Table 2.
Prognostic biomarkers.
| References | Cancer Type | Biomarker Name-Gene | Function | Sample Type | Biomarker Behavior |
Application |
|---|---|---|---|---|---|---|
| [24] | HNSCC | Methylation signature of the promoter of 5 genes, GATA4, GRIA4, IRX4 ALDH1A2, OSR2 | GATA4: encodes GATA binding protein 4, a member of the GATA family of zinc-finger transcription factors. GRIA4: encodes a glutamate receptor. IRX4: encodes Iroquois homeobox 4. ALDH1A2: encodes aldehyde dehydrogenase 1 family member A2, an enzyme that catalyzes the synthesis of retinoic acid from retinaldehyde. OSR2: odd-skipped related transcription factor 2. |
Tissue | GATA4, GRIA4, IRX4: promoter hypermethylation. ALDH1A2 and OSR2: promoter hypomethylation. |
Prognosis |
| [25] | HNSCC | FAM135B | Involved in the maintenance of the nucleolus, cell proliferation, cell differentiation, and apoptosis. | Tissue | hypermethylation → favorable prognostic feature | Prognosis |
| [26] | HNSCC | HOXA9 | Encodes a transcription factor involved in the maintenance of the nucleolus, in cell proliferation and differentiation, and in apoptosis. | Tissue | Promoter hypermethylation → progression and metastasis. | Prognosis |
| [28] | HNSCC | PROM1/ CD133 | Encodes a pentaspan membrane glycoprotein, often expressed on adult stem cells. | Tissue | Promoter hypermethylation-low expression → poor overall survival and relapse-free survival. | Prognosis |
| [29] | HNSCC | CTHRC1 | Encodes an extracellular matrix protein, involved in the modulating of the tumor microenvironment. | Tissue | Overexpression → decreased overall survival (OS). |
Prognosis |
| [30] | HNSCC | PLAU | Encodes a protease, involved in apoptosis, epithelial–mesenchymal transition (EMT), and Ras/MAPK pathway. | Tissue | Hypomethylation → higher clinical stage, more aggressive metastatic disease. Hypermethylation → increased survival time. |
Prognosis |
| [31] | HNSCC | MTHFD1L | Encodes a cytoplasmic enzyme, involved in the formation of tetrahydrofolate (THF) within mitochondria. | Tissue | High expression → decreased OS. | Prognosis |
| [32] | HNSCC | opioid receptor mu 1(OPRM1) | Encodes an opioid receptor (G-protein-coupled receptor). | Tissue, plasma |
Hypermethylation → aggressive clinical behavior. | Prognosis |
| [32] | HNSCC | opioid-related nociceptin receptor 1(OPRL1) | Encodes an opioid receptor (G-protein-coupled receptor). | Tissue, plasma |
Hypermethylation → aggressive clinical behavior. | Prognosis |
| [33] | HNSCC | XPR1 | Encodes a cell surface receptor for certain types of murine leukemia viruses that is involved in the maintenance of the intracellular phosphate homeostasis by mediating phosphate export from the cell. | Tissue | High expression → lower OS, DSS and PFI. | Prognosis |
| [34] | Oral and oropharyngeal squamous cell carcinoma (OSCC) | p16INK4A p14ARF | Tumor suppressors, encode cell cycle regulatory proteins. | Tissue | Promoter hypermethylation-low expression. P16 promoter hypermethylation → progression of premalignant lesions to OSCC, advanced disease, local recurrence, and lower DSS (disease-specific survival). |
Prognosis |
| [35] | HNSCC | SST | Tumor suppressor, encodes a growth hormone release-inhibitory factor. | Tissue | Promoter hypermethylation-low expression. Hypermethylation → decreased disease-free survival, tumor recurrence after resection. |
Prognosis |
| [35] | HNSCC | SSTR1 | Tumor suppressor, encodes a somatostatin receptor type 1. | Tissue | Promoter hypermethylation-low expression. Hypermethylation → decreased disease-free survival, tumor recurrence after resection. |
Prognosis |
| [36] | HNSCC | GAL | Tumor suppressor, encodes a 30-amino acid peptide in humans, that targets the galanin system via receptors GALR1, GALR2, and GALR3. |
Tissue | Promoter hypermethylation-low expression. Hypermethylation → reduced disease-free survival. |
Prognosis |
| [36] | HNSCC | GALR1/2 | Tumor suppressors, encode galanin receptors (G protein-coupled receptors). | Tissue | Promoter hypermethylation-low expression. Hypermethylation → reduced disease-free survival. |
Prognosis |
| [37] | OTSCC | MIR10B | Encodes a miRNA that targets oncogenes NR4A3 and BCL2L11. | Tissue | Hypermethylation-low expression → downregulation of NR4A3 and BCL2L11 → better disease-free survival. | Prognosis |
