.000107 0.000955 0.43407 Butanoate metabolism 40 8 0.000241 0.00193 0.17638 Methane metabolism 34 7 0.0005 0.003634 0.16466 Propanoate metabolism 35 7 0.000602 0.004016 0.12951 Citrate cycle (TCA cycle) 20 5 0.001318 0.007533 0.26557 Taurine and hypotaurine metabolism 20 5 0.001318 0.007533 0.38489 Synthesis and degradation of ketone bodies 6 3 0.001466 0.007819 0.7 Glycolysis or Gluconeogenesis 31 6 0.001805 0.009023 0.1067 Phenylalanine metabolism 45 7 0.002836 0.013345 0.11906 Cyanoamino acid metabolism 16 4 0.004148 0.018434 0 Valine, leucine and isoleucine biosynthesis 27 5 0.005379 0.02265 0.06148 D-Glutamine and D-glutamate metabolism 11 3 0.010305 0.041221 0.35294 Glyoxylate and dicarboxylate metabolism 50 6 0.019902 0.075817 0.17539 Galactose metabolism 41 5 0.030814 0.11205 0.02238 Nicotinate and nicotinamide metabolism 44 5 0.040303 0.13614 0.03827 Sulfur metabolism 18 3 0.040842 0.13614 0.06614 Pyrimidine metabolism 60 6 0.044201 0.14144 0.12927 Pentose phosphate pathway 32 4 0.048054 0.14238 0.08639 Pyruvate metabolism 32 4 0.048054 0.14238 0.41957 Blood Tryptophan metabolism 79 17 5.43E-11 4.34E-09 0.37451 Aminoacyl-tRNA biosynthesis 75 14 2.46E-08 9.85E-07 0.05634 Nitrogen metabolism 39 8 1.56E-05 0.000415 0.00763 Arginine and proline metabolism 77 10 8.53E-05 0.001706 0.31805 Phenylalanine metabolism 45 7 0.000347 0.005551 0.15431 Alanine, aspartate and glutamate metabolism 24 5 0.000645 0.008606 0.31244 Valine, leucine and isoleucine biosynthesis 27 5 0.001141 0.013035 0.06148 Phenylalanine, tyrosine and tryptophan 27 4 0.008451 0.084507 0.0818 biosynthesis Propanoate metabolism 35 4 0.020956 0.16842 0.00145 Taurine and hypotaurine metabolism 20 3 0.021836 0.16842 0.38489 D-Arginine and D-ornithine metabolism 8 2 0.023158 0.16842 0 Valine, leucine and isoleucine degradation 40 4 0.032606 0.21738 0.0414 D-Glutamine and D-glutamate metabolism 11 2 0.042862 0.25255 0.35294 Nicotinate and nicotinamide metabolism 44 4 0.044197 0.25255 0.02448 Urine Aminoacyl-tRNA biosynthesis 75 15 5.2E-08 4.16E-06 0.11268 Phenylalanine metabolism 45 9 3.06E-05 0.001224 0.15056 Nitrogen metabolism 39 8 7.19E-05 0.001918 0.00067 Citrate cycle (TCA cycle) 20 5 0.000684 0.013678 0.26222 Pyrimidine metabolism 60 8 0.001556 0.018168 0.09832 Propanoate metabolism 35 6 0.001656 0.018168 0.12996 Alanine, aspartate and glutamate metabolism 24 5 0.001663 0.018168 0.32194 Glycine, serine and threonine metabolism 48 7 0.001817 0.018168 0.44376 Glyoxylate and dicarboxylate metabolism 50 7 0.002317 0.020598 0.18108 Valine, leucine and isoleucine biosynthesis 27 5 0.002887 0.023098 0.07367 Purine metabolism 92 9 0.006909 0.050249 0.04686 Methane metabolism 34 5 0.008077 0.053845 0.16439 Pantothenate and CoA biosynthesis 27 4 0.017227 0.10601 0.253 beta-Alanine metabolism 28 4 0.019529 0.10923 0.25694 Cyanoamino acid metabolism 16 3 0.020481 0.10923 0 Arginine and proline metabolism 77 7 0.024373 0.12186 0.31778 Pyruvate metabolism 32 4 0.03059 0.14395 0.23703 Taurine and hypotaurine metabolism 20 3 0.0374 0.16622 0.36331 Table S9. Pathway enrichment analyses based on the differential

