Issue
Identification of G2607A mutation in EGFR gene with a significative rate in Moroccan patients with Bladder Cancer
Corresponding Author(s) : M. El Mzibri
Cellular and Molecular Biology,
Vol. 63 No. 5: Issue 5
Abstract
The epidermal growth factor receptor (EGFR) is involved in the regulation of several cellular processes and in the development of many human cancers. Somatic mutations of EGFR at tyrosine kinase domain have been associated with clinical response to tyrosine kinase inhibitors (TKIs) in lung cancer patients. In this study, we evaluated the frequency of point mutations in EGFR for future use of TKI in clinical treatment of bladder cancer. A total, 50 Moroccan patient specimens with bladder cancer and 48 healthy controls were analysed for EGFR mutations in the region delimiting exons 18-21 by PCR amplification and direct sequencing. Our results showed the absence of mutations in the EGFR kinase domain in these exons in all analysed specimens. However, sequence analysis of the EGFR-TK domain, revealed the presence of (G2607A) polymorphism at exon 20. Statistical analysis showed significant difference in the frequencies of G2607A polymorphism between cancer cases and healthy controls (p=0.0001) and the frequencies of the GG and GA/AA genotypes among the cancer cases were 28% and 72%, respectively. Moreover, allelic frequencies of G2607A polymorphism showed significant difference between cancer cases and healthy controls (p=0.0025). Data analysis showed no significant association between G2607A polymorphism and patients' age, clinical stage and tumor grade (p > 0.05). However, a significant difference was found between this polymorphism and patients' sex that could be a sampling bias due to the very limited number of women with bladder cancer. Our findings highlight that, mutations in EGFR kinase domain is a rare event in bladder cancer, suggesting, that treatment of bladder cancer patients with TKI may not be effective. However, the EGFR G2607A polymorphism in exon 20 is frequent in bladder cancer cases and must be further explored for its relevance in the treatment of this disease.
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- Kaufman DS, Shipley WU, Feldman AS. Bladder cancer. The Lancet. 2009; 374: 239-49.
- Jemal A, Bray F, Center MM, Ferlay J, Ward E. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90.
- Benider A, Bendahhou K, Afghar S, Charrat B, Ahmadaye IK. Registre des cancers de la region du grand Casablanca pour la periode 2008-2012. Eds 2016.
- Tazi MA, Er-Raki A, Benjaafar N.Cancer incidence in Rabat. Morocco: 2006-2008. Ecancer 2013; 7:338.
- Sapre N, Herle P, Anderson PD, Corcoran NM, Hovens CM. Molecular biomarkers for predicting outcomes in urothelial carcinoma of the bladder. Pathology. 2014; 46: 274-82.
- Mason RA, Morlock EV, Karagas MR, Kelsey KT, Marsit CJ, Schned AR, Andrew AS. EGFR pathway polymorphisms and bladder cancer susceptibility and prognosis. Carcinogenesis. 2009; 30: 1155-60.
- Isla D, De Castro J, Juan O, Grau S, Orofino J, Gordo R, Rubio-Terrés C, Rubio-Rodríguez D. Costs of adverse events associated with erlotinib or afatinib in first-line treatment of advanced EGFR-positive non-small cell lung cancer. Clinicoecon Outcomes Res. 2016; 9: 31-8.
- Arias-Pulido H, Joste N, Chavez A, Muller CY, Dai D, Smith HO, Verschraegen CF. Absence of epidermal growth factor receptor mutations in cervical cancer. Int. J. Gynecol. Cancer. 2008; 18: 749-54.
- Dominguez-Escrig JL, Kelly JD, Neal DE, King SM, Davies BR. Evaluation of the therapeutic potential of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in preclinical models of bladder cancer. Clin Cancer Res. 2004; 10: 4874-84.
- Nutt JE, Lazarowicz HP, Mellon JK, Lunec J. Gefitinib (‘Iressa', ZD1839) inhibits the growth response of bladder tumour cell lines to epidermal growth factor and induces TIMP2. Br, J Cancer. 2004; 90: 1679-85.
