Oncometabolites as biomarkers in thyroid cancer: a systematic review

Figures & data

Figure 1 Several metabolic pathways in normal and cancer cells.

Abbreviation: TCA, tricarboxylic acid.

Figure 2 Flow diagram of study selection for the current systematic review.

Table 1 Thirteen targeted studies related to the cometabolites in TC

	Title of article	First author	Year	Country	Sample size	Type of study	Metabolite measurement techniques	List of targeted metabolites	Significant different metabolites
1.	Unbalanced estrogen metabolism in TC^Citation36	Muhammad Zahid	2013	USA (Omaha)	n: 40 TC n: 40 HI	Case/control	ULC TMS	Catechol estrogen quinones, estrogen-3,4-quinines, 38 estrogen metabolites (conjugates and DNA adducts) Estrogens (E1 and E2)	Estrogen metabolites
2.	A SSEAT for “Functional” BiomarkerDiscovery^Citation37	Josep Villanueva	2008	USA (New York)	n: 48 metastatic TC n: 48 HI	Case/control	MALDI-TOF MS	Fibrinogen α, C3f (complement C3), complement C4 precursor ITIH4, apolipoprotein A-IV Clusterin precursor, C-terminus of β-chain minus Arg-transthyretin precursor	N/A
3.	Human IgG Fc-glycosylation profiling reveals associations with age, sex, female sex hormones, and TC^Citation38	Guoqiang Chen	2012	China	n: 138 TC	Case/control	MALDI-FTICR	Seven glycosylation features for IgG	Fc-glycosylation
4.	Multicompartment metabolism in papillary thyroid cancer^Citation39	Joseph M. Curry	2016	USA	n: 27 NTC n: 6 FA n: 5 MNG	Case/control	IHC	TOMM20 MCT4	Multiple tumor compartments with glycolysis in fibroblasts and OXPHOS
5.	Biochemical markers in the follow-up of medullary thyroid cancer^Citation40	Jan Willem B. de Groot	2006	The Netherlands	n: 46 MTC	Prospective study	GC	Calcitonin and CEA, plasma tryptophan Plasma platelet serotonin, urine 5-hydroxyindole acetic acid, MIMAA, 3-MT, HVA, VMA, VA, MOPEG, DOPAC	Plasma calcitonin Carcinoembryonic antigen, chromogranin A
6.	Predictive value of sphingosine kinase 1 expression in papillary thyroid carcinoma^Citation41	SUNG-IM DO	2017	Korea	n: 110 PTC n: 16 MNG n: 81 NTC	Case/control	IHC	Sphingosine kinase 1 metabolites	Sphingosine kinase 1
7.	Metabolic changes enhance the cardiovascular risk with differentiated thyroid carcinoma – a case–control study from Manipal Teaching Hospital of Nepal^Citation42	Ankush Mittal	2012	Nepal	n: 50 DTC n: 50 HI	Case/control	ELISA CHOD-PAP and GPO-PAP method	fT3, fT4, TSH, total cholesterol Triglycerides, HDL, LDL, VLDL glucose, insulin, fibrinogen CRP	Hypercoagulable state Atherogenic lipid profile
8.	3, 30-Diindolylmethane modulates estrogen metabolism in patients with TPD: a pilot study^Citation43	Shilpi Rajoria	2011	New York, New Jersey	n: 7 TPD	Clinical trial study (a pilot study)	GC-MS	Estrogen metabolites 2-hydroxyestrones (C-2) 16α-hydroxyestrone (C-16)	Antiestrogenic activity that results in more of C-2 product compared with C-16
10.	Perioperative dynamics and significance of amino acid profiles in patients with cancer^Citation45	Yu Gu	2015	China	n: 56 GC n: 28 BC n: 33 TC	Case/control	Amino acid analyzer with spectrophotometrical detection	PFAAs (Asp, Thr, Ser, Glu, Gly, Ala, Cys, Val, Met, Ile, Leu, Tyr, Phe, Lys, His, Arg, Pro, NH3, NEAAs, EAAs, BCAAs, GAAs, TAAs)	PFAA
11.	Estrogens in female TC: alteration of urinary profiles in preoperative cases and postoperative cases^Citation46	Seon Hwa Lee	2003	South Korea	n: 18 premenopausal PTC women (preoperative and postoperative patients in luteal phase)	Case/control	Highly sensitive GC-MS	Estrogen metabolites 16alpha-OH E1/2-OH E1 Catechol estrogens (2-OH E1)	2-hydroxylation in estrogen metabolism
12.	Increased expression of phosphatidylcholine (16:0/18:1) and (16:0/18:2) in thyroid papillary cancer^Citation47	Seiji Ishikawa	2012	Japan	n: 7 TC cases	Case series	HE-stained, tandem mass (MS/MS) analysis, imaging mass spectrometry analysis	Phosphatidylcholine (16:0/18:1), phosphatidylcholine (16:0/18:2), sphingomyelin (d18:0/16:1)	Phosphatidylcholine Sphingomyelin
13.	Application of metabolomics in prediction of lymph node metastasis in papillary thyroid carcinoma^Citation48	Ji Won Seo	2018	Korea	n: 52 metastatic PTC	Case series	H-NMR spectroscopy	Isoleucine, leucine, valine, lactate, threonine, alanine, uracil, lysine, glutamate, methionine, aspartate, choline, phosphocholine, glycerophosphocholine, taurine, myo-inositol, glycine, phosphoethanolamine, inosine, thyrosine, hypoxanthine, formate, succinate, uridine	Lactate