metabolites of colorectal cancer

Pathway name Total Hits P-value FDR Impact Blood Alanine, aspartate and glutamate metabolism 24 10 1.36E-05 0.000273 0.78253 Aminoacyl-tRNA biosynthesis 75 20 2.86E-06 0.000114 0.22536 Arginine and proline metabolism 77 15 0.002068 0.023628 0.55976 Cyanoamino acid metabolism 16 4 0.044414 0.18701 0 Cysteine and methionine metabolism 56 10 0.02059 0.10981 0.43961 Glycine, serine and threonine metabolism 48 17 1.93E-07 1.55E-05 0.52887 Nitrogen metabolism 39 13 1.24E-05 0.000273 0.0083 Pantothenate and CoA biosynthesis 27 7 0.006799 0.050866 0.32666 Taurine and hypotaurine metabolism 20 7 0.001007 0.013427 0.38489 Valine, leucine and isoleucine biosynthesis 27 7 0.006799 0.050866 0.1839 Ascorbate and aldarate metabolism 45 8 0.037621 0.1672 0.17171 Citrate cycle (TCA cycle) 20 7 0.001007 0.013427 0.38395 Glycerophospholipid metabolism 39 9 0.005137 0.050866 0.52208 Glyoxylate and dicarboxylate metabolism 50 10 0.009429 0.062863 0.24443 Linoleic acid metabolism 15 5 0.006994 0.050866 0.65625 Pentose and glucuronate interconversions 53 9 0.036878 0.1672 0.14949 Phenylalanine metabolism 45 9 0.013559 0.083437 0.25214 Primary bile acid biosynthesis 47 9 0.017895 0.10226 0.10898 Propanoate metabolism 35 7 0.028315 0.14157 0.11527 Tissue Aminoacyl-tRNA biosynthesis 75 20 8.36E-09 5.51E-07 0.22536 Arginine and proline metabolism 77 20 1.38E-08 5.51E-07 0.62571 Nitrogen metabolism 39 14 2.61E-08 6.97E-07 0.0083 Glycine, serine and threonine metabolism 48 14 5.13E-07 9.09E-06 0.56649 Alanine, aspartate and glutamate metabolism 24 10 5.68E-07 9.09E-06 0.8566 Glutathione metabolism 38 11 9.98E-06 0.000133 0.43265 Cysteine and methionine metabolism 56 13 2.16E-05 0.000247 0.68918 beta-Alanine metabolism 28 9 2.63E-05 0.000263 0.33438 Pantothenate and CoA biosynthesis 27 7 0.000939 0.007644 0.253 Taurine and hypotaurine metabolism 20 6 0.000955 0.007644 0.46583 Glycolysis or Gluconeogenesis 31 7 0.002255 0.016402 0.1067 Sulfur metabolism 18 5 0.003772 0.025149 0.22677 Propanoate metabolism 35 7 0.004679 0.028793 0.12951 Valine, leucine and isoleucine biosynthesis 27 6 0.005085 0.029055 0.0689 Citrate cycle (TCA cycle) 20 5 0.006172 0.032919 0.22842 Butanoate metabolism 40 7 0.009998 0.046068 0.19176 Pyrimidine metabolism 60 9 0.010186 0.046068 0.21459 Glyoxylate and dicarboxylate metabolism 50 8 0.010365 0.046068 0.33976 Cyanoamino acid metabolism 16 4 0.014296 0.060194 0 Methane metabolism 34 6 