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Metabolomics in cancer research: Supplementary data

1 Supplementary Data

2 Supplementary methods

3 Additional information regarding the search strategy used in the main paper

4 Supplementary tables

5 Supplementary Table 1: List of reported metabolites to be altered in human cancers

6 Supplementary figures

7 Supplementary Figure 1: General overview over the metabolomics workflow

8

1 Metabolomics in cancer research: Supplementary data

9 Supplementary methods

10 Search strategy

11 The search strategy was described in the main paper. For the Web of Knowledge search an

12 additional refinement step was necessary to reduce irrelevant findings. The following research

13 areas of low relevance were excluded:

14 Plant Science, Biophysics, Agriculture, Environmental Sciences Ecology, Microbiology,

15 Computer Science, Mathematics, Cardiology, Engineering, Automation control Systems,

16 Marine Freshwater Biology, Behavioral Science, Physics, Developmental Biology, Zoology,

17 Psychiatry, Energy Fuels, Infectious Disease, Parasitology, Mycology, Rheumatology,

18 Psychology, Veterinary Sciences, Dentistry, Legal Medicine, Polymer Science,

19 Anesthesiology, Robotics, Sports Science, Forestry, Tropical Medicine, Virology, Water

20 Resources, Electrochemistry, Evolutionary Biology, Fisheries, Materials Science,

21 Oceanography, Substance Abuse, Geology, Nuclear Science Technology, Operations

22 Research Management, Orthopedics, Allergy, Biodiversity, Educational Research,

23 Metallurgy, Optics, Emergency Medicine, Geochemistry, History philosophy of science,

24 Mathematical methods in Social sciences, Mechanics, Social Issues, Thermodynamics

25 Additionally the abstracts had to contain one of the following keywords:

26 “MS” OR “mass spectrometry” OR “patients”.

2 Metabolomics in cancer research: Supplementary data

27 Supplementary tables

28 Supplementary Table 1: List of reported metabolites altered in human cancers. Metabolites in bold were reported from a study that validated 29 findings within an independent study population. For these validated findings the type of cancer was also listed. Moreover hits in the HMDB for 30 abnormal concentrations of these metabolites in other pathological conditions were reported.

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

Tryptophan C00078 Bladder, RCC, Breast, 18 Various (>5 diseases) CRC, Nasopharyngeal, Ovarian C00079 Amino acid Ovarian 16 Phenylketonuria + various (>5 diseases) Lactate C00186 Nasopharyngeal 16 Various (>5 diseases) C00082 Amino acid Bladder, RCC, CRC, 16 Various (>5 diseases) Nasopharyngeal Glutamate C00217 Amino acid Breast 15 Various (>5 diseases) Carnitines1 C00318 Carnitines Bladder, RCC, CRC, 15 Not assigned for group of Ovarian metabolites C00037 Amino acid Breast, 14 Various (>5 diseases) Nasopharyngeal C00183 Amino acid 14 C00065 Amino acid Nasopharyngeal 13 Various (>5 diseases) Palmitic acid C00249 Fatty acid RCC 13 N/A C00031 Sugar RCC 12 Diabetes + various hormonal imbalances C00097 Amino acid CRC 12 Multiple sclerosis, stroke, peripheral neuropathy, dementia, AIDS Fumarate C00122 TCA cycle CRC, RCC 12 Fumaric academia, lung cancer