- Grivas PD, Day KC, Karatsinides A, Paul A, Shakir N, Owainati I, Liebert M, Kunju LP, Thomas D, Hussain M, Day ML. Evaluation of the antitumor activity of dacomitinib in models of human bladder cancer. Mol Med. 2013; 19: 367-76.
- Lyer G, Al-Ahmadie H, Schultz N, Hanrahan AJ, Ostrovnaya I, Balar AV. Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. Journal of Clinical Oncology. 2013; 31: 3133-40.
- Berrada N, Amzazi S, Abbar M, Ameur A, Khyatti M, Al-Bouzidi A and Attaleb M. Mutational Analysis of FGFR3 and HRAS Genes in Bladder Cancer and Washing Cell Sediments of Moroccan Patients. Epidemiology. 2015; 5:4
- Blehm KN, Spiess PE, Bondaruk JE. Mutations within the kinase domain and truncations of the epidermal growth factor receptor are rare events in bladder cancer: implications for therapy. Clin Cancer Res. 2006; 12: 4671.
- Chaux A, Cohen JS, Schultz L.High epidermal growth factor receptor immunohistochemical expression in urothelial carcinoma of the bladder is not associated with EGFR mutations in exons 19 and 21: a study using formalin fixed, paraffin-embedded archival tissues. Hum Pathol. 2012; 43: 1590.
- Alexander RE, Montironi R, Lopez-Beltran A. EGFR alterations and EML4-ALK rearrangement in primary adenocarcinoma of the urinary bladder. Mod Pathol. 2014; 27: 107.
- Flaig TW, Su LJ, McCoach C.Dual epidermal growth factor receptor and vascular endothelial growth factor receptor inhibition with vandetanib sensitizes bladder cancer cells to cisplatin in a dose- and sequence-dependent manner. BJU Int. 2009; 103: 1729.
- Ross JS, Wang K, Al-Rohil RN, Nazeer T, Sheehan CE, Otto GA, He J, Palmer G, Yelensky R, Lipson D, Ali S, Balasubramanian S, Curran JA, Garcia L, Mahoney K, Downing SR, awryluk M, Miller VA, Stephens PJ. Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy. Mod Pathol. 2014; 27: 271-80.
- Amador ML, Oppenheimer D, Perea S, Maitra A, Cusatis G, Iacobuzio-Donahue C, Baker SD, Ashfaq R, Takimoto C, Forastiere A, Hidalgo M.An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors. Cancer Res. 2004; 64: 9139-43.
- Ma F, Sun T, Shi Y, Yu D, Tan W, Yang M, Wu C, Chu D, Sun Y, Xu B, Lin D.Polymorphisms of EGFR predict clinical outcome in advanced non-small-cell lung cancer patients treated with Gefitinib. Lung Cancer. 2009; 66: 114-9.
- Ma F, Xu B, Lin D, Sun T, Shi Y. Effect of rs2293347 Polymorphism in EGFR on the Clinical Efficacy of Gefitinib in Patients with Non-small Cell Lung Cancer. Zhongguo Fei Ai Za Zhi. 2011; 14: 642–5.
- Ichihara S, Toyooka S, Fujiwara Y, Hotta K, Shigematsu H, Tokumo, M, Soh J, Asano H, Ichimura K, Aoe K, Aoe M, Kiura K, Shimizu K, Date H, Shimizu N.The impact of epidermal growth factor receptor gene status on gefitinib-treated Japanese patients with non-small-cell lung cancer. Int J Cancer. 2007; 120: 1239-47.
- Chintala L, Kurzrock R. Epidermal growth factor receptor mutation and diverse tumors: case report and concise literature review. Mol Oncol. 2010; 4: 306-8
- Baulcombe D. DNA events: an RNA microcosm. Science. 2002; 297: 2002- 3.
- Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science. 2004; 304: 1497-500.
- Epstein JI, Amin MB, Reuter VR, Mosto FK. The World Health Organization / international Society of Urological Pathology consensus classification of urotltelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. The American journal of surgical pathology. 1998; 22: 1435-48.
- Sobin LH, Gospodariwicz M, Wittekmd C.TNM Classifcation of Malignant Ttnnors. UICC International Union Against Cancer. Oxford: Wiley-Blackwell. 2009; 262-5.