Abbreviations: 3-MT, 3-methoxytyramine; aMT6, melibiose 6-sulfatoxymelatonin; BC, breast cancer; CEA, carcinoembryonic antigen; C3f, complement C3f; DOPAC, 3,4-Dihydroxyphenylacetic acid; DTC, differentiated thyroid carcinoma; FPA, fibrinogen α; fT3, free triiodothyronine; fT4, free thyroxine; GC, gastric cancer; GC-MS, gas chromatography–mass spectrometry; GC-TOF-MS, gas chromatography–time-of-flight mass spectrometry; GLA, alpha-galactosidase; HDL, high-density lipoprotein; HI, healthy individual; HVA, homovanillic acid; IHC, immunohistochemistry; ITIH4, inter-α-trypsin inhibitor heavy chain H4; LDL, low-density lipoprotein; MALDI-FTICR, matrix-assisted laser desorption ionization–Fourier transform ion cyclotron resonance; MALDI-TOF MS, matrix assisted laser desorption ionization–time of flight mass spectrometry; MCT4, monocarboxylate transporter 4; MIMAA, N’-methylimidazole acetic acid; MNG, multinodular goiter; MOPEG: 3-methoxy-4-hydroxyphenylglycol; MTC, medullary thyroid cancer; N/A, not applicable; NAT, normal adjacent tissue; NTC, noncancerous thyroid tissue; OA, oxaloacetate; OXPHOS, Mitochondrial oxidative phosphorylation; PFAA, plasma-free amino acid; PHE, phenylalanine; PTC, papillary thyroid carcinoma; PUFA, polyunsaturated fatty acid; SSEAT, Sequence-specific Exopeptidase Activity Test; TC, thyroid cancer; TMS, tandem mass spectrometry; TOMM20, translocase of outer mitochondrial membrane 20; TSH, thyroid-stimulating hormone; TPD, thyroid proliferative disease; ULC, ultra performance liquid chromatography; VA, valine; VLDL, very-low-density lipoprotein.

