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Liouta, G.; Adamaki, M.; Tsintarakis, A.; Zoumpourlis, P.; Liouta, A.; Agelaki, S.; Zoumpourlis, V. DNA Methylation for Head and Neck Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/43650 (accessed on 13 April 2024).
Liouta G, Adamaki M, Tsintarakis A, Zoumpourlis P, Liouta A, Agelaki S, et al. DNA Methylation for Head and Neck Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/43650. Accessed April 13, 2024.
Liouta, Galateia, Maria Adamaki, Antonis Tsintarakis, Panagiotis Zoumpourlis, Anastasia Liouta, Sofia Agelaki, Vassilis Zoumpourlis. "DNA Methylation for Head and Neck Cancer" Encyclopedia, https://encyclopedia.pub/entry/43650 (accessed April 13, 2024).
Liouta, G., Adamaki, M., Tsintarakis, A., Zoumpourlis, P., Liouta, A., Agelaki, S., & Zoumpourlis, V. (2023, April 30). DNA Methylation for Head and Neck Cancer. In Encyclopedia. https://encyclopedia.pub/entry/43650
Liouta, Galateia, et al. "DNA Methylation for Head and Neck Cancer." Encyclopedia. Web. 30 April, 2023.
DNA Methylation for Head and Neck Cancer
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Head and neck squamous cell carcinoma (HNSCC) is a term collectively used to describe all cancers that develop in the oral and nasal cavities, the paranasal sinuses, the salivary glands, the pharynx, and the larynx.  A biomarker is a biological finding that stands in for and optimally forecasts a clinically related outcome or an intermediate result that is more difficult to detect. It is a specific characteristic that is measured as an indicator of the normal biological procedures, pathological mechanisms or responses to an exposure or interference. Recent evidence suggests that DNA methylation can alter the expression of genes in a way that it favors tumorigenesis and tumor progression in HNSCC, and therefore represents a potential source for biomarker identification.

head and neck cancer DNA methylation diagnostic biomarkers

1. Introduction

Head and neck squamous cell carcinoma (HNSCC) is a general term that includes all cancers that develop in the oral and nasal cavities, the paranasal sinuses, the salivary glands, the pharynx, and the larynx [1]. Most of these cancers are initiated in the squamous cells that line the moist surfaces inside the head and neck (hence the term head and neck squamous cell carcinoma), and are characterized by heterogeneity in their phenotypic, clinical, and biological features [2][3][4][5]. According to the Globocan online database, in 2020, it was estimated that there were 931,931 new cases of HNSCC and 467,125 related deaths worldwide [6]. The majority of patients who will be diagnosed at an early stage can be cured [4]. However, patients with locally advanced and aggressive disease, who account for 75% of the newly diagnosed cases, are likely to experience relapse and have a 5-year overall survival (OS) rate of 50%, despite advances in surgical treatment, radiotherapy, and chemotherapy [4][5]. Consequently, there is a need for the identification and application of tools with high sensitivity and specificity that would enable diagnosis at the earliest possible stage, inform clinicians of the possible prognosis of patients, contribute to the early detection of relapses, and provide information on the progression of the disease after the application of specific treatments [7]