- El Hamdani W, Amrani M, Attaleb M, Laantri N, Ennaji MM, Khyatti M, El Mzibri M. EGFR, p16INK4a and E-cadherin immuno-histochemistry and EGFR point mutations analyses in invasive cervical cancer specimens from Moroccan women. Cell Mol Biol (Noisy-le–Grand). 2010; 56: 1373-84.
- Naji F, Attaleb M, Laantri N, Benchakroun N, El Gueddari B, Benider A, Azeddoug H, Ennaji MM, El Mzibri M, Khyatti M.Identification of G2607A mutation in EGFR gene with a significative rate in Moroccan patients with nasopharyngeal carcinoma. Cell Mol Biol (Noisy-le–Grand). 2010; 56: 1442-6.
- Cheetham PJ, and Petrylak DP.New Agents for the Treatment of Advanced Bladder Cancer. Oncology (Williston Park). 2016; 30: 571–9.
- Bethune G, Bethune D, Ridgway N, Xu Z.Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. J Thorac Dis. 2010; 2: 48-51.
- Villares GJ, Zigler M, Blehm K, Bogdan C, McConkey D, Colin D, Bar-Eli M.Targeting EGFR in bladder cancer. World J Urol. 2007; 25: 573-9.
- Barber TD, Vogelstein B, Kinzler KW, Velculescu VE.Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med. 2004; 351: 2883.
- Marchetti A, Martella C, Felicioni L, Barassi F, Salvatore S, Chella A, Camplese, PP, Iarussi T, Mucilli F, Mezzetti A, Cuccurullo F, Sacco R, and Buttitta F.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. 2005; 523: 857- 65.
- Zhang W, Stabile LP, Keohavong P, Romkes M, Grandis JR, Traynor AM, and Siegfried JM.Mutation and polymorphism in the EGFR-TK domain associated with lung cancer. J. Thorac. Oncol. 2006; 1: 635- 47.
- Metzger B, Chambeau L, Begon DY, Faber C, Kayser J, Berchem G, Pauly M, Boniver J, Delvenne P, Dicato M, Wenner T. The human epidermal growth factor receptor (EGFR) gene in European patients with advanced colorectal cancer harbors infrequent mutations in its tyrosine kinase domain. BMC Med Genet. 2011; 12: 144
- Su MC, Lien HC, Jeng YM.Absence of epidermal growth factor receptor exon 18-21 mutation in hepatocellular carcinoma. Cancer Lett. 2005; 224: 117-21.
- Longatto-Filho A, Pinheiro C, Martinho O, Moreira MA, Ribeiro LF, Queiroz GS, Schmitt FC, Baltazar F, Reis RM. Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma. BMC Cancer. 2009; 9: 212.
- Fukushima T, Favereaux A, Huang H, Shimizu T, Yonekawa Y, Nakazato Y, Ohagki H.Genetic alterations in primary glioblastomas in Japan. J Neuropathol Exp Neurol. 2006; 65: 12-8.
- Horstmann M, Witthuhn R, Falk M, Stenzl A. Gender-specific differences in bladder cancer: a retrospective analysis. Gend Med. 2008; 5: 385-94.
- Rose TL, Deal AM, Nielsen ME, Smith AB, Milowsky MI. Sex disparities in use of chemotherapy and survival in patients with advanced bladder cancer. Cancer. 2016; 122: 2012-20.
- Kaneko K, Kumekawa Y, Makino R, Nozawa H, Hirayama Y, Kogo M, Konishi K, Katagiri A, Kubota Y, Muramoto T, Kushima M, Ohmori T, Oyama T, Kagawa N, Ohtsu A, Imawari M. EGFR gene alterations as a prognostic biomarker in advanced esophageal squamous cell carcinoma. Front Biosci (Landmark Ed). 2010; 15: 65-72.
- 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.