Table 2 The list of 16 untargeted studies related to the cometabolites in TC

	Title of article	First author	Year	Country	Sample size	Type of study	Metabolite measurement techniques	Significant different metabolites
1.	Development of data independent acquisition workflows for metabolomic analysis on a quadrupole-orbitrap platform^Citation49	Juntuo Zhou	2017	China	n: 30 TC n: 27 HI	Case/control	LC-DIA-MS	Carnitine Trimethylamine N-oxide Some amino acids
2.	Analysis on the metabolite composition of serum samples from patients with papillary thyroid carcinoma using NMR^Citation50	Wen-Xin Zhao	2015	China	n: 20 PTC n: 20 BTN n: 20 HI	Case/control	NOEPR-CPMG NMR	A list of metabolites involves glucose metabolism, lipids, amino acids, and nucleic acid
3.	Detection of metastatic breast and TC in lymph nodes by desorption electrospray ionization mass spectrometry imaging^Citation51	Jialing Zhang	2017	USA	n: 18 NLN n: 8 LNMP n: 16 LNMBC	Case/control	DESI-MS	Ceramides Glycerophosphoinositol
4.	Serum metabolic profiling and features of papillary thyroid carcinoma and nodular goiter^Citation52	Zhenzhen Yao	2011	China	n: 30 PTC n: 80 MNG n: 30 HI	Case/control	Liquid chromatography-LTQ Orbitrap MS	3-Hydroxybutyric acid
5.	Distinct metabolomic profiles of papillary thyroid carcinoma and benign thyroid adenoma^Citation53	Yanan Xu	2015	China	n: 57 PTC n: 48 BTA	Case/control	GC-TOFMS UPLC–Q-TOF-MS	Purine and pyrimidine metabolites Taurine Hypotaurine
6.	Serum and urine ^1H NMR-based metabolomics in the diagnosis of selected thyroid diseases^Citation54	Wojciech Wojtowicz	2017	Poland	n: 20 NN n: 13 FA n: 17 TC n: 17 HI	Case/control	NMR	Amino acids: alanine, creatine, glutamine, tyrosine, valine Carboxylic acids: acetate, citrate, formate, lactate Monosaccharides: glucose Alcohols: glycerol Imidazolinones: creatinine
7.	Metabolic alteration of urinary steroids in premenopausal and postmenopausal women and men with papillary thyroid carcinoma^Citation55	Man Ho Choi	2011	Korea	n: 21 premenopausal female n: 19 postmenopausal female n: 16 male PTC	Case/control	GC-MS	Androgens Androstenedione Androstenediol 16α-hydroxy DHEA Corticoid
9.	Metabolomics approach to thyroid nodules: a high-resolution magic-angle spinning NMR-based study^Citation31	Paolo Miccoli	2012	Italy, France, Brazil	n: 28 PTC n: 40 FA n: 4 BN	Case/control	HRMAS HRMAS-NMR	Lactate Taurine Phosphocholine Myo-inositol Scyllo-inositol
10.	Metabolomic analysis of percutaneous fine-needle aspiration specimens of thyroid nodules: potential application for thepreoperative diagnosis of TC^Citation57	Inseon Ryoo	2016	Korea	n: 35 PTC n: 69 BN	Case/control	NMR	Lactate Glycine Citrate Glutamine Glutamate Choline O-phosphocholine
11.	A distinct serum metabolic signature of distant metastatic papillary thyroid carcinoma^Citation58	Chen-Tian Shen	2017	China	n: 37 distant metastatic PTC n: 40 ablation group	Case/control	GC-TOF-MS	Phthalimide, cyclohexanamine, aminooxyacetic acid, 3-hydroxypyruvate, carbamate, canavanine, creatine, asparagine, uridine, 4-deoxypyridoxine, 2-hydroxypyridine, γ-aminobutyric acid, myo-inositol, pyroglutamic acid, stearic acid, palmitic acid, fructose, heptadecanoic acid, phenyl acetate, glycerol-3-phosphate, lactose, arachidic acid, uric acid, valine, palmitoleic acid, γ-linoleic acid, parabanic acid, picolinic acid, oxalic acid, uracil, d-altrose
12.	Toward the reliable diagnosis of indeterminate thyroid lesions: a HRMAS NMR-based metabolomics case of study^Citation59	Liborio Torregrossa	2012	Italy, France, Brazil	n: 72 PTC	Case series	HRMAS	↑ PHE, taurine, and lactate ↓ Choline and choline derivatives ↓ myo- and scyllo-inositol
13.	Exhaled breath volatile biomarker analysis for TC^Citation60	Lei Guo	2015	China	n: 39 PTC n: 25 MNG	Case/control	GC/MS	Sulfurous acid, cyclohexylmethyl hexyl ester, isolongifolene-5-ol, 3,5-Decadien-7-yne, 6-t-butyl-2,2,9,9-tetramethyl, cyclohexanone, 4-hydroxybutyric acid, phenol, 2,2-dimethyldecane, ethylhexanol, ethylene glycol mono vinyl ester, cyclopropane, 1-bromo-1-(3-methyl-1-pentenylidene)–2,2,3,3-tetramethyl, (3-Methyl-oxiran-2-yl)-methanol, cyclopentane, 1,1,3-trimethyl-3-(2-methyl-2-propenyl), trans-2-dodecen-1-ol
14.	Association of PBDEs and hydroxylated metabolites (OH-PBDEs) serum levels with thyroid function in TC patients^Citation61	Sisi Lui	2017	China	n: 33 PTC	Case series	Chemiluminescence enzyme immunoassay	Diphenylethers (PBDEs) Hydroxylated metabolites (OH-PBDEs)
15.	Noninvasive diagnosis of papillary thyroid microcarcinoma: a NMR-based metabolomics approach^Citation62	Jinghui Lu	2016	China, Italy	n: 35 PTC	Case series	HRMAS H-NMR	Lysine Glutamate Tyrosine Catecholamines (dopamine, norepinephrine, and epinephrine)
16.	Follicular adenomas exhibit a unique metabolic profile. ^1H NMR studies of thyroid lesions^Citation63	StanisławDeja	2013	Poland	n: 45 TC n: 19 HI	Cohort	H-NMR	Isoleucine, valine, alanine, NACs, methionine, citrate, creatine, choline, GPC, scyllo-inositol, taurine, glycine, myo-inositol, lactate, histidine, tyrosine, phenylalanine

