Dysregulation and detection methods of EGFR in oral cancer. A narrative review.

  • Carolina Somarriva Facultad de Odontología, Universidad Andrés Bello.
  • Alejandra Fernández Facultad de Odontología, Universidad Andrés Bello. Centro de Investigación Biomédica, Universidad de Los Andes.
  • Jorge Candia Facultad de Odontología, Universidad Andrés Bello.
  • Javier Campos Centro de Investigación Biomédica, Universidad de Los Andes.
  • Daniela Albers Centro de Investigación Biomédica, Universidad de Los Andes. Facultad de Odontología, Universidad Mayor.
  • Jorge Briceño Facultad de Odontología, Universidad Andrés Bello.


Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein, with an intracellular domain and tyrosine kinase function (TK) involved in cell proliferation. Dysfunctions in EGFR signaling pathways have been associated with oral malignant tumors such as oral squamous cell carcinoma (OSCC). Dysfunctions of EGFR may result from: increased EGF ligand; EGFR overexpression and copy number gain of the EGFR gene (EGFR CNG); EGFR mutations; failure in the downregulation of EGFR; and EGFR crosstalk. Of these alterations, overexpression of EGFR is by far the most studied dysfunction in OSCC. Clinicians should identify possible alterations of EGFR in the oral mucosa of patients, as EGFR can act as a biomarker for the diagnosis and prognosis of OSCC. Currently, there are several methods and techniques for detecting EGFR. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR), are used to identify overexpression of EGFR, EGFR CNG and EGFR mutations, respectively. Detection of EGFR as a biomarker is key to identify any oral malignant transformation. Consequently, it becomes imperative to implement a non-invasive and inexpensive method of early diagnosis for OSCC in clinical practice.


1. Cohen S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J Biol Chem. 1962;237:1555–62.
2. Carpenter G. Receptors for epidermal growth factor and other polypeptide mitogens. Annu Rev Biochem. 1987;56:881–914.
3. McIntyre JB, Bose P, Klimowicz AC, Brockton NT, Petrillo S, Matthews W, Easaw J, Magliocco A, Dort JC. Specific and sensitive hydrolysis probe-based real-time PCR detection of epidermal growth factor receptor variant III in oral squamous cell carcinoma. PLoS One. 2012;7(2):e31723.
4. Pan S, Yuan C, Tagmount A, Rudel RA, Ackerman JM, Yaswen P, Vulpe CD, Leitman DC. Parabens and Human Epidermal Growth Factor Receptor Ligand Cross-Talk in Breast Cancer Cells. Environ Health Perspect. 2016;124(5):563–9.
5. Holbro T, Civenni G, Hynes NE. The ErbB receptors and their role in cancer progression. Exp Cell Res. 2003;284(1):99–110.
6. Veale D, Kerr N, Gibson GJ, Harris AL. Characterization of epidermal growth factor receptor in primary human non-small cell lung cancer. Cancer Res. 1989;49(5):1313–7.
7. Sheu JJ, Hua CH, Wan L, Lin YJ, Lai MT, Tseng HC, Jinawath N, Tsai MH, Chang NW, Lin CF, Lin CC, Hsieh LJ, Wang TL, Shih IeM, Tsai FJ. Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinoma. Cancer Res. 2009;69(6):2568–76.
8. Krasinskas AM. EGFR Signaling in Colorectal Carcinoma. Patholog Res Int. 2011;2011:932932.
9. Szabó B, Nelhubel GA, Kárpáti A, Kenessey I, Jóri B, Székely C, Peták I, Lotz G, Hegedus Z, Hegedus B, Füle T, Döme B, Tímár J, Tóvári J. Clinical significance of genetic alterations and expression of epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinomas. Oral Oncol. 2011;47(6):487–96.
10. Arriola E, Taus Á, Casadevall D. Is there a role for epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor wild-type non-small cell lung cancer? World J Clin Oncol. 2015;6(4):45–56.