2. DNA Methylation Biomarkers with Diagnostic Potential

A diagnostic biomarker is used to identify or verify the occurrence of a disease or a situation of interest, or to designate a specific disease subtype [8].
MicroRNAs (miRNAs) represent small, non-coding RNAs that are involved in gene expression either through repression of translation or through direct degradation of the target mRNA and are also actively implicated in oncogenesis [9]. The methylation status of three promoter sites of microRNA 9 (miRNA 9), namely miR-9-1, miR-9-2, and miR-9-3, are perhaps the most widely studied microRNAs in patients with HNSCC [9]. Oral and oropharyngeal carcinomas are characterized by higher miR-9-1 and miR-9-3 methylation levels, as compared to laryngeal carcinomas, while miR-9 expression appears to be reduced [9]. Consequently, the methylation patterns of miR-9-1 and miR-9-3 are regarded as sensitive and highly specific for the diagnosis of HNSCC, especially oral and oropharyngeal carcinomas [9].
The EDNRB gene encodes the B-type endothelin receptor (G protein-coupled receptor) that activates a phosphatidylinositol-calcium second messenger system, while DCC, a tumor suppressor gene, encodes a transmembrane protein with structural homology to NCAM, which is involved in the differentiation of epithelial and neuronal cells [10]. The promoters of both genes have been found to be hypermethylated in 40% of saliva samples from patients with oral cavity cancer (OCC) and precancerous lesions [10]. Thus, hypermethylation of DCC and EDNRB has been associated with malignant histopathological diagnosis, independent of other factors such as age, smoking, and alcohol consumption; this further suggests that these genes can be used as individual biomarkers of malignant transformation for the screening of high-risk patients, as well as for the identification of patients who might appear to be at low risk during physical examination, but are categorized as high risk based on the salivary methylation biomarkers [10].
The mediator complex subunit 15 gene (MED15/PCQAP) encodes a cofactor that contributes greatly to the modulation of transcription initiation in the promoters of many genes [11]. Two CpG dinucleotide clusters (at the 5′ or 3′ end) of this gene have been identified to be methylated in HNSCC tumors in patients who have been smokers, but not in normal tissue samples derived from the same subjects, with subsequent validation of the findings in saliva samples [11]. It has therefore been concluded that these CpG methylation sites may be used as potential non-invasive biomarkers for HNSCC detection [11]. Specifically, the 5′-CpG site has emerged as a stronger diagnostic biomarker than the 3′-CpG site, with the DNA methylation levels of both sites being comparatively lower in saliva samples of HPV+ patients as compared to HPV− patients [11]. Moreover, it has been reported that the differential methylation of ZNF14, ZNF160, and ZNF420, all of which are members of the zinc finger gene family, constitutes an important biomarker of HNSCC identification, exhibiting 100 % specificity in primary tissue and saliva samples [12].