- Nakazaki K, Kato Y, Taguchi T, Inayama Y, Ishiguro Y, Kondo N, Horiuchi C, Sakakibara A, Tsukuda M.Heterozygous mutation (G/G→G/A) at nt 2607 of the EGFR gene is closely associated with increases in EGFR copy number and mRNA half-life, but impaired EGFR protein synthesis in squamous cell carcinomas of the head and neck - implication for gefitinib efficacy. Oncol Lett. 2010; 1: 1017-20.
- Hsieh YY, Tzeng CH, Chen MH, Chen PM, Wang WS. Epidermal growth factor receptor R521K polymorphism shows favorable outcome to cetuximab-based treatment in KRAS wild-type colorectal cancer patients. Cancer Sci. 2012; 4: 791–6.
- Nie Q, Yang X, An S, Zhang XC, Yang JJ. CYP1A1*2A polymorphism as a predictor of clinical outcome in advanced lung cancer patients treated with EGFR-TKI and its combined effects with EGFR intron 1 (CA) polymorphism. Eur J Cancer. 2011; 13: 1962–70.
- Krohn V, Wiegand S, Werner JA, Mandic R. EGFR codon 497 polymorphism-implications for receptor sensitivity to inhibitors in HNSCC cell lines. Anticancer Res. 2011; 1: 59–65.
- Liu Z, Liu L, Li M, Feng L, Zhang Q. Epidermal growth factor receptor mutation in gastric cancer. Pathology. 2011; 3: 234–8.
- Sasaki H, Okuda K, Takada M, Kawahara M, Kitahara N. A novel EGFR mutation D1012H and polymorphism at exon 25 in Japanese lung cancer. J Cancer Res Clin Oncol. 2008; 12: 1371–6.
References
Kaufman DS, Shipley WU, Feldman AS. Bladder cancer. The Lancet. 2009; 374: 239-49.
Jemal A, Bray F, Center MM, Ferlay J, Ward E. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90.
Benider A, Bendahhou K, Afghar S, Charrat B, Ahmadaye IK. Registre des cancers de la region du grand Casablanca pour la periode 2008-2012. Eds 2016.
Tazi MA, Er-Raki A, Benjaafar N.Cancer incidence in Rabat. Morocco: 2006-2008. Ecancer 2013; 7:338.
Sapre N, Herle P, Anderson PD, Corcoran NM, Hovens CM. Molecular biomarkers for predicting outcomes in urothelial carcinoma of the bladder. Pathology. 2014; 46: 274-82.
Mason RA, Morlock EV, Karagas MR, Kelsey KT, Marsit CJ, Schned AR, Andrew AS. EGFR pathway polymorphisms and bladder cancer susceptibility and prognosis. Carcinogenesis. 2009; 30: 1155-60.
Isla D, De Castro J, Juan O, Grau S, Orofino J, Gordo R, Rubio-Terrés C, Rubio-Rodríguez D. Costs of adverse events associated with erlotinib or afatinib in first-line treatment of advanced EGFR-positive non-small cell lung cancer. Clinicoecon Outcomes Res. 2016; 9: 31-8.
Arias-Pulido H, Joste N, Chavez A, Muller CY, Dai D, Smith HO, Verschraegen CF. Absence of epidermal growth factor receptor mutations in cervical cancer. Int. J. Gynecol. Cancer. 2008; 18: 749-54.
Dominguez-Escrig JL, Kelly JD, Neal DE, King SM, Davies BR. Evaluation of the therapeutic potential of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in preclinical models of bladder cancer. Clin Cancer Res. 2004; 10: 4874-84.
Nutt JE, Lazarowicz HP, Mellon JK, Lunec J. Gefitinib (‘Iressa', ZD1839) inhibits the growth response of bladder tumour cell lines to epidermal growth factor and induces TIMP2. Br, J Cancer. 2004; 90: 1679-85.
Grivas PD, Day KC, Karatsinides A, Paul A, Shakir N, Owainati I, Liebert M, Kunju LP, Thomas D, Hussain M, Day ML. Evaluation of the antitumor activity of dacomitinib in models of human bladder cancer. Mol Med. 2013; 19: 367-76.
Lyer G, Al-Ahmadie H, Schultz N, Hanrahan AJ, Ostrovnaya I, Balar AV. Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. Journal of Clinical Oncology. 2013; 31: 3133-40.
