Understanding the Epitranscriptome for Avant-Garde Brain Tumour Diagnostics
Abstract
:Simple Summary
Abstract
1. Introduction
2. Epitranscriptomic Diversity and the Cellular Roles of RNA Modifications
2.1. N6-Methyladenosine (m6A) RNA Modification
2.1.1. m6A Writers
2.1.2. m6A Readers
2.1.3. m6A ‘Erasers’
2.1.4. Repelled Proteins
2.2. Other RNA Modifications
2.2.1. N6,2-O-Dimethyladenosine: m6Am Modifications
2.2.2. N1-Methyladenosine: m1A Modifications
2.2.3. 5-Methylcytosine (m5C) and 5-Hydroxymethylcytidine (hm5C) Modifications
2.2.4. Adenosine-to-Inosine (A-to-I) Modifications
2.2.5. Pseudouridine (Ψ) Modifications
3. Epitranscriptomics in Neurobiology and Brain Cancer
3.1. m6A Regulators in Neural Development and Physiology
3.2. m6A Regulators in Glioma Stem-like Cells (GSCs) and Tumourigenicity
3.3. m6A Modifications and Regulators in Glioblastoma with Potential Therapeutic Implications for Improving Treatment Response
3.4. Other RNA Modifications Implicated in Glioblastoma Biology and Treatment
4. Epitranscriptomics in Diagnosis
4.1. RNA Methylation Detection Methods
4.2. Epitranscriptomics in Current Diagnostic Approaches
4.3. Epitranscriptomics in Glioma Diagnostics
Increased m6A Regulator(s) | Decreased m6A Regulator(s) | Data Used | Observations/Role | Ref. |
---|---|---|---|---|
YTHDF2 | TCGA, REMBRANDT French, Kawaguchi, Paugh | YTHDF2 is linked to glioma malignancy and invasiveness. | [198] | |
YTHDF2, YTHDF1, METTL3, RBM15, HNRNPC | ALKBH5, WTAP, YTHDC2, ZC3H13 METTL14, FTO | TCGA | YTHDF1 overexpression correlates with the advanced stage of disease. YTHDF1 contributes to glioma progression. | [100] |
eIF3e | Oncomine, TCGA | eIF3 subunits show varied expression in distinct regions of GBM tumours. eIF3e proteins expression correlates with glioma grade, highest expression in GBM, and increases in recurrences. eIF3e upregulation in recurrences may have a role in treatment resistance. | [211] | |
eIF3b, eIF3i, eIF3k and eIF3m (poor OS) | eIF3a and eIF3l (better OS) | CGGA, TCGA | Expression of eIF3d, eIF3e, eIF3f, eIF3h, and eIF3l correlates with the IDH-mutant status of gliomas. eIF3i and eIF3k expressions increase with tumour grade and are associated with poor OS. eIF3i is an independent prognostic factor in IDH-mutant LGG and can predict the 1p/19q codeletion status in IDH-mutant LGG. High eIF3i expression correlates with cell proliferation, mRNA processing, translation, T-cell receptor signalling, NF-kB signalling, and many others. | [202] |
METTL3 | CGGA, TCGA | METTL3 promotes the malignant progression of gliomas in vitro and in vivo. METTL3 correlates with poor OS in IDH-wildtype but not in IDH-mutant gliomas. | [205] | |
eIF3A, FMR1, FTO, METTL14, METTL16, METTL3, RBMX, YTHDC, YTHDF3 and ZC3H13 (IDH-mutant vs. IDH-wildtype) | ALKBH5, IGF2BP2, IGF2BP3, RBM15, WTAP and YTHDF1 (IDH-mutant vs. IDH-wildtype) | CGGA, TCGA, REMBRANDT | Expression of m6A regulators is associated with Prognosis, grade, IDH, and 1p/19q status. Lower m6A regulators expression (except FTO) is associated with longer OS. A prognostic risk signature—ALKBH5, IGF2BP3, KIAA1429, and YTHDF2. | [101] |