Other genes with abnormal methylation patterns and consequently with differential expression patterns in HNSCC tissues have been detected through bioinformatics analysis [13]. Two hypermethylated genes with concomitant low expression, FAM135B and ZNF610, and two hypomethylated genes with concomitant high expression, HOXA9 and DCC, have been identified, and their diagnostic utility has been validated through ROC curve analysis [13]. In contrast to these observations, the HOXA9 promoter appears to be characterized by considerably higher methylation levels in pathological tissues, as compared to normal controls, and may therefore serve as an early diagnostic biomarker in patients with HNSCC [14]. Nonetheless, a statistically significant difference in HOXA9 methylation seems to exist between men and women with HNSCC [14].
In HPV+ oropharyngeal squamous cell carcinoma (OPSCC), 20 differentially methylated DNA regions (DMRs) have been identified in the following genes: KCNA3, EMBP1, CCDC181, DPP4, ITGA4, BEND4, CTNND2, ELMO1, SFMBT2, C1QL3, MIR129-2, ATP5EP2, OR6S1, NID2, HOXB4, ZNF439, ZNF93, VSTM2B, ZNF137P, and ZNF773 [15]. The methylation levels in HPV+ OPSCC are remarkably higher than those in normal samples and non-HPV-related HNSCC, and as such, these 20 DMRs have been suggested as potential diagnostic biomarkers in patients with HPV+ OPSCC [15].
Prominin 1 (PROM1) encodes a pentaspan membrane glycoprotein, often expressed on adult stem cells [16]. The PROM1 promoter appears to be hypermethylated in HNSCC tissues, as compared to normal head and neck tissues, while increasing methylation levels are negatively associated with PROM1 gene expression, with the highest methylation levels observed in smokers and elderly patients [16]. Overall, the methylation status of PROM1 may serve as a valuable biomarker for the early diagnosis of HNSCC [16].
The collagen triple helix repeat containing 1 (CTHRC1) gene encodes an extracellular matrix protein that acts as a modulator of the tumor microenvironment, and appears to be overexpressed in HNSCC tissues, as compared to healthy tissues, due to promoter hypomethylation [17]. Furthermore, plasminogen activator urokinase (PLAU) overexpression may be an independent diagnostic and prognostic biomarker in HNSCC [18]. PLAU is a protease involved in numerous different signaling pathways, including apoptosis, epithelial-mesenchymal transition (EMT), and Ras/MAPK; hypomethylation of PLAU gene as well as hypomethylation and subsequent downregulation of miR-23b-3p, a microRNA that targets PLAU, may be responsible for the overexpression and the oncogenic role of PLAU in HNSCC [18].
Other genes with potential diagnostic utility in HNSCC include methylenetetrahydrofolate dehydrogenase 1 (MTHFD1L), the opioid receptor genes OPRL1 (opioid-related nociceptin receptor 1) and OPRM1 (opioid receptor mu 1), and the xenotropic and multimodal retrovirus receptor 1 (XPR1). MTHFD1L expression levels have been found to be significantly higher in 24 subtypes of HNSCC, compared to normal controls, and to be accompanied by promoter hypomethylation [19]. Similarly, in plasma liquid biopsy samples from patients with OCC, OPRL1 and OPRM1 genes appear to be highly methylated as compared to normal tissue derived from the same patients [20]. Last but not least, XPR1, a cell surface receptor for certain types of murine leukemia viruses, exhibits markedly increased expression in HNSCC tissues, as compared to healthy controls, while promoter methylation is significantly lower than that in healthy controls [21].
Table 1 includes a list of DNA methylation biomarkers with diagnostic potential [9][10][11][12][13][14][15][16][17][18][19][20][21].
Table 1. Diagnostic and Screening biomarkers.