3 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

Threonine C00188 Amino acid 12 Lysophosphocholines1 - Bladder, RCC, Ovarian 11 Not assigned for group of metabolites Myo-inositol C00137 Second messenger RCC 11 C00148 Amino acid Nasopharyngeal 11 Various (>5 diseases) Glutamine C00303 Amino acid 11 Malate C00497 TCA cycle Breast, RCC 11 Anoxia Pyroglutamate C01879 Glutamate derivative Breast 11 Various (>5 diseases) C00123 Amino acid 10 Citrate C00158 TCA cycle CRC, RCC 10 Various (>5 diseases) Bile acids1 - Bile acid Bladder, RCC, Ovarian 9 Not assigned for group of metabolites Hypoxanthine C00262 Nucleotide/ nucleoside metabolism Breast, 9 Various (>5 diseases) Nasopharyngeal, Lymphoma Oleic acid C00712 Fatty acid 9 Hippurate C01586 Gut microbiota metabolite CRC, RCC 9 Various (>5 diseases) Succinate C00042 TCA cycle Breast, RCC 8 Severely malnourished children, lung cancer Arachidonic acid C00219 Fatty acid RCC 8 Hypertension, gestational diabetes C00041 Amino acid CRC 7 Various (>5 diseases) C00047 Amino acid 7 Aspartate C00049 Amino acid CRC 7 Cirrhosis, epilepsy, Alzheimer’s disease Asparagine C00152 Amino acid 7 C00259 Sugar CRC 7 -5-phosphate

4 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB) isomerase deficiency

Kynurenine C00328 metabolism CRC 7 N/A Myristic acid C06424 Fatty acid CRC 7 N/A Uridine C00299 Nucleotide/ nucleoside metabolism CRC 7 Lesch-Nyhan syndrome, Canavan disease C00124 Sugar 6 C00135 Amino acid 6 Cholesterol C00187 Steroid metabolism 6 C00791 Phosphorylation Breast 6 Chronic renal failure + various (>5 diseases) Stearic acid C01530 Fatty acid 6 Urea C00086 Breast, CRC 6 Cirrhosis, heart transplant Lysophosphoethanolamines1 - 5 Pyruvate C00022 Glycolysis CRC 5 Heart transplant, 2- methylglutaconic aciduria, diabetes type I C00077 Urea cycle 5 Taurine C00245 Bile acid metabolism Breast 5 Various (>5 diseases) C00407 Amino acid 5 Phosphocholine C00588 PC metabolism 5 2-Hydroxybutyrate C05984 Fatty acid metabolism CRC 5 Pyruvate dehydrogenase deficiency Uracil C00106 Nucleotide/ nucleoside metabolism CRC, RCC 5 Various (>5 diseases) Gangliosides1 - Bladder, RCC 4 Not assigned for group of metabolites Heptadecanoic acid - Fatty acid Breast 4 N/A Oleamide - Fatty acid metabolism 4

5 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

Phosphate C00009 4 2-Oxoglutarate C00026 TCA cycle 4 C00095 Sugar RCC 4 Diabetes Beta-alanine C00099 Amino acid metabolism RCC 4 Dihydropyrimidine dehydrogenase deficiency, GABA transaminase deficiency, hyper-beta- alaninemia Aminoadipate C00956 Lysine metabolism 4 Ribose C00121 Sugar 4 C00159 Sugar 4 Inosine C00294 Nucleotide/ nucleoside metabolism 4 Pipecolic acid C00408 Lysine metabolism 4 Linoleic acid C01595 Fatty acid 4 1-Methyladenosine C02494 Nucleotide/ nucleoside metabolism 4 Hydroxybutyrate C05984 Propanoate metabolism / byproduct of 4 methylation Nucleosides1 Nucleotide/ nucleoside metabolism 4 2,2-Dimethylguanosine - Nucleotide/ nucleoside metabolism 3 Tocopherol - Vitamin RCC 3 α-Toc.: cancer; γ-Toc.: prostate cancer, endometrial cancer Adenosine C00054 Nucleotide/ nucleoside metabolism 3 Glycerol-phosphate C00093 Glycerolipid metabolism 3 Choline C00114 PC metabolism 3 Glycerol C00116 Glycerolipid metabolism RCC 3 Heart transplant, diabetes, glycerol kinase deficiency