11. Epstein DM, Buck E. Old dog, new tricks: extracellular domain arginine methylation regulates EGFR function. J Clin Invest. 2015;125(12):4320–2.
12. Tynan CJ, Lo Schiavo V, Zanetti-Domingues L, Needham SR, Roberts SK, Hirsch M, Rolfe DJ, Korovesis D, Clarke DT, Martin-Fernandez ML. A tale of the epidermal growth factor receptor: The quest for structural resolution on cells. Methods. 2016;95:86–93.
13. Dorsey K, Agulnik M. Promising new molecular targeted therapies in head and neck cancer. Drugs. 2013;73(4):315–25.
14. Tseng JS, Wang CL, Yang TY, Chen CY, Yang CT, Chen KC, Hsu KH, Tsai CR, Chang GC. Divergent epidermal growth factor receptor mutation patterns between smokers and non-smokers with lung adenocarcinoma. Lung Cancer. 2015;90(3):472–6.
15. Schneider MR, Yarden Y. Structure and function of epigen, the last EGFR ligand. Semin Cell Dev Biol. 2014;28:57–61.
16. Ribeiro DC, Gleber-Netto FO, Sousa SF, Bernardes VD, Guimarães-Abreu MH, Aguiar MC. Immunohistochemical expression of EGFR in oral leukoplakia: association with clinicopathological features and cellular proliferation. Med Oral Patol Oral Cir Bucal. 2012;17(5):e739–44.
17. Nagalakshmi K, Jamil K, Pingali U, Reddy MV, Attili SS. Epidermal growth factor receptor (EGFR) mutations as biomarker for head and neck squamous cell carcinomas (HNSCC) Biomarkers. 2014;19(3):198–206.
18. Ohnishi Y, Watanabe M, Yasui H, Kakudo K. Effects of epidermal growth factor on the invasive activity and cytoskeleton of oral squamous cell carcinoma cell lines. Oncol Lett. 2014;7(5):1439–42.
19. Egloff AM, Rothstein ME, Seethala R, Siegfried JM, Grandis JR, Stabile LP. Cross-talk between estrogen receptor and epidermal growth factor receptor in head and neck squamous cell carcinoma. Clin Cancer Res. 2009;15(21):6529–40.
20. Knudsen SL, Mac AS, Henriksen L, van Deurs B, Grøvdal LM. EGFR signaling patterns are regulated by its different ligands. Growth Factors. 2014;32(5):155–63.
21. Zhang Z, Dong Z, Lauxen IS, Filho MS, Nör JE. Endothelial cell-secreted EGF induces epithelial to mesenchymal transition and endows head and neck cancer cells with stem-like phenotype. Cancer Res. 2014;74(10):2869–81.
22. Aggarwal H, Aggarwal A, Agrawal DK. Epidermal growth factor increases LRF/Pokemon expression in human prostate cancer cells. Exp Mol Pathol. 2011;91(2):496–501.
23. Niesen J, Stein C, Brehm H, Hehmann-Titt G, Fendel R, Melmer G, Fischer R, Barth S. Novel EGFR-specific immunotoxins based on panitumumab and cetuximab show in vitro and ex vivo activity against different tumor entities. J Cancer Res Clin Oncol. 2015;141(12):2079–95.
24. Yazdi MH, Faramarzi MA, Nikfar S, Abdollahi M. A Comprehensive Review of Clinical Trials on EGFR Inhibitors Such as Cetuximab and Panitumumab as Monotherapy and in Combination for Treatment of Metastatic Colorectal Cancer. Avicenna J Med Biotechnol. 2015;7(4):134–44.
25. Cosway B, Lovat P. The role of autophagy in squamous cell carcinoma of the head and neck. Oral Oncol. 2016;54:1–6.
26. Bagan JV, Mata-Roig M, Cortio-Gimeno J, Murillo-Cortes J, Hens-Aumente E, Poveda-Roda R, Bagan L. Epidermal growth factor receptor copy number in potentially malignant oral disorders and oral squamous cell carcinoma: a short communication and preliminary study. J Oral Pathol Med. 2012;41(9):662–6.