References

  1. Arantes, L.M.R.B.; De Carvalho, A.C.; Melendez, M.E.; Lopes Carvalho, A. Serum, Plasma and Saliva Biomarkers for Head and Neck Cancer. Expert Rev. Mol. Diagn. 2018, 18, 85–112.
  2. Miranda-Galvis, M.; Loveless, R.; Kowalski, L.P.; Teng, Y. Impacts of Environmental Factors on Head and Neck Cancer Pathogenesis and Progression. Cells 2021, 10, 389.
  3. Leemans, C.R.; Snijders, P.J.F.; Brakenhoff, R.H. The Molecular Landscape of Head and Neck Cancer. Nat. Rev. Cancer 2018, 18, 269–282.
  4. Mesia, R.; Iglesias, L.; Lambea, J.; Martínez-Trufero, J.; Soria, A.; Taberna, M.; Trigo, J.; Chaves, M.; García-Castaño, A.; Cruz, J. SEOM Clinical Guidelines for the Treatment of Head and Neck Cancer 2020. Clin. Transl. Oncol. 2021, 23, 913–921.
  5. The Cancer Genome Atlas Network Comprehensive Genomic Characterization of Head and Neck Squamous Cell Carcinomas. Nature 2015, 517, 576–582.
  6. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J. Clin. 2021, 71, 209–249.
  7. Amenábar, J.M.; Da Silva, B.M.; Punyadeera, C. Salivary Protein Biomarkers for Head and Neck Cancer. Expert Rev. Mol. Diagn. 2020, 20, 305–313.
  8. Califf, R.M. Biomarker Definitions and Their Applications. Exp. Biol. Med. 2018, 243, 213–221.
  9. Minor, J.; Wang, X.; Zhang, F.; Song, J.; Jimeno, A.; Wang, X.-J.; Lu, X.; Gross, N.; Kulesz-Martin, M.; Wang, D.; et al. Methylation of MicroRNA-9 Is a Specific and Sensitive Biomarker for Oral and Oropharyngeal Squamous Cell Carcinomas. Oral Oncol. 2012, 48, 73–78.
  10. Schussel, J.; Zhou, X.C.; Zhang, Z.; Pattani, K.; Bermudez, F.; Jean-Charles, G.; McCaffrey, T.; Padhya, T.; Phelan, J.; Spivakovsky, S.; et al. EDNRB and DCC Salivary Rinse Hypermethylation Has a Similar Performance as Expert Clinical Examination in Discrimination of Oral Cancer/Dysplasia versus Benign Lesions. Clin. Cancer Res. 2013, 19, 3268–3275.
  11. Ovchinnikov, D.A.; Wan, Y.; Coman, W.B.; Pandit, P.; Cooper-White, J.J.; Herman, J.G.; Punyadeera, C. DNA Methylation at the Novel CpG Sites in the Promoter of MED15/PCQAP Gene as a Biomarker for Head and Neck Cancers. Biomark. Insights 2014, 9, BMI.S16199.
  12. Beck, T.N.; Golemis, E.A. Genomic Insights into Head and Neck Cancer. Cancers Head Neck 2016, 1, 1.
  13. Zhou, C.; Ye, M.; Ni, S.; Li, Q.; Ye, D.; Li, J.; Shen, Z.; Deng, H. DNA Methylation Biomarkers for Head and Neck Squamous Cell Carcinoma. Epigenetics 2018, 13, 398–409.
  14. Zhou, C.; Li, J.; Li, Q.; Liu, H.; Ye, D.; Wu, Z.; Shen, Z.; Deng, H. The Clinical Significance of HOXA9 Promoter Hypermethylation in Head and Neck Squamous Cell Carcinoma. J. Clin. Lab. Anal. 2019, 33, e22873.
  15. Ren, S.; Gaykalova, D.; Wang, J.; Guo, T.; Danilova, L.; Favorov, A.; Fertig, E.; Bishop, J.; Khan, Z.; Flam, E.; et al. Discovery and Development of Differentially Methylated Regions in Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma. Int. J. Cancer 2018, 143, 2425–2436.
  16. Hu, Z.; Liu, H.; Zhang, X.; Hong, B.; Wu, Z.; Li, Q.; Zhou, C. Promoter Hypermethylation of CD133/PROM1 Is an Independent Poor Prognosis Factor for Head and Neck Squamous Cell Carcinoma. Medicine 2020, 99, e19491.
  17. Sial, N.; Ahmad, M.; Hussain, M.S.; Iqbal, M.J.; Hameed, Y.; Khan, M.; Abbas, M.; Asif, R.; Rehman, J.U.; Atif, M.; et al. CTHRC1 Expression Is a Novel Shared Diagnostic and Prognostic Biomarker of Survival in Six Different Human Cancer Subtypes. Sci. Rep. 2021, 11, 19873.
  18. Huo, Z.; Li, X.; Zhou, J.; Fan, Y.; Wang, Z.; Zhang, Z. Hypomethylation and Downregulation of MiR-23b-3p Are Associated with Upregulated PLAU: A Diagnostic and Prognostic Biomarker in Head and Neck Squamous Cell Carcinoma. Cancer Cell Int. 2021, 21, 564.
  19. Sial, N.; Rehman, J.U.; Saeed, S.; Ahmad, M.; Hameed, Y.; Atif, M.; Rehman, A.; Asif, R.; Ahmed, H.; Hussain, M.S.; et al. Integrative Analysis Reveals Methylenetetrahydrofolate Dehydrogenase 1-like as an Independent Shared Diagnostic and Prognostic Biomarker in Five Different Human Cancers. Biosci. Rep. 2022, 42, BSR20211783.
  20. Ishikawa, R.; Imai, A.; Mima, M.; Yamada, S.; Takeuchi, K.; Mochizuki, D.; Shinmura, D.; Kita, J.; Nakagawa, T.; Kurokawa, T.; et al. Novel Prognostic Value and Potential Utility of Opioid Receptor Gene Methylation in Liquid Biopsy for Oral Cavity Cancer. Curr. Probl. Cancer 2022, 46, 100834.
  21. Wang, L. Bioinformatics Analyses Proposed Xenotropic and Polytropic Retrovirus Receptor 1 as a Potential Diagnostic and Prognostic Biomarker and Immunotherapeutic Target in Head and Neck Squamous Cell Carcinoma. Auris Nasus Larynx 2022, 50, 134–150.
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