6 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

Amino acids C00151 Lung 3 Not assigned for group of metabolites Nicotinamide C00153 Vitamin 3 Ethanolamine C00189 PC metabolism 3 Sarcosine C00213 Glycine, serine, theronine metabolism Prostate 3 Sarcosinemia Glyceric acid C00258 Glycine, serine, theronine metabolism, 3 phosphate pathway, glycerolipid metabolism Aconitic acid C00417 TCA cycle 3 Sphinganine C00836 Sphingolipid metabolism 3 Trigonelline C01004 Coffee metabolite 3 Hydroxyproline C01015 Collagen degradation, proline metabolism 3 C01157 C05147 3-Hydroxybutanoic acid C01089 Fatty acid metabolism (ketone body) 3 Pseudouridine C01168 Nucleotide/ nucleoside metabolism 3 p-cresol C01468 Gut microbiota metabolite CRC 3 Hemodialysis 5-Hydroxyindoleacetate C05635 Tryptophan metabolism 3 Docosahexaenoic acid C06429 Fatty acid 3 Azelaic acid C08261 Dicarboxylic acid, possibly derived from 3 plasticizers Uric acid C00366 purine metabolism Breast, 3 Gout, diabetes + various (>5 Nasopharyngeal diseases) N-2-Succinyladenosine - Nucleotide/ nucleoside metabolism 2 N-Acetylglycine - 2 Thiodiglycolic acid - 2 Phosphoric acid C00013 2

7 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

S-Adenosylmethionine C00019 Methylation 2 Oxalic acid C00048 Glyoxylate and dicarboxylate metabolism 2 C00062 Amino acid 2 C00073 Amino acid 2 Inositol-phosphate C00081 Nucleotide/ nucleoside metabolism 2 Glucose-1-phosphate C00092 Glycolysis RCC 2 N/A Ribose-5-phosphate C00117 Sugar metabolism / nucleotide/ nucleoside 2 metabolism C00134 Polyamine metabolism CRC 2 Leukemia, pancreatic Cancer N-Acetylglucosamine C00140 Aminosugar metabolism RCC 2 N/A Adenine C00147 Nucleotide/ nucleoside metabolism 2 4-Hydroxybenzoate C00156 Phenylalanine metabolism CRC 2 Hypertension (mild) Propanoic Acid C00163 Fatty acid 2 Benzoate C00180 Phenylalanine metabolism (microbial) Breast 2 Breast cancer Glucuronic acid C00191 Conjugation of xenobiotic compounds CRC 2 N/A C00208 Sugar 2 Orotate C00295 Nucleotide/ nucleoside metabolism 2 C00300 Phosphorylation 2 Isocitrate C00311 TCA cycle 2 C00327 Urea cycle 2 Glucosamine C00329 Amino sugar and nucleotide sugar 2 metabolism Phosphoethanolamine C00346 PC metabolism Breast 2 N/A Malonic acid C00383 Pyrimidine metabolism, beta-alanine Breast 2 Heart transplant, malonyl- metabolism CoA decarboxylase

8 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB) deficiency Histamine C00388 Histidine metabolism 2 Pyrimidine C00396 Nucleotide/ nucleoside metabolism 2 Cytidine C00475 Nucleotide/ nucleoside metabolism 2 Glutaric acid C00489 Fatty acid metabolism, lysine metabolism 2 Itaconic acid C00490 2 Meso-erythritol C00503 Sugar alcohol CRC 2 N/A 4-Hydroxyphenylacetate C00642 Gut microbiota metabolite 2 Naphthalene C00829 2 N-Acetyl-aspartate C01042 Neurotransmitter metabolism Breast 2 Canavan disease C01083 Sugar metabolism 2 Decanoic acid C01571 Fatty acid 2 Glycocholic acid C01921 Bile acid 2 Dodecanoic acid C02679 Fatty acid 2 3-Hydroxy- C02794 Tryptophan metabolism 2 Dopamine C03758 Hormone 2 Phenylacetylglutamine C04148 Phenylalanine metabolism 2 Homovanillate C05582 Tyrosine metabolism Breast, CRC 2 Schizophrenia, aromatic L- amino acid decarboxylase deficiency, hypertension (mild) Phenylacetylglycine C05598 Phenylalanine metabolism Bladder, RCC 2 Heart failure Adipic acid C06104 Dicarboxylic acid, possibly derived from 2 food (gelatin) and plasticizers Nervonic acid C08323 Fatty acid 2 1-Deoxyglucose - 2