Berrada N, Amzazi S, Abbar M, Ameur A, Khyatti M, Al-Bouzidi A and Attaleb M. Mutational Analysis of FGFR3 and HRAS Genes in Bladder Cancer and Washing Cell Sediments of Moroccan Patients. Epidemiology. 2015; 5:4
Blehm KN, Spiess PE, Bondaruk JE. Mutations within the kinase domain and truncations of the epidermal growth factor receptor are rare events in bladder cancer: implications for therapy. Clin Cancer Res. 2006; 12: 4671.
Chaux A, Cohen JS, Schultz L.High epidermal growth factor receptor immunohistochemical expression in urothelial carcinoma of the bladder is not associated with EGFR mutations in exons 19 and 21: a study using formalin fixed, paraffin-embedded archival tissues. Hum Pathol. 2012; 43: 1590.
Alexander RE, Montironi R, Lopez-Beltran A. EGFR alterations and EML4-ALK rearrangement in primary adenocarcinoma of the urinary bladder. Mod Pathol. 2014; 27: 107.
Flaig TW, Su LJ, McCoach C.Dual epidermal growth factor receptor and vascular endothelial growth factor receptor inhibition with vandetanib sensitizes bladder cancer cells to cisplatin in a dose- and sequence-dependent manner. BJU Int. 2009; 103: 1729.
Ross JS, Wang K, Al-Rohil RN, Nazeer T, Sheehan CE, Otto GA, He J, Palmer G, Yelensky R, Lipson D, Ali S, Balasubramanian S, Curran JA, Garcia L, Mahoney K, Downing SR, awryluk M, Miller VA, Stephens PJ. Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy. Mod Pathol. 2014; 27: 271-80.
Amador ML, Oppenheimer D, Perea S, Maitra A, Cusatis G, Iacobuzio-Donahue C, Baker SD, Ashfaq R, Takimoto C, Forastiere A, Hidalgo M.An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors. Cancer Res. 2004; 64: 9139-43.
Ma F, Sun T, Shi Y, Yu D, Tan W, Yang M, Wu C, Chu D, Sun Y, Xu B, Lin D.Polymorphisms of EGFR predict clinical outcome in advanced non-small-cell lung cancer patients treated with Gefitinib. Lung Cancer. 2009; 66: 114-9.
Ma F, Xu B, Lin D, Sun T, Shi Y. Effect of rs2293347 Polymorphism in EGFR on the Clinical Efficacy of Gefitinib in Patients with Non-small Cell Lung Cancer. Zhongguo Fei Ai Za Zhi. 2011; 14: 642–5.
Ichihara S, Toyooka S, Fujiwara Y, Hotta K, Shigematsu H, Tokumo, M, Soh J, Asano H, Ichimura K, Aoe K, Aoe M, Kiura K, Shimizu K, Date H, Shimizu N.The impact of epidermal growth factor receptor gene status on gefitinib-treated Japanese patients with non-small-cell lung cancer. Int J Cancer. 2007; 120: 1239-47.
Chintala L, Kurzrock R. Epidermal growth factor receptor mutation and diverse tumors: case report and concise literature review. Mol Oncol. 2010; 4: 306-8
Baulcombe D. DNA events: an RNA microcosm. Science. 2002; 297: 2002- 3.
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science. 2004; 304: 1497-500.
Epstein JI, Amin MB, Reuter VR, Mosto FK. The World Health Organization / international Society of Urological Pathology consensus classification of urotltelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. The American journal of surgical pathology. 1998; 22: 1435-48.
Sobin LH, Gospodariwicz M, Wittekmd C.TNM Classifcation of Malignant Ttnnors. UICC International Union Against Cancer. Oxford: Wiley-Blackwell. 2009; 262-5.
El Hamdani W, Amrani M, Attaleb M, Laantri N, Ennaji MM, Khyatti M, El Mzibri M. EGFR, p16INK4a and E-cadherin immuno-histochemistry and EGFR point mutations analyses in invasive cervical cancer specimens from Moroccan women. Cell Mol Biol (Noisy-le–Grand). 2010; 56: 1373-84.
