Table 1.
Summary of metabolomics studies on thyroid cancer in the last 25 years.
| Technique | Method | Study Site | Sample | Study Design | Altered Metabolites | Reference |
|---|---|---|---|---|---|---|
| NMR | MRS | Spatially resolved information | Non-invasive method | 8 TC vs. 5 CTR | Ch ↑ | [46] |
| MRS | Non-invasive method | 8 MN vs. 17 BN | Ch ↑ | [47] | ||
| MRS | Non-invasive method | 8 PTC vs. 18 BN | Ch ↑ | [48] | ||
| 1H-NMR | Tissue | Tissue | 19 MN vs. 24 BN | TGL, K ↑ | [44] | |
| 2D 1H-NMR | Tissue | 32 MN vs. 61 BN | Cross peaks from CHL/cholesteryl esters and di-/TGL ↑; two unassigned cross peaks ↓ | [45] | ||
| HR-MAS-NMR | Tissue | Tissue: 72 TC vs. 28 CTR; Tissue: 38 MN vs. 34 BN; Aspirate ex vivo: 12 TC vs. 12 CTR | Tissue TC vs. CTR: F, Y, S, K, TAU, Q, E, A, I, L and V ↑; Lip ↓. Tissue MN vs. BN: LAC and TAU ↑; Lip, Ch, PC, myo- and scyllo-IST ↓ |
[53] | ||
| HR-MAS-NMR | Tissue | 38 MN vs. 34 BN | F, TAU and LAC ↑; Ch and Ch derivatives, myo- and scyllo-IST ↓ | [54] | ||
| HR-MAS-NMR | Tissue | 52 MN vs. 46 BN | Y, S, A, L, F↑; myo- and scyllo-IST and CIT ↓ | [57] | ||
| 1H-NMR | Tissue extracts | Tissue extracts | 15 TC vs. 19 BN and 27 CTR | CHL ↑; DLC ↓ | [49] | |
| 1H-NMR | Tissue extracts | 45 thyroid lesions vs. 19 CTR from the same participant | M, A, E, G, LAC, Y, F and HPX ↑; ACT ↓ | [58] | ||
| 1H-NMR | Tissue extracts | 32 LNM vs. 20 absence of LNM; 19 lateral LNM vs. 33 absence of lateral LNM |
No statistically altered metabolites | [61] | ||
| 1H-NMR | Tissue extracts | 16 PTC vs. 16 CTR from the same participant | L, V, G, TAU, LAC, Ch, ETA, GPC and LDL↑; CIT, VLDL ↓ | [62] | ||
| 1H-NMR | Tissue extracts | 11 TC vs. 10 CTR from the same participant | LAC, F ↑ | [63] | ||
| 1H-NMR | FNAB | Aspirates | 34 PTC vs. 69 BN | LAC, Ch, O-PC, G↑; CIT, E, Q ↓ | [60] | |
| 31P-NMR | Systemic profiling | Plasma | 16 MN vs. 17 hypothyroid in remission and 14 euthyroidism in remission and 23 healthy euthyroid controls | MN vs. hypothyroid in remission: PE + SM and PC ↓ | [50] | |
| 1H-NMR | Serum | 20 PTC vs. 20 BN and 20 CTR | PTC vs. CTR: V, L, I, LACA, A, E, K, G ↑; Lip, Ch and Y ↓ | [84] | ||
| 1H-NMR | Serum | 17 PTC vs. 17 BN and 20 CTR | PTC vs. BN: KYN, HIP, NIC, XNT ↑; Q, CIT, O-ALC, GSH, W, Y, HoS, β-A ↓ PTC vs. CTR: myo- and scyllo-IST, W, PPN, LAC, HoC, 3-Me GTA, N, D, Ch ↑; ACM ↓ |
[85] | ||
| 1H-NMR | Serum | 41 PTC vs. 55 BN and 40 CTR | L, LAC, A, G, K and Ch ↑; GLU ↓ | [86] | ||
| 1H-NMR | Serum and urine | 17 PTC vs. 33 BN and 17 CTR | PTC vs. CTR: Serum: CRE ↑; V, A, CRN and Y ↓; Urine: CIT and ACT ↓ | [88] | ||
| HR-MAS-NMR | Combination | Tissue and Aspirates | 4 PTC, 4 FA, 5 CTR | NA | [51] | |
| HR-MAS-NMR and 1H-NMR | Tissue and plasma | Tissue: 16 PTMC vs. 11 CTR tissues from the same participants; Plasma: 26 PTMC vs. 17 CTR volunteers | Tissue: F, Y, LAC, S, C, K, Q/E, TAU, L, A, I and V ↑; FA ↓. Plasma: same as tissue as well as GLU, MAN, PYR and 3-HBA ↑ and V, Y, P, K, L ↓ |
[56] | ||
| MS | IMS and MS/MS | Spatially resolved information | Tissue | 7 PTC vs. 7 CTR from the same participants | PC (16:0/18:1) and (16:0/18:2) and SM (d18:0/16:1) ↑ | [71] |
| IMS and MALDI-FTIR MS | Tissue and serum | Tissue: 16 MN vs. 5 BN and 15 CTR Serum: 124 MN vs. 43 BN and 122 CTR |