ALBKH5, RBM15, YTHDF and WTAP (increased tumour grade) | FTO | CGGA, TCGA | RBM15, METTL3, METTL14, ALKBH5, FTO, YTHDC1, and YTHDF2 are significantly differentially expressed between IDH-mutant and IDH-wildtype LGG. METTL3, FTO, and YTHDC1 are significantly differentially expressed between IDH-mutant and IDH-wildtype GBM. The risk signature comprises RBM15, WTAP, ALBKH5, FTO, YTHDC1, YTHDF1, and YTHDF2, all of which are independent prognostic markers and predictive of clinicopathological features and treatment sensitivity. | [105] |
RBM15, RBM15B, METTL3, METTL14, WTAP, HNRNPA2B1, HNRNPC, YTHDF1, YTHDF2, YTHDF3, and YTHDC2 (gliomas vs. control) ALKBH5, RBM15, WTAP and YTHDF2 (in GBM vs. LGG) | FTO and ZC3H13 (gliomas vs. control) FTO, KIAA1429, METTL3, ZC3H13, HNRNPC, and YTHDC2 (in GBM vs. LGG) | CGGA | Four m6A-related lncRNAs that have prognostic values: LINC00900 and MIR155HG, increased in higher-grade tumours, while MIR9-3HG and LINC00515 have lower expression in HGG vs. LGG. | [107] |
IGF2BP3 | YTHDC2 | TCGA, CGGA cBioportal | IGF2BP3 expression increases with tumour grade and correlates with shorter OS. YTHDC2 and IGF2BP3 are negative and positive prognostic factors for OS. | [212] |
HNRNPC, WTAP, YTHDF2 and, YTHDF1 | TCGA | Defined prognostic risk signature: HNRNPC, ZC3H13, and YTHDF2. HNRNPC plays an important role in malignancy and contributes to the development of gliomas. High expression of HNRNPC correlates with a favourable prognosis. | [213] | |
LINC00265 | C6orf3, GDNF-AS1, LINC00925, LINC00237 | TCGA, CGGA | Twenty-four prognostic m6A-related lncRNAs were identified as prognostic lncRNAs. m6A-related lncRNA prognostic signature (m6A-LPS). | [107] |
METTL14, IGF2BP2, IGF2BP3, HNRNPA2B1, YTHDF1, YTHDF3,HNRNPC, RBMX, WTAP, YTHDF2, and IGF2BP1 | TCGA, CGGA | Defined prognostic risk signature: ALKBH5, IGF2BP2, IGF2BP3, HNRNPA2B1, YTHDF1, YTHDF2, RBM15, and WTAP. | [206] |
5. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Disease/Condition | Upregulated | Downregulated | m6A Levels | Ref. |
---|---|---|---|---|
Non-small-cell lung carcinoma | METTL3, METTL14, RBM15 | ALKBH5, FTO | ↑ | [142] |
Breast cancer | METTL14 | FTO | ↑ | [143] |
Gastric cancer | ALKBH5, FTO | ↑ | [144] | |
Acute myeloid leukaemia | WTAP | [151] | ||
Colorectal cancer | IGF2BP2 | ↑ | [152] | |
Rheumatoid arthritis | ALKBH5, FTO, YTHDF2 | ↑ | [145] | |
Diabetes | FTO | ↓ | [147] | |
Spinal cord injury | FTO, METTL14, RBMX, YTHDF2, YTHDC2, HNRNPA2B1 | [153] | ||
Systemic lupus erythematosus | METTL3, METTL14, WTAP, FTO, ALKBH5, YTHDF2 | [154] | ||
COVID-19 | METTL3, FTO | ↓ | [149] | |
Aging | ↓ | [148] | ||
Smoking and air pollution | ↓ | [150] | ||
Myocardial infarction (in rats) | ↑ | [155] | ||
Ischemic stroke | ↑ | [146] |
Disease/Condition | RNA Modification or Epitranscriptomic Regulator | Sample Type | Observations/Role | Ref. |
