Tumor Biology

, Volume 37, Issue 7, pp 9089–9098 | Cite as

Mutation analysis of EGFR and its correlation with the HPV in Indian cervical cancer patients

  • Rehana Qureshi
  • Himanshu Arora
  • Shilpi Biswas
  • Ahmad Perwez
  • Afreen Naseem
  • Saima Wajid
  • Gauri Gandhi
  • Moshahid Alam Rizvi
Original Article


Cervical cancer is a major cause of morbidity and mortality particularly in developing countries. Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene is associated with increased sensitivity to tyrosine kinase inhibitors (TKIs). In this study, the presence of EGFR mutations in cervical cancer and its correlation with HPV were identified. EGFR mutations were found in 31 out of 95 patients (32.63 %). Results showed the presence of EGFR mutations in 5.263 % of patients in exon 19. In exon 20, mutations were predominant in 25.26 % patients. While in exon 21, 8.421 % of patients had mutations. HPV, which is associated with cervical cancer development, was found in 95.78 % (HPVL1), 92.63 % (HPV16), and 3.15 % (HPV18) of patients. No correlation was found between HPV16 and EGFR mutations (p = 0.0616). Overall, mutations like V742R, Q787Q, Q849H, E866E, T854A, L858R, E872Q, and E688Q were found. Next, impact of TKI inhibitor (gefitinib) was checked with respect to presence or absence of mutation considering Q787Q mutation in exon 20 (G/A genotype) which is present in 25.2 % patients. Mutated cervical cancer cell lines showed higher sensitivity to gefitinib. Overall, this study suggests the importance of mutations in EGFR gene and indicates their relevance with respect to TKIs treatment in Indian cervical cancer patients.


EGFR Mutation HPV16 Correlation 


Compliance with ethical standards

Conflicts of interest



This study was supported by the UGC- Dr. D.S. Kothari Postdoctoral fellowship, Government of India.

Supplementary material

13277_2016_4789_MOESM1_ESM.xlsx (37 kb)
ESM 1 (XLSX 37 kb)
13277_2016_4789_MOESM2_ESM.xlsx (10 kb)
ESM 2 (XLSX 10 kb)