| [37] | OTSCC | FUT3, TRIM5, TSPAN7, MAP3K8, RPS6KA2, SLC9A9, NPAS3 TIMM8A, RNF113A genes |
FUT3: regulates the expression of Lewis antigens in the human Lewis blood group system [54]. TRIM5: acts as a selective autophagy receptor that targets autophagic substrates via direct recognition [55]. TSPAN7: cell surface glycoprotein and may have a role in the control of neurite outgrowth, synaptic transmission, and viral-induced inflammation [56]. MAP3K8: proto-oncogene that participates in the MAP kinase and JNK signaling pathways [57]. RPS6KA2: controls cell growth and differentiation [58]. SLC9A9: autism-risk gene localized in the endosomal system that is involved in the endocytic regulation of autophagy and cell survival [59]. NPAS3: encodes a transcription factor that is expressed in the developing central nervous system [61]. TIMM8A: localizes to the intermembrane space in mitochondria where it functions in the import of nuclear-encoded proteins into the mitochondrial inner membrane [60]. RNF113A: involved in gene regulation and DNA repair [62]. |
Tissue | Methylation signature, differential methylation among the various categories of parameters. | Prognosis |
| [38] | HNSCC | PDCD1 (PD-1) | Programmed cell death protein 1, immune inhibitory receptor (also known as CD279 or PDCD1), a member of the extended CD28/CTLA-4 family, it is stably expressed only on T cells exposed to a chronic antigen. | Tissue | Hypermethylation → shorter OS after surgical resection. | Prognosis |
| [39] | HPV negative hypopharyngeal cancer | COL1A2 | Encodes a fibrillar collagen found in most connective tissues and is the main component of the organic part of bones. | Tissue | Hypermethylation-low expression → reduced survival and a higher likelihood of relapse. | Prognosis |
| [39] | HPV negative laryngeal cancer | COL1A2 | Encodes a fibrillar collagen found in most connective tissues and is the main component of the organic part of bones. | Tissue | Hypermethylation-low expression → worse survival. | Prognosis |
| [39] | HPV negative laryngeal cancer | p16, VEGFR1, VEGFR3, DAPK, TAC1, GALR1, NPY1R, SSTR1 | p16: tumor suppressor gene that prevents oncogenic transformation through the induction of cellular senescence [63]. VEGFR1: stimulates angiogenesis and vascular permeability [64]. VEGFR3: regulates the development and maintenance of the lymphatic system [65]. DAPK: involved in multiple cellular signaling pathways that trigger autophagy, apoptosis, and cell survival [66]. TAC1: functions as a neurotransmitter interacting with both nerve receptors and smooth muscle cells [67]. GALR1: acts as a neuropeptide that modulating various physiological functions, including nociception, cognition, and neuroendocrine regulation [68]. NPY1R: acts as a neuropeptide that regulates several physiological processes including food intake, emotional regulation, and cardiovascular function [69]. SSTR1: neuropeptide that is involved in neurotransmission, secretion, and cell proliferation [70]. |
Tissue | Hypermethylation-low expression → worse survival, higher risk of recurrence. | Prognosis |
| [40] | HNSCC, especially in HPV-negative | PITX1 3 exon | Encodes a transcription factor in embryogenesis that is involved in mouth and hindlimb formation and pituitary development, it is an upstream inducer of RASAL1 and therefore an important mediator of the Ras signaling pathway. | Tissue | Hypermethylation-low expression → increased risk for death. | Prognosis |
| [40] | HNSCC, especially in HPV-negative | C5orf66-AS1 lincRNA | Encodes a long intergenic non-coding RNA, involved in tumorigenesis, likely by acting as (post)-transcriptional regulator of PITX1. | Tissue | Hypermethylation-low expression → increased risk for death. Hypomethylation → better overall survival. |
Prognosis |
| [41] | HNSCC | Methylation signature of ZNF10 TMPRSS12 ERGIC2 RNF215 |
