Table 1. Candidate biomarkers for lung cancer early detection and for the management of CT-detected undetermined lung nodules [updated from Seijo et al. (21)].
| Candidates | Biomarker | Target | Phase | References | Trial |
|---|---|---|---|---|---|
| Serum/plasma | |||||
| Specific proteins/AAbs | Three proteins (CEA, CA-125, and CYFRA 21-1) and 1 AAb (NY-ESO-1) | RMS | Clinical validation | (62) | |
| Two proteins (LG3BP and C163A) and clinical features | DIPN | Clinical validation | (63) | NCT01752114 | |
| Seven AAbs (p53, NY-ESO-1, CAGE, GBU4-5, SOX2, HuD, and MAGE A4) | RMS | Clinical validation | (64,65) | NCT01700257 | |
| DIPN | (66) | ||||
| Four AAbs (FCGR2A, EPB41L3, LINGO1, and S100A7L2) | DIPN | Discovery | (67) | ||
| Six proteins (CEA, CA-125, SCC, CYFRA 21–1, NSE, and proGRP) | DIPN | Discovery | (68) | ||
| A signature of complement-derived fragments and tumor-associated proteins | RMS | Discovery | Unpublished | ||
| DIPN | |||||
| Complement fragment C4d | RMS | Discovery | (69) | ||
| DIPN | (70) | ||||
| miRNA | Ratios among 24 miRNAs | RMS | Clinical validation | (4,71,72) | NCT02247453 |
| DIPN | |||||
| Signature of 13 microRNA + 6 for normalization | RMS | Clinical validation | (73-76) | COSMOS II trial | |
| DIPN | |||||
| Signature of 2 microRNA | DIPN | Discovery | (77) | ||
| Signature of 14 microRNA | RMS | Discovery | (78) | ||
| DNA methylation | SHOX2 and PTGER4 methylation | DIPN | Discovery | (79) | |
| Analysis of 11,787 CpG sites across 595 regions in the genome (PanSeer assay) | (80) | ||||
| Circulating tumor nucleic acids | ctDNA; NGS technology | RMS | Discovery | (81,82) | NCT02889978 |
| ctDNA; CAPP-Seq. | DIPN | Clinical validation | (83) | ||
| ctDNA; Lung-CLiP | RMS | Clinical validarion | (84) | ||
| ctDNA; Ion Torrent DNA Sequencing technology | DIPN | Discovery | (85) | ||
| ctDNA; TEC-Seq technology | RMS | Discovery | (86) | ||
| Signature of 29 genes (RNA) | DIPN | Discovery | (87) | ||
| ctDNA mutation and proteins (CA-125, CEA, CA19-9, PRL, HGF, OPN, MPO, and TIMP-1) | DIPN | Discovery | (88) | ||
| Analysis of fragmentation patterns of cell-free DNA | (89) | ||||
| mRNA gene expression classifier | Twenty-three gene classifier | DIPN | Clinical validation | NCT01309087, NCT00746759 | |
| SNPs | Twenty SNPs for COPD and clinical features | RMS | Clinical validation | (90) | NCT01176383 |
| Bronchoscopy, sputum, breath and urine | |||||
| DNA methylation | SHOX2 and RASSF1A methylation | RMS | Discovery | (91) | |
| MiRNA | Signature of 3 microRNA | DIPN | Discovery | (92) | |
| Chromosome aberrations | Chromosome regions copy number or fusions (FISH) | DIPN | Discovery | (93) | |
| Exhaled breath | VOC-nanoparticle biometric tagging (NBT) | DIPN | Discovery | ||
| VOC-field asymmetric ion mobility spectrometry (FAIMS) | Clinical validation | NCT02612532 | |||
| Tumor cells | >700 morphological features (by cell CT) | RMS | Discovery | ||
| DIPN | |||||
| Buccal nanocytology | RMS | Discovery | (94) | ||
| Porphyrin differential uptake by tumor cells | RMS | Discovery | (95) | ||
| Urine markers | Metabolites | RMS | Discovery | (59) | |
| Mixed | |||||
| Array of biospecimens | Gene expression and proteomic signatures in bronchial airway brushing, proteomic and cytokine signatures in serum | DIPN | Clinical validation | (96) | NCT01785342 |
| RMS | Clinical validation | NCT02504697 |
DIPN, diagnosis of indeterminate pulmonary nodules; RMS, risk management in screening context; ctDNA, circulating tumor DNA; NGS, next-generation sequencing; SNP, single-nucleotide polymorphism; COPD, chronic obstructive pulmonary disease.