Lack of Mutations in Protein Tyrosine Kinase Domain Coding Exons 19 and 21 of the EGFR Gene in Oral Squamous Cell Carcinomas

  • Mehta, Dhaval Tushar (Human Genetics Laboratory, Sree Balaji Medical and Dental College and Hospital, Bharath University) ;
  • Annamalai, Thangavelu (Oral and Maxillofacial Surgery, Rajah Muthiah Dental College and Hospital, Annamalai University) ;
  • Ramanathan, Arvind (Human Genetics Laboratory, Sree Balaji Medical and Dental College and Hospital, Bharath University)
  • Published : 2014.06.15


Background: The epidermal growth factor receptor (EGFR) plays a vital role in the activation and inactivation of receptor tyrosine kinases. Mutations in exons 19 and 21 of EGFR are commonly found to be associated with non small cell lung carcinoma and triple negative breast cancer, enhancing sensitivity to EGFR targeting chemotherapeutic agents. Since amplification and prolonged activation of EGFR molecules have been identified in oral squamous cell carcinomas (OSCC), we investigated whether OSCCs carried mutations in exons 19 and 21 of EGFR to their incidence. Materials and Methods: Tumor chromosomal DNA isolated from forty surgically excised oral squamous cell carcinoma tissues was subjected to PCR amplification with intronic primers flanking exons 19 and 21 of the EGFR gene. The PCR amplicons were subsequently subjected to direct sequencing to elucidate the mutation status. Results: Data analysis of the EGFR exon 19 and 21 coding sequences did not show any mutations in the forty OSCC samples that were analyzed. Conclusions: To the best of our knowledge, this is the first study to have investigated the genetic status of exons 19 and 21 of EGFR in Indian OSCCs and identified that mutation in EGFR exon 19 and 21 may not contribute towards their genesis. The absence of mutations also indicates that oral cancerous lesions may not be as sensitive as other cancers to chemotherapeutic agents targeting EGFR.


