Table 3. Metabolomics of fluid-based biomarkers for lung cancer beyond blood.
| Biomarkers | Sample | Method | Group (N) | Performance | Confounding factors† | Reference |
|---|---|---|---|---|---|---|
| 2 metabolites model: creatine riboside(↑), N-acetylneuraminic(↑) | Urine | LC-MS | Discovery set: NSCLC =469; Healthy =536. Validation set: NSCLC =80; Healthy =78 | CREATINE riboside: P<0.00001***; N-acetylneuraminic acid: P<0.00001***; creatine riboside: P<0.00001***; N-acetylneuraminic acid: P<0.00001*** | Age, gender, ethnicity (matched), smoking status (adjusted) | (45) |
| Carnitine(↑), acylcarnitines(↓) | Urine | UHPLC-Q-TOF-MS/MS | NSCLC =20; Healthy =20 | AUC =0.958 | Age, gender | (46) |
| 4 metabolites model: 1-methylhistidine(↑), xanthosine(↓), 8-hydroxynevirapine(↓), tyrosyl-tyrosine(↓) | Urine | UPLC-Q-TOF/MS | Discovery set: NSCLC =30; Healthy =30. Validation set: NSCLC =38; Healthy =42 | 1-methylhistidine: AUC =0.95; xanthosine: AUC =0.874; 8-hydroxynevirapine: AUC =0.867; tyrosyl-tyrosine: AUC =0.822 | Age (matched), gender, smoking status | (47) |
| 4-Methoxyphenylacetic acid | Urine | 1H NMR | NSCLC =28; Healthy =17 | AUC =0.85 | Age (P=0.022*), gender (matched), smoking status | (48) |
| PGE-major urinary metabolite (PGE-MUM)(↑) |
Urine | Radioimmunoassay | NSCLC =369 | Pre-op: P=0.005 (**), HR =3.017 (95% CI: 0.135–24.47); Post-op: P=0.027 (*) (95% CI: 1.284–32.49) | Gender (P=0.006**); smoking status (P=0.002**) | (49) |
| 2 metabolites model: creatine riboside(↑), N-acetylneuraminic(↑) | Urine | UPLC-MS/MS | LC =178; Healthy =351 | Creatine riboside: AUC =0.84; N-acetylneuraminic acid: AUC =0.90 | Age, gender, ethnicity (P>0.05); smoking status (P<0.0001***) | (50) |
| Ganglioside GM1 (18:1/12:0) | Sputum | FIE-MS and GC-MS | LC =23; Healthy =33 | AUC =0.854 | Age, gender, smoking status | (51) |
| ANN model; 6 metabolites model: phenylacetic acid, L-fucose, caprylic acid, acetic acid, propionic acid, and glycine | Sputum | FIE-MS | LC =23; Healthy =33; SCLC =5; NSCLC =17 | AUC =0.99, sensitivity 96%, specificity 94%. AUC =1.00, sensitivity 80%, specificity 100% | Age (P>0.05), gender (P>0.05) | (52) |
| 5 metabolites model: hydroxyphenyllactic acid(↑), phytosphingosine(↑), N-nonanoylglycine(↑), sphinganine(↑), S-carboxymethyl-L-cysteine(↑) | Sputum | LC-MS | LC =76; Healthy =67 | Hydroxyphenyllactic acid: P=1.08E−08***; phytosphingosine: P=1.15E−07***; N-nonanoylglycine: P=1.88E−09***; sphinganine: P=1.06E−08***; S-carboxymethyl-L-cysteine: P=8.67E−09*** | Age (matched) gender, smoking status |
(53) |
| 4 metabolites model: diethanolamine(↑), cytosine(↓), lysine(↓), tyrosine(↑) | Saliva | CE-MS | LC =41; benign lung lesion = 21 | Diethanolamine: AUC =0.612; cytosine: AUC =0.586; lysine: AUC =0.620; tyrosine: AUC =0.618 | Age, gender | (54) |
| Glycerol and phosphoric acid | BALF | DI-ESI-QTOF-MS and GC-MS | LC =24; benign lung lesion =31 | Glycerol: AUC =0.88, sensitivity 80%, specificity 90%; phosphoric acid: AUC =0.79, sensitivity 80%, specificity 60% | Age, gender | (55) |
| Phosphoric acid(↓), isocitric acid(↓), inositol(↓), L-Glycine(↓) | Serum, urine, BALF | GC-MS | LC =32; Healthy =29 | Phosphoric acid: AUC =0.79; isocitric acid: AUC =0.57; inositol: AUC =0.58; L-Glycine: AUC =0.74 | Not available | (56) |
| Oleic acid (18:1, free fatty acid)(↑), ceramide (d18:1/16:0)(↓) | Pleural effusion | LC-MS/MS | LC =32; tuberculosis =18 | Oleic acid: AUC =0.962; ceramide: AUC =0.854 | Age, gender (P>0.05) | (57) |
†, this column summarizes whether confounding variables (e.g., age, gender, smoking status, comorbidities) were reported or statistically controlled; *, P<0.05; **, P<0.01; ***, P<0.001. ↑, upregulated in LC; ↓, downregulated in LC. AUC, area under the curve; BALF, bronchoalveolar lavage fluid; CE-MS, capillary electrophoresis-mass spectrometry; CI, confidence interval; DI-ESI-QTOF-MS, direct infusion high resolution mass spectrometry; FIE-MS, flow infusion electrospray ionization mass spectrometry; GC-MS, gas chromatography-mass spectrometry; HR, hazard ratio; LC, lung cancer; LC-MS, liquid chromatography-mass spectrometry; LC-MS/MS, liquid chromatography-tandem mass spectrometry; NSCLC, non-small cell lung cancer; PGE, prostaglandin E; PGE-MUM, prostaglandin E-major urinary metabolite; Post-op, postoperative; Pre-op, preoperative; SCLC, small cell lung cancer; UHPLC-Q-TOF-MS/MS, ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry; UPLC-MS/MS, ultra-performance liquid chromatography-tandem mass spectrometry; UPLC-Q-TOF/MS, ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry; 1H-NMR, proton nuclear magnetic resonance.