ZNF10: encodes a transcription repressor, involved in development, differentiation, and metabolism. TMPRSS12: encodes a member of the serine protease family that participates in immune response and blood coagulation and production, it is associated with human infertility. ERGIC2 protein: encodes an endoplasmic reticulum (ER) resident protein implicated in protein trafficking between ER and Golgi bodies. RNF125 gene: encodes a novel E3 ubiquitin-protein ligase that may be involved in the T-cell receptor signaling pathway, plays a role in tumorigenesis and metastasis, strengthens p53 degradation, and suppresses p53 function. |
Tissue | Hypermethylation of ZNF10 as well as TMPRSS12 and ERGIC2 → unfavorable prognosis. Hypomethylation-high expression of RNF125 → poorer overall survival. |
Prognosis |
| [42] | HNSCC | IDO1 | Encodes an indoleamine 2,3-dioxygenase (IDO)—an enzyme that limits the rate of conversion of the crucial amino acid tryptophan to kynurenine, it is strongly expressed in many types of tumors and has been shown to play a role in immunosuppression through increased tryptophan metabolism in the tumor microenvironment (TME). Increased expression of IDO1 can result in suppression of anti-tumor T-cells, differentiation of CD4+ T-cells into immunosuppressive regulatory T-cells (Tregs), and polarization of anti-gene cells into a tolerogenic phenotype. | Tissue | Hypermethylation of the lateral promoter → poor overall survival. | Prognosis, |
| [43] | Oral squamous cell carcinoma (OSCC) | Methylation signature of cg17892178 and cg17378966 in NID2 and IDO1 |
NID2: encodes for a cell adhesion protein involved in maintaining the structure of the vascular extracellular matrix [71]. IDO1: rate-limiting enzyme involved in tryptophan catabolism; also acts as an immune checkpoint molecule on the surface of dendritic cells [72]. |
Tissue | AUC = 0.81 indicated that the signature prognostic risk score based on two CpGs was a good prognostic factor of survival in patients with OSCC. | Prognosis |
| [44] | HNSCC | five DMG model PAX9, STK33, GPR150, INSM1, and EPHX3 |
Encode genes that are involved in extracellular matrix, cell adhesion, and immune responses. | Tissue | Hypomethylation of PAX9, STK33, GPR150, INSM1, and EPHX3 → lower survival time and increased tumor-related mortality PAX9, GPR150, INSM1, and EPHX3 with hypermethylation and weak expression and hypomethylation and elevated expression → strongly associated with OS. |
Prognosis |
| [45] | HNSCC | RYR2 | Encodes an important component of the intracellular Ca2+ release pathway, it is associated with the sarcoplasmic or endoplasmic reticulum of various cell types, particularly in cardiomyocytes. | Tissue, cell lines |
Variable methylation profile. Gradual promoter hypermethylation-low expression → upcoming cancerous transformation of dysplastic lesions. |
Prognosis |
| [46] | HNSCC | nuclear factor I (NFI): NFIA, NFIB, NFIC and NFIX | Transcription factors | Tissue | Promoter hypermethylation-low expression. Decreased levels of NFIA, NFIB, and NFIC → shorter overall survival. |
Prognosis |
| [47] | HNSCC | DKK1 | Encodes a protein with inhibitory activity on the Wnt signaling pathway. | Tissue | Promoter hypomethylation-high expression. Overexpression → worse OS-DFS. |
Prognosis |
| [49] | HPV+ OPC |
CALML5 | Encodes a skin-specific calcium-binding protein, which is strongly related to the differentiation of keratinocytes. It is a regulator of the final differentiation of epidermal cells and CALML5 high-density conditions promote the translocation of YAP1 into the cytoplasm. | Tissue, plasma |
Methylation → shorter DFS. | Prognosis |
| [49] | HPV+ OPC |
DNAJC5G | Encodes a protein that inhibits the replication efficiencies of adenovirus, vaccinia virus, and HIV-1. | Tissue, plasma |
Methylation → shorter DFS. | Prognosis |
| [49] | HPV+ OPC |
LY6D | Encodes a membrane-bound protein with a glycosylphosphatidylinositol anchor. It has an important role in the adhesion of head and neck cancer cells to endothelial cells, and is detected of micrometastases in lymph nodes of HNSCC patients. | Tissue, plasma |
Methylation → shorter DFS. | Prognosis |
| [48] | HNSCC | SEC61G | Encodes a transmembrane heterotrimeric channel protein that transports nascent polypeptides and proteins to the ER, mediating membrane protein degradation. | Tissue | Hypomethylation-high expression. Overexpression → worse OS. |
Prognosis |