27. Do H, Krypuy M, Mitchell PL, Fox SB, Dobrovic A. High resolution melting analysis for rapid and sensitive EGFR and KRAS mutation detection in formalin fixed paraffin embedded biopsies. BMC Cancer. 2008;8:142.
28. Khattri A, Zuo Z, Brägelmann J, Keck MK, El Dinali M, Brown CD, Stricker T, Munagala A, Cohen EE, Lingen MW, White KP, Vokes EE, Seiwert TY. Rare occurrence of EGFRvIII deletion in head and neck squamous cell carcinoma. Oral Oncol. 2015;51(1):53–8.
29. Grimm M, Iftner T, Altaki H, Iftner A, Peters JP, Munz A, Reinert S. Detection of mutation-specific epidermal growth factor receptor (E746-A750del) and lack of detection of human papillomavirus in oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2014;43(10):1199–205.
30. Guo G, Gong K, Wohlfeld B, Hatanpaa KJ, Zhao D, Habib AA. Ligand-Independent EGFR Signaling. Cancer Res. 2015;75(17):3436–41.
31. Melchers LJ, Clausen MJ, Mastik MF, Slagter-Menkema L, Langendijk JA, van der Laan BF, van der Wal , van der Vegt B, Roodenburg JL, Schuuring E E. Head and neck squamous cell carcinomas do not express EGFRvIII. Int J Radiat Oncol Biol Phys. 2014;90(2):454–62.
32. Jutten B, Rouschop KM. EGFR signaling and autophagy dependence for growth, survival, and therapy resistance. Cell Cycle. 2014;13(1):42–51.
33. Hsieh CH, Chang JW, Hsieh JJ, Hsu T, Huang SF, Liao CT, Wang HM. Epidermal growth factor receptor mutations in patients with oral cavity cancer in a betel nut chewing-prevalent area. Head Neck. 2011;33(12):1758–64.
34. Zhen L, Fan D, Yi X, Cao X, Chen D, Wang L. Curcumin inhibits oral squamous cell carcinoma proliferation and invasion via EGFR signaling pathways. Int J Clin Exp Pathol. 2014;7(10):6438–46.
35. Capuani F, Conte A, Argenzio E, Marchetti L, Priami C, Polo S, Di Fiore PP, Sigismund S, Ciliberto A. Quantitative analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells. Nat Commun. 2015;6:7999.
36. Yang CH, Chou HC, Fu YN, Yeh CL, Cheng HW, Chang IC, Liu KJ, Chang GC, Tsai TF, Tsai SF, Liu HP, Wu YC, Chen YT, Huang SF, Chen YR. EGFR over-expression in non-small cell lung cancers harboring EGFR mutations is associated with marked down-regulation of CD82. Biochim Biophys Acta. 2015;1852(7):1540–9.
37. Wang D, Su L, Huang D, Zhang H, Shin DM, Chen ZG. Downregulation of E-Cadherin enhances proliferation of head and neck cancer through transcriptional regulation of EGFR. Mol Cancer. 2011;10:116.
38. El Zein N, D'Hondt S, Sariban E. Crosstalks between the receptors tyrosine kinase EGFR and TrkA and the GPCR, FPR, in human monocytes are essential for receptors-mediated cell activation. Cell Signal. 2010;22(10):1437–47.
39. Thomas SM, Bhola NE, Zhang Q, Contrucci SC, Wentzel AL, Freilino ML, Gooding WE, Siegfried JM, Chan DC, Grandis JR. Cross-talk between G protein-coupled receptor and epidermal growth factor receptor signaling pathways contributes to growth and invasion of head and neck squamous cell carcinoma. Cancer Res. 2006;66(24):11831–9.