  1. Asahina H, Yamazaki K, Kinoshita I, et al (2006). A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer, 95, 998-1004.
  2. Barber TD, Vogelstein B, Kinzler KW et al (2004). Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med, 27, 2283.
  3. Benchekroun MT, Saintigny P, Thomas SM, et al (2010). Epidermal growth factor receptor expression and gene copy number in the risk of oral cancer. Cancer Prev Res, 3, 800-9.
  4. Bhargava R, Gerald WL, Li AR, et al (2005). EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations. Mod Pathol, 18, 1027-33.
  5. Braakhuis B, Rietbergen M, Buijze M, et al (2013). TP53 mutation and human papilloma virus status of oral squamous cell carcinomas in young adult patients. Oral dis, [Epub ahead of print].
  6. Brand TM, Iida M, Li C, Wheeler DL (2011). The nuclear epidermal growth factor receptor signaling network and its role in cancer. Discov Med, 12, 419-32.
  7. D'Angelo SP, Pietanza MC, Johnson ML, et al (2011). Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol, 29, 2066-70.
  8. Huang S, Chuang W, Chen I, et al (2009). EGFR protein overexpression and mutation in areca quid-associated oral cavity squamous cell carcinoma in Taiwan. Head Neck, 31, 1068-77.
  9. Gazdar AF (2009). Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene, 28, 24-31.
  10. Generali D, Leek R, Fox SB, et al (2007). EGFR mutations in exons 18-21 in sporadic breast cancer. Ann Oncol, 18, 203-5.
  11. Hsieh CH, Chang JW, Hsieh JJ, et al (2011). Epidermal growth factor receptor mutations in patients with oral cavity cancer in a betelnut chewing-prevalent area. Head Neck, 33, 1758-64.
  12. Huang Y, Chang Y (2011). "The Eighth Chapter" Prostate Cancer: From Bench to Bedside. Croatia, Intech publisher, 2011.
  13. Inoue A, Suzuki T, Fukuhara T, et al (2006). Prospective phase ii study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol, 24, 3340-6.
  14. Jayaraman B, Valiathan GM, Jayakumar K, et al (2012). Lack of mutation in p53 and H-ras genes in phenytoin induced gingival overgrowth suggests its non cancerous nature. Asian Pac J Cancer Prev, 13, 5535-8.
  15. Lee JW, Soung YH, Kim SY, et al (2004). Absence of EGFR mutation in the kinase domain in common human cancers besides non-small cell lung cancer. Int J Cancer, 113, 510-11.
  16. Lee JW, Soung YH, Seo SH, et al (2005). Carcinoma of the head and neck somatic mutations of egfr gene in squamous cell carcinoma of the head and neck. Clin Cancer Res, 11, 2879-82.
  17. Lee JW, Soung YH, Seo SH, et al (2006). Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res, 12, 57-61.
  18. Lo HW, Cao X, Zhu H, et al (2010). Cyclooxygenase-2 is a novel transcriptional target of the nuclear EGFR-STAT3 and EGFR VIII-STAT3 signaling axes. Mol Cancer Res, 8, 232-45.
  19. Li M, Zhang Q, Liu L, et al (2011). The different clinical significance of EGFR mutations in exon 19 and 21 in non-small cell lung cancer patients of China. Neoplasma, 58, 74-81.
  20. Li TJ, Ciu J (2013). COX-2, MMP-7 expression in oral lichen planus and oral squamous cell carcinoma. Asian Pac J Trop Med, 6, 640-3.
  21. Liu Q, Ma G, Yang H, et al (2013). Lack of epidermal growth factor receptor gene mutations in exons 19 and 21 in primary lymphoepithelioma-like carcinoma of the lung. Thoracic Cancer, 5, 63-7.
  22. Loeffler-Ragg J, Witsch-Baumgartner M, Tzankov A, et al (2005). Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma. Eur J Cancer, 42, 109-11.
  23. Lynch TJ, Bell DW, Sordella R, et al (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med, 350, 2129-39.
  24. Marchetti A, Martella C, Felicioni L, et al (2005). EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol, 23, 857-65.
  25. Martin-Ezquerra G, Salgado R, Toll A, et al (2010). Multiple genetic copy number alterations in oral squamous cell carcinoma: study of MYC, TP53, CCDN1, EGFR and ERBB2 status in primary and metastatic tumours. Br J Dermatol, 163, 1028-35.
  26. Mitsudomi T, Yatabe Y (2009). Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J, 277, 301-8.
  27. Pao W, Miller V, Zakowski M, et al (2004). EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA, 101, 13306-11.
  28. Oh B, Lee R, Chung S, Ho Kim K (2011). Epidermal growth factor receptor mutations in colorectal cancer patients. J Korean Soc Coloproctol, 27, 127-32.
  29. Olivier M, Hollstein M, Hainaut P (2010). TP53 mutations in human cancers: Origins, consequences, and clinical use. Cold Spring Harb Perspect Biol, 2, 001008.
  30. Paez JG, Janne PA, Lee JC, et al (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science, 304, 1497-500.
  31. Pennock S, Wang Z (2008). A tale of two Cbls: interplay of c-Cbl and Cbl-b in epidermal growth factor receptor downregulation. Mol Cell Biol, 28, 3020-37.
  32. Peraldo-Neia C, Migliardi G, Mello-Grand M, et al (2011). Epidermal Growth Factor Receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer. BMC Cancer, 11, 31.
  33. Rajendran S, Muthupalani RS, Ramanathan A (2013). Lack of RING finger domain (RFD) mutations of the c-cbl gene in oral squamous cell carcinomas in Chennai, India. Asian Pac J Cancer Prev, 14, 1073-5.
  34. Sasaki H, Okuda K, Endo K, et al (2007). CCND1 messenger RNA expression is correlated with EGFR mutation status in lung cancer. Clin Lung Cancer, 8, 493-6.
  35. Shintani S, Li C, Mihara M, et al (2004). Gefitinib ('Iressa', ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, up-regulates p27KIP1 and induces G1 arrest in oral squamous cell carcinoma cell lines. Oral Oncol, 40, 43-51.
  36. Soo-Chin L, Seng-Gee L, Ross S (2006). Lack of somatic mutations in EGFR tyrosine kinase domain in hepatocellular and nasopharyngeal carcinoma. Pharmacogenetics Genomics, 16, 73-4.
  37. Teng YH, Tan WJ, Thike A, et al (2011). Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative breast cancer: possible implications for targeted therapy. Breast Cancer Res, 13, 35.
  38. Tushar MD, Ramanathan A (2013). Tyrosine 1045 codon mutations in exon 27 of EGFR are infrequent in oral squamous cell carcinomas. Asian Pac J Cancer Prev, 14, 4279-82.
  39. Valiathan GM, Thenumgal SJ, Jayaraman B, et al (2012). Common docking domain mutation E322K of the ERK2 gene is infrequent in oral squamous cell carcinomas. Asian Pac J Cancer Prev, 13, 6155-7.
  40. Van Damme N, Deron P, Van Roy N, et al (2010). Epidermal growth factor receptor and K-RAS status in two cohorts of squamous cell carcinomas. BMC Cancer, 10, 189.
  41. Woelk T, Sigismund S, Penengo L, Polo S (2007). The ubiquitination code: a signalling problem. Cell Div, 2, 11.
  42. Weber F, Fukino K, Sawada T, et al (2005). Variability in organ-specific EGFR mutational spectra in tumour epithelium and stroma may be the biological basis for differential responses to tyrosine kinase inhibitors. Br J Cancer, 92, 1922-6.
  43. Zanaruddin SNS, San Yee P, Yii Hor S, et al (2013). Common oncogenic mutations are infrequent in oral squamous cell carcinoma of Asian origin. PLoS ONE, 8, 80229.

Cited by

  1. Hypermethylation of Promoter Region of LATS1 - a CDK Interacting Protein in Oral Squamous Cell Carcinomas - a Pilot Study in India vol.16, pp.4, 2015,
  2. BRD7 Promoter Hypermethylation as an Indicator of Well Differentiated Oral Squamous Cell Carcinomas vol.16, pp.4, 2015,