9 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

Altrose - Sugar 2 Ceramides1 - 2 Xylonic acid - Sugar acid 2 Proline-betaine - Proline metabolism 2 Leucylproline - Dipeptide 2 1,2,4-Benzenetricarboxylic acid - 1 1,2-Dihydro-1,1,6-trimethylnaphtalene - Likely to be derived from food (alcoholic 1 beverages) 1,6-Anhydroglucose - Likely to be derived from food (maillard 1 reaction) 13-Octadecenoic acid - Fatty acid 1 14'-Apo-beta-carotenal - Vitamin 1 1-Methylinsosine - Nucleotide/ nucleoside metabolism 1 1-Monohexadecanoylglycerol - Triglyceride synthesis 1 1-O-Heptadexylglycerol - Triglyceride synthesis 1 1-Phenanthrene-carboxylic acid - Xenobiotic compound 1 2,2,5-Trimethyl-3,4-hexanedione - 1 2,3-Dihydroxy-2(3H)-furanone - Likely to be derived from food (possible 1 maillard reaction) 2,3-Dihydroxy-propanoic acid - 1 2,5-Furandicarboxylic acid - Likely to be derived from food (maillard 1 reaction) 27-Nor-5-beta-cholestane-3,7,12,24,25 - Cholesterol metabolism Ovarian 1 N/A pentol glucuronide 2-ethyl,2-propen-1-ol - 1 2H-benzimidazol-2-one - 1

10 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

2-Methyl-3-phenyl-2-propenal - 1 2-Methylglutaconic acid - Isoleucine metabolism 1 2-Nonenal - Fatty acid metabolite 1 2-O-Mesylarabinose - Sugar derivative 1 2'-O-Methylcytidine - Nucleotide/ nucleoside metabolism 1 2-Piperidinone - Ovarian 1 N/A 3-Hexanol - 1 3-Hydroxy-2-methyl-butanoic Acid - Fatty acid metabolism, isoleucine 1 metabolism 3-Methylcrotonic acid - biotin metabolism 1 4-Androsten-3-beta,17 beta diol disulfate - Steroid metabolism 1 4-Ketoglucose - Sugar metabolism 1 5-Dimethyl-2(2H)-isoxazolone - 1 5-Methylcytidine - Nucleotide/ nucleoside metabolism 1 5-Methyldodecane - Branched alkane, predominantly found on 1 plant (hops) surfaces (found in alcoholic beverage) 7-Hydroxyoctanoic acid - Fatty acid metabolism 1 Aminoquinoline - 1 Azaprostanoic acid - Prostaglandin metabolism 1 Benzeneacetonitrile - Derived from Food, cyanogenic glycosides 1 Canavaninosuccinate - Aspartate metabolism 1 Chlorobenzoic acid - Xenobiotic drug byproduct 1 Docosatrienol - Prostaglandin metabolism 1 Galactonate-gamma-lactone - Sugar derivatives 1 Gamma-glutamyl-dipeptides - Peptides 1

11 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

N-2-phenylacetly-glutamine - Peptides 1 Heneicosane - Alkane2 1 Hexadecane nitrile - 1 Hexanoylglycine - Fatty acid metabolism 1 Hydroxyphenyl lactic acid - Tyrosine metabolism 1 Hydroxyproline-dipeptide - Peptide 1 Indole-3-carboxylic acid - Tryptophan metabolism Breast 1 N/A Methionine sulfoxide - Methionine metabolism 1 Methylglucopyranoside - 1 N(6)-(N-threonylcarbonyl)-adenosine - Nucleotide/ nucleoside metabolism 1 N-2-Furoylglycine - Possibly derived from furan derivatives in 1 food (maillard reaction) N-6-Methyladenosine - Nucleotide/ nucleoside metabolism 1 Nigerose - Sugar 1 Nonahexacontanoic acid - Fatty acid 1 Oxazolethione - 1 Palatinose - Sugar 1 Pentacosane - Alkane2 1 1-Pentadecanol - Fatty alcohol 1 Phenylpropiolic acid - Possibly of exogenous origin 1 Phe-Phe - Dipeptide Ovarian 1 N/A Picolinic acid - Tryptophan metabolism 1 Pregnen-diol disulfate - Steroid metabolism 1 S-Methylcysteine - Methylation 1 Threonylcarbamoyl adenosine - Nucleotide/ nucleoside metabolism 1