  1. 1.
    Fraguas S, Barberan S, Cebria F. EGFR signaling regulates cell proliferation, differentiation and morphogenesis during planarian regeneration and homeostasis. Dev Biol. 2011;354:87–101.CrossRefPubMedGoogle Scholar
  2. 2.
    Arteaga C. Targeting HER1/EGFR: a molecular approach to cancer therapy. Semin Oncol. 2003;30:3–14.CrossRefGoogle Scholar
  3. 3.
    Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist. 2002;7 Suppl 4:2–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Movva S, Rodriguez L, Arias-Pulido H, Verschraegen C. Novel chemotherapy approaches for cervical cancer. Cancer. 2009;115:3166–80.CrossRefPubMedGoogle Scholar
  5. 5.
    Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer. 2001;37 Suppl 4:S9–15.CrossRefPubMedGoogle Scholar
  6. 6.
    Schrevel M, Gorter A, Kolkman-Uljee SM, Trimbos JB, Fleuren GJ, Jordanova ES. Molecular mechanisms of epidermal growth factor receptor overexpression in patients with cervical cancer. Modern Pathol: Off J US Can Acad Pathol Inc. 2011;24:720–8.CrossRefGoogle Scholar
  7. 7.
    Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.CrossRefPubMedGoogle Scholar
  8. 8.
    Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.CrossRefPubMedGoogle Scholar
  9. 9.
    Lee JW, Soung YH, Kim SY, Nam HK, Park WS, Nam SW, et al. Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin Cancer Res: Off J Am Assoc Cancer Res. 2005;11:2879–82.CrossRefGoogle Scholar
  10. 10.
    Gu D, Scaringe WA, Li K, Saldivar JS, Hill KA, Chen Z, et al. Database of somatic mutations in EGFR with analyses revealing indel hotspots but no smoking-associated signature. Hum Mutat. 2007;28:760–70.CrossRefPubMedGoogle Scholar
  11. 11.
    Li M, Zhang Q, Liu L, Liu Z, Zhou L, Wang Z, et al. The different clinical significance of EGFR mutations in exon 19 and 21 in non-small cell lung cancer patients of China. Neoplasma. 2011;58:74–81.CrossRefPubMedGoogle Scholar
  12. 12.
    Rosell R, Taron M, Reguart N, Isla D, Moran T. Epidermal growth factor receptor activation: how exon 19 and 21 mutations changed our understanding of the pathway. Clin Cancer Res: Off J Am Assoc Cancer Res. 2006;12:7222–31.CrossRefGoogle Scholar
  13. 13.
    Soonthornthum T, Arias-Pulido H, Joste N, Lomo L, Muller C, Rutledge T, et al. Epidermal growth factor receptor as a biomarker for cervical cancer. Ann Oncol: Off J Eur Soc Med Oncol / ESMO. 2011;22:2166–78.CrossRefGoogle Scholar
  14. 14.
    Chapman WB, Lorincz AT, Willett GD, Wright VC, Kurman RJ. Epidermal growth factor receptor expression and the presence of human papillomavirus in cervical squamous intraepithelial lesions. Int J Gynecol Pathol: Off J Int Soc Gynecol Pathol. 1992;11:221–6.CrossRefGoogle Scholar
  15. 15.
    Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol. 2002;55:244–65.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    H. zur Hausen, Papillomavirus infections--a major cause of human cancers, Biochimica et biophysica acta, 1288 (1996) F55-78.Google Scholar
  17. 17.
    Zhang B, Srirangam A, Potter DA, Roman A. HPV16 E5 protein disrupts the c-Cbl-EGFR interaction and EGFR ubiquitination in human foreskin keratinocytes. Oncogene. 2005;24:2585–8.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Straight SW, Hinkle PM, Jewers RJ, McCance DJ. The E5 oncoprotein of human papillomavirus type 16 transforms fibroblasts and effects the downregulation of the epidermal growth factor receptor in keratinocytes. J Virol. 1993;67:4521–32.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Tsai TC, Chen SL. The biochemical and biological functions of human papillomavirus type 16 E5 protein. Arch Virol. 2003;148:1445–53.CrossRefPubMedGoogle Scholar
  20. 20.
    Duensing S, Munger K. Mechanisms of genomic instability in human cancer: insights from studies with human papillomavirus oncoproteins. Int J Cancer J Int Cancer. 2004;109:157–62.CrossRefGoogle Scholar
  21. 21.
    Teng YH, Tan WJ, Thike AA, Cheok PY, Tse GM, Wong NS, et al. Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative breast cancer: possible implications for targeted therapy. Breast Cancer Res: BCR. 2011;13:R35.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Bumrungthai S, Munjal K, Nandekar S, Cooper K, Ekalaksananan T, Pientong C, et al. Epidermal growth factor receptor pathway mutation and expression profiles in cervical squamous cell carcinoma: therapeutic implications. J Transl Med. 2015;13:244.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Mehdi SJ, Alam MS, Batra S, Rizvi MM. Allelic loss of 6q25-27, the PARKIN tumor suppressor gene locus, in cervical carcinoma. Med Oncol. 2011;28:1520–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Josefsson A, Magnusson P, Gyllensten U. Human papillomavirus detection by PCR and typing by dot-blot. Methods Mol Med. 1999;20:171–93.PubMedGoogle Scholar