---|---|---|---|---|
Smoking and air pollution | Global m6A levels | Peripheral blood | Decreased global m6A levels were found in smokers compared to non-smokers. | [150] |
Aging | Global m6A levels | PBMCs | Decrease in overall m6A with aging. m6A-modified transcripts have higher expression than the nonmodified ones. DROSHA and AGO2 have high methylation levels in younger subjects. | [148] |
COVID-19 | m6A levels, METTL3, FTO | PBMCs | Increased METTL3 and FTO in COVID-19 patients. m6A modification has an essential role in the clinical status of COVID-19 patients | [149] |
Spinal cord injury (SCI) | FTO, METTL14, RBMX, YTHDF2, YTHDC2, HNRNPA2B1 | PBMCs, GEO data | METTL14, FTO, RBMX, YTHDF2, HNRNPA2B1, and YTHDC2 downregulated in SCI. AKT2/3 and PIK3R1 are potential m6A-related therapeutic targets. | [153] |
Myocardial infarction (MI) | 5mdC, 5mrC, m6A levels | Heart tissue and blood (rats) | Increased levels of 5mdC, 5mrC, and m6A in heart tissue eight weeks after surgery. | [155] |
Rheumatoid arthritis | ALKBH5, FTO, YTHDF2, m6A levels | Peripheral blood | Decreased ALKBH5, FTO, and YTHDF2 as risk factors. Global m6A is increased and negatively correlates with decreased FTO gene expression. | [145] |
Type 2 diabetes (T2DM) | FTO | Peripheral blood | m6A levels are lower in T2DM patients, probably caused by the higher FTO expression. Higher FTO level is associated with T2DM risk. | [147] |
Systemic lupus erythematosus (SLE) | METTL3, WTAP, FTO, ALKBH5, YTHDF2 | Peripheral blood | Decreased METTL3, WTAP, FTO, ALKBH5, and YTHDF2 gene expression in the blood of SLE patients. ALKBH5 as a risk factor and involved in SLE pathogenesis. | [160] |
Systemic lupus erythematosus (SLE) | METTL14, ALKBH5, YTHDF2 | PBMCs | Decreased expression of METTL14, ALKBH5, and YTHDF2 in SLE. | [154] |
Endometriosis | FTO, HNRNPC, HNRNPA2B1 | GSE6364 data | FTO, HNRNPC, and HNRNPA2B1 have biomarker potential. | [161] |
Lung adenocarcinoma | HNRNPC, METTL3, YTHDC2, KIAA1429, ALKBH5, YTHDF1 | Tissue | HNRNPC, METTL3, YTHDC2, KIAA1429, ALKBH5, and YTHDF1 linked to clinical features, pathological stages, gender, and survival. | [158] |
Lung adenocarcinoma | HNRNPC | Tissue | HNRNPC high expression correlates with gender, age, ethnicity, lymph node metastasis, smoking history, TNM staging, and poor prognosis. | [156] |
Lung adenocarcinoma | IGF2BP3 | Tissue | IGF2BP3 correlates with poor prognosis, tumour length, differentiation, T stage, and gender. IGF2BP3 is an independent prognosis factor and potential oncogene. | [157] |
Lung adenocarcinoma | KIAA1429, RBM15, METTL3, HNRNPC, HNRNPA2B1, YTHDF1, YTHDF2 | Tissue | METTL3, YTHDF1, and YTHDF2 are prognostic biomarkers and suggest better OS and RFS. | [159] |
Lung adenocarcinoma | METL3, VIRMA, RBM15, YTHDF1, YTHDF2, LRPPRC, HNRNPA2B, IGFBP3, RBMX, FTO, ALKBH5, WTAP, METTL16, METTL14, ZC3H13 | Tissue | Risk factors that predict worse prognosis. | [162] |