Abbreviations: BN, benign nodule; BTA, benign thyroid adenoma; BTN, benign thyroid nodule; DESI-MS, desorption electrospray ionization mass spectrometry; DHEA, dehydroepiandrosterone; FA, follicular adenoma; GC-TOF-MS, gas chromatography–time-of-flight mass spectrometry; GC-MS, gas chromatography–mass spectrometry; HI, healthy individual; HRMAS, high-resolution magic angle spinning; LC-DIA-MS, liquid chromatography–data independent-mass spectrometry; LNMBC, lymph node with metastatic breast cancer; LNMP, lymph node with metastatic NAC, N-acetyl-cysteine; PHE, phenylalanine; PTC; MNG, multinodular goiter; NAT, normal adjacent tissue; NOEPR, nuclear over Hauser effect spectroscopy with P re-saturation; CPMG, Carr-Pure-Me boom-Gill sequence; NLN, normal lymph node; NMR, nuclear magnetic resonance; NN, non-neoplastic nodule; OH-PBDE, hydroxylated polybrominated diphenylether; PBDE, polybrominated diphenylether; PTC, papillary thyroid carcinoma; TC, thyroid cancer; UPCL-Q-TOF-MS, The ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry.

ZahidMGoldnerWBeselerCLRoganEGCavalieriELUnbalanced estrogen metabolism in thyroid cancerInt J Cancer201313311n/a9

 Web of Science ®Google Scholar

VillanuevaJNazarianALawlorKYiSSRobbinsRJTempstPA sequence-specific exopeptidase activity test (SSEAT) for “functional” biomarker discoveryMol Cell Proteomics20087350951817986438

 PubMed Web of Science ®Google Scholar

ChenGWangYQiuLHuman IgG Fc-glycosylation profiling reveals associations with age, sex, female sex hormones and thyroid cancerJ Proteomics201275102824283422365975

 PubMed Web of Science ®Google Scholar

CurryJMTassonePCotziaPMulticompartment metabolism in papillary thyroid cancerLaryngoscope2016126102410241826666958

 PubMed Web of Science ®Google Scholar

de GrootJWKemaIPBreukelmanHBiochemical markers in the follow-up of medullary thyroid cancerThyroid200616111163117017123344

 PubMed Web of Science ®Google Scholar

DoSIKimHSKimKPredictive value of sphingosine kinase 1 expression in papillary thyroid carcinomaAnticancer Res201737105399540528982849

 PubMed Web of Science ®Google Scholar

MittalAPoudelBPandeyaDRGuptaSPSathianBYadavSKMetabolic changes enhance the cardiovascular risk with differentiated thyroid carcinoma – a case control study from Manipal Teaching Hospital of NepalAsian Pac J Cancer Prev20121352335233822901217

 PubMedGoogle Scholar

RajoriaSSurianoRParmarPS3,3′-diindolylmethane modulates estrogen metabolism in patients with thyroid proliferative disease: a pilot studyThyroid201121329930421254914