40. Guo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol. 2004;5(10):816–26.
41. Zhang Q, Bhola NE, Lui VW, Siwak DR, Thomas SM, Gubish CT, Siegfried JM, Mills GB, Shin D, Grandis JR. Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer. Mol Cancer Ther. 2007;6(4):1414–24.
42. Santosh AB, Jones T, Harvey J. A review on oral cancer biomarkers: Understanding the past and learning from the present. J Cancer Res Ther. 2016;12(2):486–92.
43. Rajeswari MR, Saraswathi TR. Expression of epithelial growth factor receptor in oral epithelial dysplastic lesions. J Oral Maxillofac Pathol. 2012;16(2):183–8.
44. Aquino G, Pannone G, Santoro A, Liguori G, Franco R, Serpico R R, Florio G, De Rosa A, Mattoni M, Cozza V, Botti G, Losito S, Longo F, Staibano S, Cuda G, Lo Muzio L, Sbordone C, Bufo P, Grimaldi A, Caraglia M, Di Domenico M. pEGFR-Tyr 845 expression as prognostic factors in oral squamous cell carcinoma: a tissue-microarray study with clinic-pathological correlations. Cancer Biol Ther. 2012;13(11):967–77.
45. Huang SF, Cheng SD, Chien HT, Liao CT, Chen IH, Wang HM, Chuang WY, Wang CY, Hsieh LL. Relationship between epidermal growth factor receptor gene copy number and protein expression in oral cavity squamous cell carcinoma. Oral Oncol. 2012;48(1):67–72.
46. Bates T, Kennedy M, Diajil A, Goodson M, Thomson P, Doran E, Farrimond H, Thavaraj S, Sloan P, Kist R, Robinson M. Changes in Epidermal Growth Factor Receptor Gene Copy Number during Oral Carcinogenesis. Cancer Epidemiol Biomarkers Prev. 2016;25(6):927–35.
47. Bernardes VF, Gleber-Netto FO, Sousa SF, Rocha RM, Aguiar MC. EGFR status in oral squamous cell carcinoma: comparing immunohistochemistry, FISH and CISH detection in a case series study. BMJ Open. 2013;3(1):pii:e002077.
48. Naik DS, Sharma S, Ray A, Hedau S. Epidermal growth factor receptor expression in urinary bladder cancer. Indian J Urol. 2011;27(2):208–14.
49. Kawahara A, Fukumitsu C, Taira T, Abe H, Takase Y, Murata K, Yamaguchi T, Azuma K, Ishii H, Takamori S, Akiba J, Hoshino T, Kage M. Epidermal growth factor receptor mutation status in cell-free DNA supernatant of bronchial washings and brushings. Cancer Cytopathol. 2015;123(10):620–8.
50. Jing CW, Wang Z, Cao HX, Ma R, Wu JZ. High resolution melting analysis for epidermal growth factor receptor mutations in formalin-fixed paraffin-embedded tissue and plasma free DNA from non-small cell lung cancer patients. Asian Pac J Cancer Prev. 2014;14(11):6619–23.
51. McDevitt J, Weigum SE, Floriano PN, Christodoulides N, Redding SW, Yeh CK, McGuff S, Vigneswaran N, Thornhill MH, Williams MD. A new bio-nanochip sensor aids oral cancer detection. SPIE Newsroom. 2011:pii:003547.
How to Cite
SOMARRIVA, Carolina et al. Dysregulation and detection methods of EGFR in oral cancer. A narrative review.. Journal of Oral Research, [S.l.], v. 5, n. 7, p. 285-292, nov. 2016. ISSN 0719-2479. Available at: <http://www.joralres.com/index.php/JOR/article/view/joralres.2016.057>. Date accessed: 16 oct. 2021. doi: https://doi.org/10.17126/joralres.2016.057.


Epidermal Growth Factor Receptor; Mouth Neoplasm; Mutation.

Most read articles by the same author(s)