  25. 25.
    Jacot W, Lopez-Crapez E, Thezenas S, Senal R, Fina F, Bibeau F, et al. Lack of EGFR-activating mutations in European patients with triple-negative breast cancer could emphasise geographic and ethnic variations in breast cancer mutation profiles. Breast Cancer Res: BCR. 2011;13:R133.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kearse M, Moir R, Wilson A, Stones-Havas S, Cheung M, Sturrock S, et al. Geneious Basic: an integrated and extendable desktop software platform for the organization and analysis of sequence data. Bioinformatics. 2012;28:1647–9.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Konecny G, Crohns C, Pegram M, Felber M, Lude S, Kurbacher C, et al. Correlation of drug response with the ATP tumorchemosensitivity assay in primary FIGO stage III ovarian cancer. Gynecol Oncol. 2000;77:258–63.CrossRefPubMedGoogle Scholar
  28. 28.
    Kaarthigeyan K. Cervical cancer in India and HPV vaccination. Indian J Med Paediatr Oncol: Off J Indian Soc Med Paediatr Oncol. 2012;33:7–12.CrossRefGoogle Scholar
  29. 29.
    Wright AA, Howitt BE, Myers AP, Dahlberg SE, Palescandolo E, Van Hummelen P, et al. Oncogenic mutations in cervical cancer: genomic differences between adenocarcinomas and squamous cell carcinomas of the cervix. Cancer. 2013;119:3776–83.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007;370:890–907.CrossRefPubMedGoogle Scholar
  31. 31.
    Alam MS, Ali A, Mehdi SJ, Alyasiri NS, Kazim Z, Batra S, et al. HPV typing and its relation with apoptosis in cervical carcinoma from Indian population. Tumour Biol: J Int Soc Oncodev Biol Med. 2012;33:17–22.CrossRefGoogle Scholar
  32. 32.
    Silva AM, Lisboa BC, Cunha IW, Rocha RM, Zequi SC, Guimaraes GC, et al. Comment on: EGFR mutational status in Brazilian patients with penile carcinoma. Expert Opin Ther Targets. 2013;17:857–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Yewale C, Baradia D, Vhora I, Patil S, Misra A. Epidermal growth factor receptor targeting in cancer: a review of trends and strategies. Biomaterials. 2013;34:8690–707.CrossRefPubMedGoogle Scholar
  34. 34.
    Mantha AJ, Hanson JE, Goss G, Lagarde AE, Lorimer IA, Dimitroulakos J. Targeting the mevalonate pathway inhibits the function of the epidermal growth factor receptor. Clin Cancer Res: Off J Am Assoc Cancer Res. 2005;11:2398–407.CrossRefGoogle Scholar
  35. 35.
    Bachran D, Schneider S, Bachran C, Urban R, Weng A, Melzig MF, et al. Epidermal growth factor receptor expression affects the efficacy of the combined application of saponin and a targeted toxin on human cervical carcinoma cells. Int J Cancer J Int Cancer. 2010;127:1453–61.CrossRefGoogle Scholar
  36. 36.
    Taguchi T, Tsukuda M, Imagawa-Ishiguro Y, Kato Y, Sano D. Involvement of EGFR in the response of squamous cell carcinoma of the head and neck cell lines to gefitinib. Oncol Rep. 2008;19:65–71.PubMedGoogle Scholar
  37. 37.
    Helfrich BA, Raben D, Varella-Garcia M, Gustafson D, Chan DC, Bemis L, et al. Antitumor activity of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) in non-small cell lung cancer cell lines correlates with gene copy number and EGFR mutations but not EGFR protein levels. Clin Cancer Res. 2006;12:7117–25.CrossRefPubMedGoogle Scholar
  38. 38.
    Dikshit R, Gupta PC, Ramasundarahettige C, Gajalakshmi V, Aleksandrowicz L, Badwe R, et al. Cancer mortality in India: a nationally representative survey. Lancet. 2012;379:1807–16.CrossRefPubMedGoogle Scholar
  39. 39.
    Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, et al. Carcinoma of the fallopian tube. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet: Off Organ Int Fed Gynaecol Obstet. 2006;95 Suppl 1:S145–160.CrossRefGoogle Scholar
  40. 40.
    Vici P, Mariani L, Pizzuti L, Sergi D, Di Lauro L, Vizza E, et al. Emerging biological treatments for uterine cervical carcinoma. J Cancer. 2014;5:86–97.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Mountzios G, Soultati A, Pectasides D, Pectasides E, Dimopoulos MA, Papadimitriou CA. Developments in the systemic treatment of metastatic cervical cancer. Cancer Treat Rev. 2013;39:430–43.CrossRefPubMedGoogle Scholar
  42. 42.
    Hale RJ, Buckley CH, Gullick WJ, Fox H, Williams J, Wilcox FL. Prognostic value of epidermal growth factor receptor expression in cervical carcinoma. J Clin Pathol. 1993;46:149–53.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kersemaekers AM, Fleuren GJ, Kenter GG, Van den Broek LJ, Uljee SM, Hermans J, et al. Oncogene alterations in carcinomas of the uterine cervix: overexpression of the epidermal growth factor receptor is associated with poor prognosis. Clin Cancer Res: Off J Am Assoc Cancer Res. 1999;5:577–86.Google Scholar