MN vs. BN: PA (36:2), (36:3), (38:3) ↑ PA (38:4), (38:5), (40:5) ↓ | [72] | ||
| DESI-MS | Tissue | Tissue | 8 PTC vs. 18 CTR lymph nodes from the same participant | Q in adjacent lymph node, GSH, CDL, PI, PS and CER↑ | [73] | |
| AFADESI-IMS | Tissue | 12 PTC vs. 12 CTR from the same participant | F, L, Y ↑; CRE ↓ | [74] | ||
| GC-MS | Tissue extracts | Tissue extracts | 16 PTC vs. 16 CTR from the same participant | MLO, IN, CHL and ARA altered; GLU, FRU, GAL, MAN, 2-keto-D-GLA and RHA ↓ | [76] | |
| GC-TOF-MS and UHPLC-qTOF-MS | Tissue extracts | 57 PTC vs. CTR from the same participant; 48 BN vs. CTR from the same participant | LACA, TCA cycle intermediates, Aa, one-carbon metabolism ↑, disrupted W metabolism in PTC and BN. TAU and HTAU and ECDA ↑ in only PTC | [109] | ||
| GC-TOF-MS and UHPLC-QqQ-MS | Tissue extracts | Untargeted: 15 PTC vs. 15 CTR from the same participants; Targeted: 10 PTC vs. 10 CTR from the same participants | GOL, MLB and MEL ↓ | [77] | ||
| GC-MS | Formalin-fixed tissue | 7 FTC, 4 PTC, 4 PTC-FV, 6 MTC, 6 ATC, 3 FA, 5 CTR | Cancerous thyroid vs. normal tissue: LACA ↑; several FA and their esters ↓. MN vs. BN: myo-IST Ph, SCA and certain FA and their esters ↑; PTC vs. follicular thyroid lesions: CTA ↑; GLA ↓ |
[78] | ||
| MALDI-Q-Ion Mobility-TOF-MS | Formalin-fixed tissue sections | 3 PTC vs. 3 BN from the same participant | PC (32:0), (32:1), (34:1) and (36:3), SM (34:1) and (36:1) and PA (36:2) and (36:3) ↑ | [75] | ||
| GC-MS | Systemic profiling | Exhaled breath | 39 PTC vs. 25 BN and 32 CTR | PTC vs. BN: 1, 1, 3-triMe-3-(2-Me-2-propenyl) CPT, trans-2-dodecen-1-ol ↑; (3-Me-oxiran-2-yl)-methanol ↓; PTC vs. CTR: PHN, ETG mono vinyl ester, CPR, 1-bromo-1-(3-Me-1-pentenylidene)-2,2,3,3-tetraMe CPR ↑; CHX, 4-HBA, 2,2-dimethyldecane, ETH ↓ | [93] | |
| GC-MS | Plasma | 19 PTC vs. 16 BN and 20 CTR | PTC vs. BN: SUC ↑; PTC vs. CTR: E, α-KTG, AD-5 monoPh, 3-HBA, CPA, URA ↑; CYS, C↓ | [83] | ||
| nUHPLC-ESI-MS/MS | Plasma | 10 TC vs. 74 other cancers and 20 CTR | TC vs. other cancers and CTR: Lyso PI (18:0) and (18:1) | [91] | ||
| LC-LTQ Orbitrap MS | Serum | 30 PTC vs. 80 BN and 30 CTR | FA, AC, SPG (SPG, SPG-1-Ph), OLM and 3-HBA ↑ | [52] | ||
| GC-TOF-MS | Serum | 37 PTC-DM vs. 40 PTC-AB | N, GABA, AOA, 4- DOP ↑; PGA ↓ | [79] | ||
| LC-DIA-MS | Serum | 30 PTC vs. 27 CTR | 392 significantly changed metabolites | [68] | ||
| UPLC-QTOF-MS | Fecal matter | 15 TC vs. 15 CTR | 3,7,11,15-tetraMe-6,10,14-hexadecatrien-1-ol, TGL (16:0/16:1(9Z)/18:2(9Z, 12Z)), 10-propyl-5,9-tridecadien-1-ol ↑; DHEAS, EPKSI ↓ | [92] | ||
| HUPLC/UHPLC-MS | Serum and urine | 124 PTC vs. 76 BN and 116 CTR | PTC vs. BN and CTR: Serum β-HBA, DHA, 1-MeAD ↑, pregnanediol-3-GLC, urinary NIC mononucleotide and XNTO ↓ | [89] | ||
| UPLC-Q/TOF-MS | Tissue and systemic profiling | Tissue, serum and plasma | 141 PTC vs. 93 BN and 100 CTR plus validation sets in 6 independent centers | PTC vs. CTR: Serum: 17 significantly changed metabolites; Plasma: 42 significantly changed metabolites, such as PB, L-E ↑; myo-IST, alpha-N-phenylacetyl-L-Q, lyso PC (18:0) and (18:1) ↓ PTC vs. BN: No significant differences in serum/plasma; Tissue: 16 significantly changed metabolites |
[90] | |