 PubMed Web of Science ®Google Scholar

GuYChenTFuSPerioperative dynamics and significance of amino acid profiles in patients with cancerJ Transl Med20151313525622826

 PubMedGoogle Scholar

LeeSHKimKMJungBHChungWYParkCSChungBCEstrogens in female thyroid cancer: alteration of urinary profiles in pre- and post-operative casesCancer Lett20031891273212445674

 PubMed Web of Science ®Google Scholar

IshikawaSTateyaIHayasakaTIncreased expression of phosphatidylcholine (16:0/18:1) and (16:0/18:2) in thyroid papillary cancerPLoS One2012711e4887323139822

 PubMed Web of Science ®Google Scholar

SeoJWHanKLeeJApplication of metabolomics in prediction of lymph node metastasis in papillary thyroid carcinomaPLoS One2018133e019388329509799

 PubMed Web of Science ®Google Scholar

ZhouJLiYChenXZhongLYinYDevelopment of data-independent acquisition workflows for metabolomic analysis on a quadrupoleorbitrap platformTalanta201716412813628107906

 PubMed Web of Science ®Google Scholar

ZhaoWXWangBZhangLYYanSYYangYHAnalysis on the metabolite composition of serum samples from patients with papillary thyroid carcinoma using nuclear magnetic resonanceInt J Clin Exp Med20158101801326770396

 PubMed Web of Science ®Google Scholar

ZhangJFeiderCLNagiCDetection of metastatic breast and thyroid cancer in lymph nodes by desorption electrospray ionization mass spectrometry imagingJ Am Soc Mass Spectrom20172861166117428247296

 PubMed Web of Science ®Google Scholar

YaoZYinPSuDSerum metabolic profiling and features of papillary thyroid carcinoma and nodular goiterMol Biosyst2011792608261421713270

 PubMedGoogle Scholar

XuYZhengXQiuYJiaWWangJYinSDistinct metabolomic profiles of papillary thyroid carcinoma and benign thyroid adenomaJ Proteome Res20151483315332126130307

 PubMed Web of Science ®Google Scholar

WojtowiczWZabekADejaSSerum and urine 1H NMR-based metabolomics in the diagnosis of selected thyroid diseasesSci Rep201771910828831094

 PubMedGoogle Scholar

ChoiMHMoonJYChoSHChungBCLeeEJMetabolic alteration of urinary steroids in pre- and post-menopausal women, and men with papillary thyroid carcinomaBMC Cancer201111134221824401

 PubMedGoogle Scholar

MiccoliPTorregrossaLShintuLMetabolomics approach to thyroid nodules: a high-resolution magic-angle spinning nuclear magnetic resonance-based studySurgery201215261118112423158182

 PubMed Web of Science ®Google Scholar

RyooIKwonHKimSCMetabolomic analysis of percutaneous fine-needle aspiration specimens of thyroid nodules: potential application for the preoperative diagnosis of thyroid cancerSci Rep2016613007527440433

 PubMedGoogle Scholar

ShenCTZhangYLiuYMA distinct serum metabolic signature of distant metastatic papillary thyroid carcinomaClin Endocrinol2017876844852

 PubMed Web of Science ®Google Scholar

TorregrossaLShintuLNambiath ChandranJToward the reliable diagnosis of indeterminate thyroid lesions: a HRMAS NMR-based metabolomics case of studyJ Proteome Res20121163317332522509853

 PubMed Web of Science ®Google Scholar

GuoLWangCChiCExhaled breath volatile biomarker analysis for thyroid cancerTransl Res2015166218819525666355

 PubMed Web of Science ®Google Scholar

LiuSZhaoGLiJAssociation of polybrominated diphenylethers (PBDEs) and hydroxylated metabolites (OH-PBDEs) serum levels with thyroid function in thyroid cancer patientsEnviron Res20171591828759783

 PubMed Web of Science ®Google Scholar

LuJHuSMiccoliPNon-invasive diagnosis of papillary thyroid microcarcinoma: a NMR-based metabolomics approachOncotarget20167498176827835583

 PubMedGoogle Scholar

DejaSDawiskibaTBalcerzakWFollicular adenomas exhibit a unique metabolic profile. 1H NMR studies of thyroid lesionsPLoS One2013812e8463724376829

 PubMed Web of Science ®Google Scholar