Non-small-cell lung carcinoma (NSCLC) | m6A levels, METTL3, METTL14, RBM15, ALKBH5, FTO | Peripheral blood | Leukocyte m6A levels potential biomarker for NSCLC screening, diagnosis, and monitoring. | [142] |
Non-small cell lung cancer (NSCLC) | YTHDC2, METTL3, RBM15, HNRNPC, YTHDF2, YTHDF1, ZC3H13 | Tissue | Gene signatures classify prognostic groups. | [163] |
Non-small cell lung cancer (NSCLC) | HNRNPC | Tissue | HNRNPC predicts poor prognosis and correlates with lymph node metastasis and tumour invasion. | [164] |
Lung squamous cell carcinoma | ALKBH5, METTL3, HNRNPC, KIAA1429 | Tissue | T follicular helper cells have a prognostic signature role in predicting the survival and treatment response. | [165] |
Breast cancer | METTL14, FTO, m6A levels | Peripheral blood | m6A levels are elevated in advanced tumour stages. | [143] |
Hepatocellular carcinoma (HCC) | ALKBH5 | Tissue and cells | Loss of ALKBH5 is an independent prognostic factor. ALKBH5 inhibits HCC proliferation in vitro and in vivo. | [166] |
Hepatocellular carcinoma (HCC) | YTHDF1 | Tissue | YTHDF1 is upregulated in HCC and correlates with stage. Lower YTHDF1 expression results in better OS. YTHDF1 is involved in HCC cell cycle progression and metabolism regulation. | [167] |
Hepatocellular carcinoma (HC) | YTHDF1, YTHDF2, METTL3, KIAA1429 | Tissue | m6A regulators differentially expressed in HC. Independent prognostic risk signature: YTHDF1, YTHDF2, METTL3, and KIAA1429. | [168] |
Hepatocellular carcinoma (HCC) | METTL14 | Tissue | METTL14 expression correlates with the expression and regulates m6A methylation of hub genes, CSAD, GOT2, and SOCS2. | [169] |
Hepatocellular carcinoma (HCC) | m5C-related lncRNAs | Tissue | Prognosis value established for 8 m5C-related lncRNAs. | [170] |
Gastric cancer (GC) and benign gastric disease (BGD) | m6A levels, ALKBH5, FTO | Peripheral blood | m6A levels are elevated in advanced tumour stages. m6A decreases after surgery. FTO in stage IV disease < stage I. | [144] |
Gastric cancer | m6A levels, YTHDF1 | Tissue and cell | Constructed a diagnostic m6A score that can distinguish cancer from normal tissue. YTHDF1 expression correlates with high-risk subtype patients, and it is a possible oncogene. | [171] |
Gastric cancer (GC) | m6A levels | Tissue | m6A score is an independent prognostic biomarker. Lower m6A scores have EBV and MSI patients that are sensitive to checkpoint immunotherapy. Negative correlation between m6A score and mutation. EMT has the lowest m6A score. | [172] |
Gastric cancer (GC) | m6A levels, METTL3 | Tissue | High METTL3 expression increases m6A levels and is associated with GC proliferation, liver metastasis, and poor prognosis. | [173] |
Gastric cancer (GC) | FTO, ALKBH1 | Tissue | High expression of FTO and ALKBH1 transcripts associated with low survival. Low ALKBH1 protein expression correlates with larger tumour size and advanced TNM stages. Low FTO protein expression correlates with shorter OS. | [174] |