0.016143 0.06457 0.16466 Fatty acid biosynthesis 49 7 0.028913 0.11014 0 Pentose phosphate pathway 32 5 0.044103 0.1534 0.1082 Pyruvate metabolism 32 5 0.044103 0.1534 0.41957 Synthesis and degradation of ketone bodies 6 2 0.048423 0.16141 0.7 Urine Aminoacyl-tRNA biosynthesis 75 16 8.07E-11 6.46E-09 0.16902 Alanine, aspartate and glutamate metabolism 24 8 1.54E-07 6.18E-06 0.75404 Nitrogen metabolism 39 9 8.23E-07 2.19E-05 0.0083 Phenylalanine metabolism 45 9 3E-06 6E-05 0.20468 Citrate cycle (TCA cycle) 20 6 1.26E-05 0.000201 0.29818 Arginine and proline metabolism 77 10 4.6E-05 0.000613 0.27511 Glycine, serine and threonine metabolism 48 7 0.000338 0.003864 0.14131 Butanoate metabolism 40 6 0.000793 0.007098 0.19055 Pantothenate and CoA biosynthesis 27 5 0.000827 0.007098 0 Cysteine and methionine metabolism 56 7 0.000887 0.007098 0.30421 Tyrosine metabolism 76 8 0.001203 0.008747 0.15774 Glyoxylate and dicarboxylate metabolism 50 6 0.002617 0.017449 0.03823 Pyrimidine metabolism 60 6 0.006582 0.035189 0.11982 Phenylalanine, tyrosine and tryptophan biosynthesis 27 4 0.006598 0.035189 0.008 Valine, leucine and isoleucine biosynthesis 27 4 0.006598 0.035189 0.06148 Cyanoamino acid metabolism 16 3 0.009662 0.048309 0 Sulfur metabolism 18 3 0.013513 0.063592 0.1559 Propanoate metabolism 35 4 0.016575 0.073666 0.02982 Taurine and hypotaurine metabolism 20 3 0.018123 0.076307 0.05395 Glutathione metabolism 38 4 0.021913 0.087654 0.02999 Valine, leucine and isoleucine degradation 40 4 0.025996 0.099033 0.02232 Histidine metabolism 44 4 0.03546 0.12895 0.20312 D-Glutamine and D-glutamate metabolism 11 2 0.037696 0.13111 0.13904 beta-Alanine metabolism 28 3 0.04427 0.14757 0 Feces Alanine, aspartate and glutamate metabolism 24 6 4.13E-06 0.000165 0.7284 Aminoacyl-tRNA biosynthesis 75 15 2.07E-12 1.65E-10 0.22536 Arginine and proline metabolism 77 6 0.003326 0.033263 0.17494 Cyanoamino acid metabolism 16 3 0.003271 0.033263 0 Cysteine and methionine metabolism 56 4 0.022318 0.11903 0.13882 Glycine, serine and threonine metabolism 48 6 0.000264 0.005283 0.45459 Nitrogen metabolism 39 6 8.02E-05 0.002139 0.00067 Pantothenate and CoA biosynthesis 27 4 0.001612 0.021495 0.18014 Taurine and hypotaurine metabolism 20 3 0.006303 0.04584 0.03237 Valine, leucine and isoleucine biosynthesis 27 4 0.001612 0.021495 0.03975 Propanoate metabolism 35 4 0.00429 0.037094 0.00134 Sulfur metabolism 18 3 0.004637 0.037094 0.06614 beta-Alanine metabolism 28 3 0.01624 0.10827 0 D-Glutamine and D-glutamate metabolism 11 2 0.01835 0.11292 0.13904 Glycolysis or Gluconeogenesis 31 3 0.021393 0.11903 0.00046 Glutathione metabolism 38 3 0.03652 0.1826 0.01095 Butanoate metabolism 40 3 0.041632 0.18503 0.01774 Valine, leucine and isoleucine degradation 40 3 0.041632 0.18503 0.02232