  44. 44.
    Pillai MR, Jayaprakash PG, Nair MK. Tumour-proliferative fraction and growth factor expression as markers of tumour response to radiotherapy in cancer of the uterine cervix. J Cancer Res Clin Oncol. 1998;124:456–61.CrossRefPubMedGoogle Scholar
  45. 45.
    Lindstrom AK, Tot T, Stendahl U, Syrjanen S, Syrjanen K, Hellberg D. Discrepancies in expression and prognostic value of tumor markers in adenocarcinoma and squamous cell carcinoma in cervical cancer. Anticancer Res. 2009;29:2577–8.PubMedGoogle Scholar
  46. 46.
    Skomedal H, Kristensen GB, Lie AK, Holm R. Aberrant expression of the cell cycle associated proteins TP53, MDM2, p21, p27, cdk4, cyclin D1, RB, and EGFR in cervical carcinomas. Gynecol Oncol. 1999;73:223–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Noordhuis MG, Eijsink JJ, Ten Hoor KA, Roossink F, Hollema H, Arts HJ, et al. Expression of epidermal growth factor receptor (EGFR) and activated EGFR predict poor response to (chemo)radiation and survival in cervical cancer. Clin Cancer Res: Off J Am Assoc Cancer Res. 2009;15:7389–97.CrossRefGoogle Scholar
  48. 48.
    Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2008;26:2311–9.CrossRefGoogle Scholar
  49. 49.
    Rivera F, Garcia-Castano A, Vega N, Vega-Villegas ME, Gutierrez-Sanz L. Cetuximab in metastatic or recurrent head and neck cancer: the EXTREME trial. Expert Rev Anticancer Ther. 2009;9:1421–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Senderowicz AM, Johnson JR, Sridhara R, Zimmerman P, Justice R, Pazdur R. Erlotinib/gemcitabine for first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas. Oncology (Williston Park). 2007;21:1696–706. discussion 1706–1699, 1712, 1715.Google Scholar
  51. 51.
    Johnson JR, Cohen M, Sridhara R, Chen YF, Williams GM, Duan J, et al. Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res: Off J Am Assoc Cancer Res. 2005;11:6414–21.CrossRefGoogle Scholar
  52. 52.
    Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2005;23:2445–59.CrossRefGoogle Scholar
  53. 53.
    Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. 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 U S A. 2004;101:13306–11.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Goncalves A, Fabbro M, Lhomme C, Gladieff L, Extra JM, Floquet A, et al. A phase II trial to evaluate gefitinib as second- or third-line treatment in patients with recurring locoregionally advanced or metastatic cervical cancer. Gynecol Oncol. 2008;108:42–6.CrossRefPubMedGoogle Scholar
  55. 55.
    Candelaria M, Arias-Bonfill D, Chavez-Blanco A, Chanona J, Cantu D, Perez C, et al. Lack in efficacy for imatinib mesylate as second-line treatment of recurrent or metastatic cervical cancer expressing platelet-derived growth factor receptor alpha. Int J Gynecol Cancer: Off J Int Gynecol Cancer Soc. 2009;19:1632–7.CrossRefGoogle Scholar
  56. 56.
    Monk BJ, Mas Lopez L, Zarba JJ, Oaknin A, Tarpin C, Termrungruanglert W, et al. Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2010;28:3562–9.CrossRefGoogle Scholar
  57. 57.
    Taja-Chayeb L, Chavez-Blanco A, Martinez-Tlahuel J, Gonzalez-Fierro A, Candelaria M, Chanona-Vilchis J, et al. Expression of platelet derived growth factor family members and the potential role of imatinib mesylate for cervical cancer. Cancer Cell Int. 2006;6:22.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Siegelin MD, Borczuk AC. Epidermal growth factor receptor mutations in lung adenocarcinoma. Lab Investig; J Tech Methods Pathol. 2014;94:129–37.CrossRefGoogle Scholar
  59. 59.
    Longatto-Filho A, Pinheiro C, Martinho O, Moreira MA, Ribeiro LF, Queiroz GS, et al. Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma. BMC Cancer. 2009;9:212.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Arias-Pulido H, Joste N, Chavez A, Muller CY, Dai D, Smith HO, et al. Absence of epidermal growth factor receptor mutations in cervical cancer. Int J Gynecol Cancer: Off J Int Gynecol Cancer Soc. 2008;18:749–54.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Rehana Qureshi
    • 1
  • Himanshu Arora
    • 2
  • Shilpi Biswas
    • 1
  • Ahmad Perwez
    • 1
  • Afreen Naseem
    • 1
  • Saima Wajid
    • 3
  • Gauri Gandhi
    • 4
  • Moshahid Alam Rizvi
    • 1
  1. 1.Department of Biosciences, Genome Biology LaboratoryJamia Millia IslamiaNew DelhiIndia
  2. 2.School of Studies in Zoology and BiotechnologyVikram UniversityUjjainIndia
  3. 3.Department of BiotechnologyFaculty of Science Jamia HamdardNew DelhiIndia
  4. 4.Department of Obstetrics and Gynaecology LNJP/MMAC CampusNew DelhiIndia

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