| [50] | HNSCC | OX40 (TNFRSF4) | Encodes a tumor necrosis factor receptor, which is expressed mainly on the surface of activated T cells and is stimulated by the OX40L ligand, which is found on antigen-presenting cells, activated T cells, lymphoid tissue inductor cells, some endothelial cells, and mast cells. Its up-regulation promotes differentiation, proliferation, and prolonged survival of T cell activation through inhibition of activation-induced cell death as well as stimulation of cytokine production. | Tissue | Promoter hypermethylation → worse overall survival. Higher expression levels → longer overall survival. |
Prognosis, |
| [50] | HNSCC | GITR (TNFRSF18, AITR) | Encodes a tumor necrosis factor receptor, expressed at high levels by regulatory T cells (Tregs) and at lower levels by naïve, effector and memory T cells. The binding of the GITR ligand in conjunction with T cell receptor stimulation induces activation of the MAPK/ERK and NFkB pathway, resulting in immunoregulation of the immune system with T cell proliferation, production of proinflammatory cytokines, enhanced anti-cancer effector function and resistance of CD4+ and CD8+ T cells. GITR promotes anti-cancer immunity by enhancing effector T cell function on the one hand and inhibiting Treg proliferation. | Tissue | Promoter hypermethylation → worse overall survival. Higher expression levels → longer overall survival. |
Prognosis, |
| [51] | Oral Tongue Cancer | RIPOR3 | Encodes a member of the extracellular region, regulates cellular processes in response to stimuli that is associated with immune cell infiltrations. | Tissue | Hypermethylation-low expression. Hypermethylation-low expression → poor prognosis. High expression → higher OS, PFS. |
Prognosis |
| [52] | OSCC | CTLA4 (Cytotoxic T-lymphocyte associated protein 4) |
Encodes a protein that is expressed in activated CD4+ T cells and constitutively expressed in CD4+Foxp3+ Treg cells. It is a potent immune inhibitor by decreasing the onset of T-cell activation mediated by the interactions between antigen presenting cells (APCs) and T cells. | Tissue | Hypomethylation. High expression → higher long-term survival. |
Prognosis |
| [52] | OSCC | GPR29 | Encodes a G protein-coupled receptor. It is a chemokine receptor that is primarily expressed by T cells, immature dendritic cells, and B cells. Its unique partner CCL20 is known to be stably expressed by Th17 cells and secreted by intestinal epithelial cells in response to local enteropathogenic infection. The CCL20-CCR6 axis has a critical role in mucosal immunity, while the increased expression of CCR6 has previously been demonstrated in several cancers, with complicated anti-cancer or pre-cancer potential. | Tissue | Hypomethylation. High expression → higher long-term survival. |
Prognosis |
| [52] | OSCC | TNFSF11 | Encodes a receptor activator of nuclear factor receptor kappa-B ligand (RANKL). It binds to the RANK receptor to modulate differentiation, activation, and survival of osteoclast cells. It has also been implicated in pathways such as the innate immune response, cell proliferation, and apoptosis. | Tissue | Hypomethylation. High expression → higher long-term survival. |
Prognosis |
| [52] | OSCC | ISL1(ISL LIM homeobox 1) | Encodes the LIM-homeodomain transcription factor, which has been involved in many significant biological pathways, such as carcinogenesis, cell invasion, apoptosis, and cancer immunity. | Tissue | Hypermethylation. High expression → higher long-term survival. |
Prognosis |
| [53] | HNSCC | Nine-gene multi-omics signature (methylation status of CEACAM19, KRT17, and ST18) | CEACAM19: immunoglobulin gene encoding for a variety of glycoproteins that are implicated in embryonic development, immunity, and may also serve as receptors for viruses and bacteria [73]. KRT17: involved in the formation and maintenance of several types of skin appendages, specifically in the shape and orientation of hair [74]. ST18: neural zinc finger transcription factor that negatively regulates cell proliferation [75]. |
Tissue | Absence of high methylation of CEACAM19 → poor survival. Low expression of RPL29 and FCGR2C → poor survival. A methylation status greater than 0.625 in CEACAM19 → greater probability of survival. |
Prognosis |