12 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

FAD C00016 Riboflavin metabolism 1 Cystine C000491 Cysteine metabolism 1 C01420 CMP C00055 Phosphorylation Breast 1 N/A Formate C00058 Methylation 1 Sulfuric acid C00059 1 Fructose-6-phosphate C00085 Glycolysis 1 Biotin C00120 Vitamin 1 Oxidized C00127 Glutathione metabolism 1 Glycolic acid C00160 Glyoxylate and dicarboxylate metabolism Breast 1 Various (>5 diseases) Carbamoyl phosphate C00169 Urea cycle / nucleotide/ nucleoside 1 metabolism Methylthioadenosine C00170 Nucleotide/ nucleoside metabolism, 1 polyamine metabolism Thymine C00178 Nucleotide/ nucleoside metabolism Breast 1 Thymidine treatment, dihydropyrimidine dehydrogenase deficiency C00179 Arginine and proline metabolism, 1 polyamine metabolism Gluconolactone C00198 Pentose phosphate pathway 1 Guanine C00242 Nucleotide/ nucleoside metabolism 1 Butanoic acid C00246 Fatty acid 1 Pyridoxal C00250 Vitamin metabolism CRC 1 Sickle cell disease C00252 Sugar 1 Nicotinic acid C00253 Vitamin 1 Gluconic acid C00257 Pentose phosphate pathway 1 Homoserine C00263 Methylation 1

13 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

N-Acetyl- C00270 Aminosugar metabolism 1 Spermidine C00315 Polyamine metabolism 1 Indoleacrylic acid C00331 Tryptophan metabolism 1 Gamma-aminobutyrate C00334 Neurotransmitter 1 Dihydroorotate C00337 Nucleotide/ nucleoside metabolism 1 dTMP C00364 Nucleotide/ nucleoside metabolism 1 Cytosine C00380 Nucleotide/ nucleoside metabolism 1 Carnosine C00386 Histidine metabolism, beta alanine 1 metabolism Guanosine C00387 Nucleotide/ nucleoside metabolism 1 Mannitol C00392 Sugar alcohol 1 Dihydrouracil C00429 Nucleotide/ nucleoside metabolism 1 3-Methyl-2-oxovaleric acid C00430 Isoleucine metabolism 1 Indole C00463 Tryptophan metabolism CRC 1 Breast Cancer Retinol C00473 Vitamin 1 Ribitol C00474 Sugar alcohol 1 Shikimate C00493 Biosynthesis of aromatic amino acids 1 (plants and microorganisms) Cysteic acid C00506 Cysteine metabolism, taurine metabolism 1 2-Propenoic acid C00511 Xenobiotic component 1 Hypotaurine C00519 Taurine metabolism 1 Limonene C00521 Derived from food (plant origin) 1 Homogentisate C00544 Tyrosine metabolism 1 cAMP C00575 Second messenger 1 N-12-Acetylspermidine C00612 Polyamine metabolism 1

14 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

Gentisate C00628 Tyrosine metabolism 1 5-Hydroxytryptophan C00643 Tryptophan metabolism CRC 1 N/A Cortisol C00735 Steroid metabolism 1 Pyridine C00747 Nucleotide/ nucleoside metabolism 1 Squalene C00751 Steroid metabolism 1 Sorbitol C00794 Sugar alcohol 1 Gulonic acid C00800 Pentose and glucuronate interconversions 1 Pentanoic acid C00803 Fatty acid 1 2-Hydroxy-2-methylbutanedioic acid C00815 Possibly of microbial origin 1 4-Pyridoxic acid C00847 Vitamin metabolism 1 C00864 Vitamin 1 Aminomalonic acid C00872 Oxidative damage to proteins Breast 1 N/A Phosphoserine C01005 PC metabolism 1 3-Hydroxypropionic acid C01013 Beta-alanine metabolism 1 6-Hydroxynicotinic acid C01020 Nicotinate metabolism (possibly of 1 microbial origin) 4-Guanidinobutanoate C01035 Arginine and proline metabolism 1 2-Hydroxyglutaric acid C01087 2-oxoglutarate isomer 1 Glyceric acid-2,3-diphosphate C01159 glycolysis 1 Hydroxyphenylpyruvate C01179 Tyrosine metabolism 1 3-Hydroxyisobutyric acid C01188 Propanoyl-CoA metabolism 1 N-Acetylglucosaminylamine C01239 Aminosugar metabolism 1 Butanal C01412 Butanoate metabolism (microbial origin) 1 Phenyllactic acid C01207 Tyrosine metabolism Breast 1 Phenylketonuria Glycol C01506 1