Gastric cancer (GC) | RBM15, WTAP, METTL3, YTHDF2, YTHDF1, YTHDC1, YTHDC2, KIAA1429, ZC3H13, HNRNPC | Tissue | Hub genes associated with m6A regulators have prognostic values: AARD, ASPN, SLAMF9, MIR3117, and DUSP1. ASPN is also upregulated in GC cells. | [175] |
Pancreatic cancer | KIAA1429, HNRNPC, METTL3, YTHDF1, IGF2BP2, IGF2BP3 | Tissue, cell line | m6A-regulator risk signature. | [176] |
Pancreatic adenocarcinoma | RBM15 | Tissue | Various significant prognostic parameters. | [177] |
Colonic adenocarcinoma | YTHDF1, METTL3, KIAA1429, YTHDF3, YTHDC2, METTL14, ALKBH5 | Tissue | YTHDF1, YTHDF3, and YTHDC2 are promising biomarkers for detection, progression, and prognosis. | [178] |
Colon cancer | ALKBH5 | Tissue, cells | ALKBH5 has a tumour suppressor role in CC. Overexpression of ALKBH5 can inhibit CC invasion and metastasis and has prognostic significance. | [179] |
Colorectal cancer (CRC) | m6A levels, IGF2BP2 | PBMCs, GEO data | m6A in the blood is a prospective biomarker for CRC and a possible therapeutic target. IGF2BP2 has high expression in CRC blood. Monocytes have the most m6A modification. | [152] |
Colorectal adenocarcinoma | METTL3, YTHDF1, IGF2BP1, IGF2BP3, EIF3B, HNRNPA2B, YTHDF1, IGF2BP1, IGF2BP3 | Tissue | Potential biomarkers YTHDF1, IGF2BP1, IGF2BP3, and EIF3B. | |
Acute myeloid leukaemia | WTAP | Peripheral blood, bone marrow cells | Patients were classified into two risk groups based on WTAP expression. High WTAP more common in older patients. | [151] |
Acute myeloid leukaemia | ZC3H13, RBM15, LRPPRC, METTL14, YTHDC2 | Tissue | METTL14, YTHDC2, ZC3H13, and RBM15 expression correlates with OS. | [180] |
Neuroblastoma | METT14, WTAP, HNRNPC, YTHDF1, IGF2BP2 | Tissue | Risk prediction signature: METT14, WTAP, HNRNPC, YTHDF1, and IGF2BP2. | [181] |
Head and neck squamous cell carcinoma. | YTHDC2 | Tissue | YTHDC2 correlates with prognosis and immune infiltration level (CD4+ T cell subpopulation). YTHDC2 has a possible tumour suppressor role. | [182] |
Head and neck squamous cell carcinoma | IGF2BP2 | Tissue | IGF2BP2 was identified as a hub m6A regulator, and its high expressions are correlated with poor prognosis. | [183] |
Melanoma | ALKBH5, YTHDF1, KIAA1429 | Tissue | Prognostic risk signature: ALKBH5, YTHDF1, and KIAA1429 divides patients into high- and low-risk OS groups. | [184] |
Melanoma | YTHDF1, HNRNPA2B1 | Tissue | Tumour stage and treatment response differ between patients with/without mutations in m6A regulatory genes. | [185] |
Uveal melanoma | RBM15B, IGF2BP1, IGF2BP2, YTHDF3, YTHDF1 | Tissue | m6A regulators with prognostic value: RBM15B, IGF2BP1, IGF2BP2, YTHDF3, and YTHDF1. RBM15B is an independent prognostic factor and correlates with clinicopathologic characteristics. | [186] |
Osteosarcoma | KIAA1429, HNRNPA2B1 METTL3, YTHDF3, METTL14, FTO, YTHDF2 | Tissue | Prognostic signatures. | [187] |
Papillary thyroid carcinoma | HNRNPC, WTAP, RBM15, YTHDC2, YTHDC1, FTO, METTL14, METTL3, ALKBH5, KIAA1429, YTHDF1, ZC3H13 | Tissue | Prognostic signature RBM15, KIAA1429, FTO. | [188] |