| GC-MS | Culture cells | Thyrospheres with cancer stem-like cells | Cancer thyrospheres vs. cancer parental adherent cells and to non-cancer thyrospheres | SCA, MLI, D, E ↑; GLU, PYR, FRU ↓ | [80] | |
| NMR and MS |
1H-NMR and GC−FID/MS |
Tissue extracts | Tissue extracts | 53 thyroid lesions vs. 46 CTR from the same participant | Ch, PC, GPC, PEA, LAC, GSH, TAU, myo- and scyllo-IST, IN, FUM, URD and Aa ↑; Lip ↓ | [59] |
| Other | FT-Raman | Tissue | Tissue | 6 MN vs. 10 BN | T3 and T4 hormones ↑ | [43] |
| Hyperspectral Raman microscopy | Tissue extracts | Single cells | 5 PTC vs. 5 BN | Lip; Nuc ↑; F, W, Prot, ↓ | [42] | |
| Capillary electrophoresis | Systemic profiling | Urine | 12 TC vs. 12 CTR | IN, N2-MG, N2,N2-DMG, 1-MG ↑ | [87] | |
| Amino acid analyser | Plasma | 33 TC vs. 137 CTR | M, L, Y and K ↑ | [70] |
Study design abbreviations: AB, ablation; ATC, anaplastic thyroid carcinoma; BN, benign; CTR, healthy controls; DM, distant metastasis; FA, follicular adenomas; FTC, follicular thyroid carcinoma; LNM, lymph node metastasis; MN, malignant; MTC, medullary thyroid carcinoma; NA, not applicable; PTC, papillary thyroid carcinoma; PTC-FV, papillary thyroid carcinoma follicular variant; PTMC, papillary thyroid microcarcinoma; TC, thyroid carcinoma. Altered metabolites abbreviations: ACT, Acetone; ACM, Acetamide; ALC, Acetylcarnitine; AC, Acylcarnitine; AD, Adenosine; A, Alanine; Aa, Aminoacids; AOA, Aminooxyacetic acid; ARA, Arachidonic acid; N, Asparagine; D, Aspartate; CPA, Capric acid; CDL, Cardiolipin; CER, Ceramide; CHL, Cholesterol; Ch, Choline; CIT, Citrate; CTA, Citric acid; CRE, Creatine; CRN, Creatinine; CHX, Cyclohexanone; CPT, Cyclopentane; CPR, Cyclopropane; C, Cysteine; CYS, Cystine; DHEAS, Dehydroepiandrosterone sulfate; DOP, Deoxypyridoxine; DMG, Dimethylguanosine; DHA, Docosahexaenoic acid; DLC, Dolichol; ECDA, Eicosadienoic acid; EPKSI, Epimedokoreanoside I; ETA, Ethanolamine; ETG, Ethyleneglycol; ETH, Ethylhexanol; FA, Fatty acids; FRU, Fructose; FUM, Fumarate; GAL, Galactose; GOL, Galatinol; GABA, Gamma-aminobutyric acid; GLA, Gluconic acid; GLU, Glucose; GLC, Glucuronide; E, Glutamic acid; Q, Glutamine; GTA, Glutaric acid; GSH, Glutathione; GPC, Glycerophosphocholine; G, Glycine; HIP, Hippurate; HoC, Homocysteine; HoS, Homoserine; HBA, Hydroxybutyric acid; HTAU, Hypotaurine; HPX, Hypoxanthine; IN, Inosine; IST, Inositol; I, Isoleucine; KTG, Ketoglutarate; KYN, Kynurenine; LAC, Lactate; LACA, Lactic acid; L, Leucine; Lip, Lipids; LDL, Low density lipoprotein; K, Lysine; MLI, Malic acid; MLO, Malonic acid; MAN, Mannose; MEL, Melatonin; MLB, Melibiose, M, Methionine; Me, Methyl; MG, Methylguanosine; NIC, Nicotinic acid; Nuc, Nucleic acids; OLM, Oleamide; PHN, Phenol; F, Phenylalanine; Ph, Phosphate; PA, Phosphatidic acids; PC, Phosphatidylcholine; PE, Phosphatidylethanolamine; PI, Phosphatidylinositol; PS, Phosphatidylserine; PEA, Phosphoethanolamine; P, Proline; PB, Proline betaine; PPN, Propionate; Prot, Proteins PGA, Pyroglutamic acid; PYR, Pyruvate; RHA, Rhamnose; S, Serine; SM, Sphingomyelin; SPG, Sphingosine; SCA, Succinic acid; SUC, Sucrose; TAU, Taurine; TGL, Triglyceride; W, Tryptophan; Y, Tyrosine; URA, Uracil; URD, Uridine; V, Valine; VLDL, Very low density lipoprotein; XNT, Xanthine; XNTO, Xanthosine.