15 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

Threonic acid C01620 Ascorbate and aldarate metabolism CRC 1 N/A Acetlytyrosine C01657 1 Cysteamine C01678 Taurine metabolism 1 Ribonic acid C01685 Sugar acid 1 Galactitol C01697 Sugar alcohol 1 Butenonic acid C01771 Fatty acid 1 C01835 Sugar 1 Arabitol C01904 Sugar alcohol 1 Mandelic acid C01984 Tyrosine metabolism, phenylalanine 1 metabolism Indolelactic acid C02043 Tryptophan metabolism 1 Thromboxane C02198 Prostaglandin metabolism RCC, Bladder 1 N/A Dodecanal C02278 Fatty aldehyde 1 C02291 Cysteine metabolism 1 2-Aminobutyrate C02356 CRC 1 Kidney disease, Alzheimer’s disease, bone metastases 6-Aminohexanoic acid C02378 Likely a xenobiotic compound 1 Glucuronic acid lactone C02670 Ascorbate and aldarate metabolism 1 Ribonolactone C02674 Sugar metabolism 1 N'-Formylkynurenine C02700 Tryptophan metabolism 1 Propionylcarnitine C03017 Carnitine Ovarian 1 Celiac disease 3-Amino-2-methyl-propanoic acid C03284 Valine, Leucine, Isoleucine metabolism 1 2-Methyl-histidine C03298 Methylation 1 Acetylphenylalanine C03519 Phenylalanine metabolism (possibly of Bladder, RCC 1 N/A microbial origin) N,N-Dimethyl-arginine C03626 Arginine metabolism 1

16 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

Quinolinate C03722 Tryptophan metabolism 1 3-Hydroxy-3-methylglutarate C03761 Cholesterol metabolism 1 Pyrolline hydroxycarboxylic acid C04281 Proline metabolism 1 N2-Methylguanosine C04545 Nucleotide/ nucleoside metabolism 1 Androsterone sulfate C04555 Steroid metabolism 1 DHEA sulfate C04555 Steroid metabolism 1 Purine C05325 Nucleotide/ nucleoside metabolism 1 Nicotinuric acid C05380 Nicotinate and nicotinamide metabolism 1 Melibiose C05402 Sugar 1 Dehydroascorbate C05422 Vitamin 1 Tetrahydrocorticosterone C05476 Steroid metabolism 1 Normetanephrine C05589 Neurotransmitter 1 3-Hydroxyphenylacetate C05593 Tyrosine metabolism, Phenylalanine 1 metabolism (gut microbiota metabolite) Indoxyl C05658 Tryptophan metabolism 1 1,4-Benzenedicarboxylic acid C06337 Possibly of microbial origin 1 Octanoic acid C06423 Fatty acid 1 Eicosapentaenoic acid C06428 Fatty acid 1 p-cymene C06575 Monoterpene, derived from food or of 1 microbial origin C07064 Derived from food 1 Phenylacetate C07086 Phenylalanine metabolism 1 Ethylbenzene C07111 Xenobiotic compound 1 2-Hydroxyhippurate C07588 Possibly of microbial origin, also drug 1 (acetylsalicylic acid) metabolism N-Methylalanine C08263 Nucleotide/ nucleoside metabolism 1