Endocrine system tumours | IGF2BP1, METTL14, RBMX, HNRNPC, IGF2BP3, HNRNPA2B1 ICBLL1, RBM15B, KIAA1429, WTAP | Tissue | Prognostic signatures. | [189] |
Adrenocortical carcinoma | RBM15, ZC3H3, YTDHF1, YTDHF2, ALBH5, KIAA1429, YTHDC1, HNRNPC, WTAP, METTL3, FTO | Tissue | Independent prognostic risk signature: HNRNPC, RBM15, METTL14, and FTO. | [190] |
Clear cell renal cell carcinoma | METTL3, METTL14 | Tissue | METTL3 and METTL14 are associated with prognosis and clinicopathological features. | [191] |
Clear cell renal cell carcinoma | FTO, IGF2BP2, IGF2BP3, KIAA1429, YTHDC1, ZC3H13 | Tissue | m6A-related risk signature for prognosis. m6A regulators’ expression correlates with histological grade and staging. | [192] |
Clear cell renal cell carcinoma | ALKBH5, FTO | Tissue | ALKBH5 and FTO decreased gene expression correlates with poor OS. | [193] |
Clear cell renal cell carcinoma | METTL14 | Tissue | METTL14 probably methylates m6A in PTEN, leading to its expression change. METTL14 gene expression negatively correlates with the tumour stages and positively correlates with KIRC patients’ OS. | [194] |
Bladder cancer | HNRNPA2B1 IGF2BP1, IGF2BP3, METTL3, YTHDF2, YTHDF1, FTO, ZC3H13, YTHDF3, YTHDC1, WTAP, METTL16, METTL14 | Tissue | Identified risk factors that correlate with advanced clinical stages: RBM15, HNRNPA2B1, HNRNPC, IGF2BP2, YTHDF1, and YTHDF2. | [195] |
Bladder cancer | METTL3, WTAP, FTO, YTHDC1 | Tissue | Independent prognostic signature and predictor of clinicopathology. | [196] |
m6A Regulators | GBM vs. NT | GBM vs. AST | GBM vs. LGG | High vs. Low Grade | Refs. |
---|---|---|---|---|---|
FTO | ↓ | ↓ | ↓ | ↓ | [100,105,107] |
METTL3 | ↑ | ↓ | ↓ | [100,101,107,205] | |
RBM15 | ↑ | [100,105,107] | |||
RBM15B | ↑ | [107] | |||
ZC3H13 | ↓ | ↓ | ↓ | [100,107] | |
KIAA1429 (VIRMA) | ↓ | [107] | |||
eIF3A | ↓ | ↓ | [101,202] | ||
eIF3B | ↑ | ↑ | ↑ | [202] | |
eIF3E | ↑ | [202] | |||
eIF3I | ↑ | ↑ | ↑ | [202] | |
eIF3K | ↑ | ↑ | ↑ | [202] | |
eIF3L | ↓ | ↓ | [202] | ||
eIF3M | ↑ | ↑ | ↑ | [202] | |
FMR1 | ↓ | [101] | |||
HNRPC | ↑ | ↓ | [100,107,213] | ||
HNRNPA2B1 | ↑ | [107] | |||
IGF2BP2 | ↑ | [101] | |||
IGF2BP3 | ↑ | ↑ | ↑ | [101,212] | |
RBMX | ↓ | [101] | |||
YTHDF1 | ↑ | ↑ | [100,101,107,213] | ||
YTHDF2 | ↑ | [100,107,213] | |||
YTHDF3 | ↑ | ↓ | [101,107,214] |
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Tűzesi, Á.; Hallal, S.; Satgunaseelan, L.; Buckland, M.E.; Alexander, K.L. Understanding the Epitranscriptome for Avant-Garde Brain Tumour Diagnostics. Cancers 2023, 15, 1232. https://doi.org/10.3390/cancers15041232
Tűzesi Á, Hallal S, Satgunaseelan L, Buckland ME, Alexander KL. Understanding the Epitranscriptome for Avant-Garde Brain Tumour Diagnostics. Cancers. 2023; 15(4):1232. https://doi.org/10.3390/cancers15041232
Chicago/Turabian StyleTűzesi, Ágota, Susannah Hallal, Laveniya Satgunaseelan, Michael E. Buckland, and Kimberley L. Alexander. 2023. "Understanding the Epitranscriptome for Avant-Garde Brain Tumour Diagnostics" Cancers 15, no. 4: 1232. https://doi.org/10.3390/cancers15041232