17 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

Lignoceric acid C08320 Fatty acid Breast 1 N/A

Dodecane C08374 Alkane2 1 Thymol sulfate C09908 Derived from Food 1 Dimethylsulfone C11142 Derived from Food 1 Phytosphingosine C12144 Sphingolipid metabolism 1 Phosphothreonine C12147 metabolism 1 5-Alpha-androstan-3-beta-17-beta diol C12525 Steroid metabolism 1 disulfate Demethylphylloquinone C13309 1 1-Tridecanol C14509 Fatty alcohol 1 11-Eicosenoic acid C16526 Fatty acid 1 Nonadecanoic acid C16535 Fatty acid 1 Heptanedioic acid C16536 Fatty acid 1 Heptanoic acid C17714 Fatty acid 1 3-Amino-2-piperidone - Ornithine-lactam 1 1-Butanamide - 1 1-Hexanol - Alcohol 1 2,3-Dihydroxy-benzoic acid - Possibly of microbial origin 1 2,5-Dihydroxy-pyrazine - Derived from Food Breast 1 N/A 2-Amino-4-hydroxy-pteridinone - Vitamin metabolism, biopterin fragment 1 6-Phosphogluconic acid - Pentose phosphate pathway RCC 1 N/A Acetamine - 1 Anisole - Possibly derived from food or of microbial 1 origin

18 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

Anthracitic acid C00108 Tryptophan metabolism 1 Apronal - Drug, xenobiotic compound 1 Benzenepropanoic acid - 1 Bisethane - 1 Butanetriol - Possibly derived from food 1 Cholet-5-en-3-ol - Steroid metabolism 1 Cystamine - Taurine metabolism CRC 1 N/A Eicosatrienol - Prostaglandin metabolism 1 Epiandrosterone sulfate - Steroid metabolism 1 Fructose-1-phosphate - RCC 1 N/A - Sugar 1 Lactitol - Sugar alcohol CRC 1 N/A Piperidine - Possibly derived from food 1 Propylene - Unlikely to be formed in human metabolism 1 Pyrosine - 1 Sphingomyelines1 - Sphingolipid Bladder, RCC 1 Tridecanoic acid - Fatty acid RCC 1 2-Deoxyribonic acid - Formed during DNA damage 1 Trimethylamine-N-oxide C01104 Choline metabolism CRC 1 Various (>5 diseases) Trimethyl-lysine C03793 Carnitine metabolism 1 Tryptophan-betaine - Tryptophan metabolism 1 - Sugar 1 Urobilinoids - 1 Vaccenic acid C08367 Fatty acid 1 Xanthine C00262 Nucleotide/ nucleoside metabolism 1

19 Metabolomics in cancer research: Supplementary data

Metabolite KEGG ID Metabolic class, pathway or comment Cancer Reported Disease endpoints associated (only validated studies) Frequency with altered concentrations (HMDB)

Xylitol C00379 Sugar alcohol 1 C00310 Sugar 1 2-Hydroxy-3-methylpentanoic acid - Isoleucine metabolism 1 1-Hexadecanol C00823 Alcohol Breast 1 N/A 11-14-Eicosadienoic acid - Fatty acid 1 1-O-Heptadecylglycerol - 1 1-Monooleylglycerol - Fatty acid metabolism 1 Cortisol C00735 Steroid 1 Glucuronolactone C02670 Ascorbate and aldarate metabolism Nasopharyngeal 1 N/A N-Acetyl glutamine - Amino acid metabolism 1 Betaine (Trimethylglycine) C00719 Methylation 1 3-Hexaprenyl-4-hydroxy-5- C05313 Ubiquinone biosynthesis 1 methoxybenzoic acid 31 1 Reported as alterations in a substance class; 2 Alkanes might be derived from GC carryover of Kovats mixtures for retention index calibration; CRC: Colorectal cancer; RCC: Renal cell carcinoma

20 Metabolomics in cancer research: Supplementary data

32 Supplementary figures

33

34 Supplementary Figure 1: Workflow for a metabolomic analysis using mass spectrometry based techniques. 35 LLE: Liquid-liquid extraction; SLE: Solid liquid extraction; SPE: Solid phase extraction; SPME: Solid 36 phase micro extraction 37