Naji F, Attaleb M, Laantri N, Benchakroun N, El Gueddari B, Benider A, Azeddoug H, Ennaji MM, El Mzibri M, Khyatti M.Identification of G2607A mutation in EGFR gene with a significative rate in Moroccan patients with nasopharyngeal carcinoma. Cell Mol Biol (Noisy-le–Grand). 2010; 56: 1442-6.
Cheetham PJ, and Petrylak DP.New Agents for the Treatment of Advanced Bladder Cancer. Oncology (Williston Park). 2016; 30: 571–9.
Bethune G, Bethune D, Ridgway N, Xu Z.Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. J Thorac Dis. 2010; 2: 48-51.
Villares GJ, Zigler M, Blehm K, Bogdan C, McConkey D, Colin D, Bar-Eli M.Targeting EGFR in bladder cancer. World J Urol. 2007; 25: 573-9.
Barber TD, Vogelstein B, Kinzler KW, Velculescu VE.Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med. 2004; 351: 2883.
Marchetti A, Martella C, Felicioni L, Barassi F, Salvatore S, Chella A, Camplese, PP, Iarussi T, Mucilli F, Mezzetti A, Cuccurullo F, Sacco R, and Buttitta F.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. 2005; 523: 857- 65.
Zhang W, Stabile LP, Keohavong P, Romkes M, Grandis JR, Traynor AM, and Siegfried JM.Mutation and polymorphism in the EGFR-TK domain associated with lung cancer. J. Thorac. Oncol. 2006; 1: 635- 47.
Metzger B, Chambeau L, Begon DY, Faber C, Kayser J, Berchem G, Pauly M, Boniver J, Delvenne P, Dicato M, Wenner T. The human epidermal growth factor receptor (EGFR) gene in European patients with advanced colorectal cancer harbors infrequent mutations in its tyrosine kinase domain. BMC Med Genet. 2011; 12: 144
Su MC, Lien HC, Jeng YM.Absence of epidermal growth factor receptor exon 18-21 mutation in hepatocellular carcinoma. Cancer Lett. 2005; 224: 117-21.
Longatto-Filho A, Pinheiro C, Martinho O, Moreira MA, Ribeiro LF, Queiroz GS, Schmitt FC, Baltazar F, Reis RM. Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma. BMC Cancer. 2009; 9: 212.
Fukushima T, Favereaux A, Huang H, Shimizu T, Yonekawa Y, Nakazato Y, Ohagki H.Genetic alterations in primary glioblastomas in Japan. J Neuropathol Exp Neurol. 2006; 65: 12-8.
Horstmann M, Witthuhn R, Falk M, Stenzl A. Gender-specific differences in bladder cancer: a retrospective analysis. Gend Med. 2008; 5: 385-94.
Rose TL, Deal AM, Nielsen ME, Smith AB, Milowsky MI. Sex disparities in use of chemotherapy and survival in patients with advanced bladder cancer. Cancer. 2016; 122: 2012-20.
Kaneko K, Kumekawa Y, Makino R, Nozawa H, Hirayama Y, Kogo M, Konishi K, Katagiri A, Kubota Y, Muramoto T, Kushima M, Ohmori T, Oyama T, Kagawa N, Ohtsu A, Imawari M. EGFR gene alterations as a prognostic biomarker in advanced esophageal squamous cell carcinoma. Front Biosci (Landmark Ed). 2010; 15: 65-72.
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.
Nakazaki K, Kato Y, Taguchi T, Inayama Y, Ishiguro Y, Kondo N, Horiuchi C, Sakakibara A, Tsukuda M.Heterozygous mutation (G/G→G/A) at nt 2607 of the EGFR gene is closely associated with increases in EGFR copy number and mRNA half-life, but impaired EGFR protein synthesis in squamous cell carcinomas of the head and neck - implication for gefitinib efficacy. Oncol Lett. 2010; 1: 1017-20.
Hsieh YY, Tzeng CH, Chen MH, Chen PM, Wang WS. Epidermal growth factor receptor R521K polymorphism shows favorable outcome to cetuximab-based treatment in KRAS wild-type colorectal cancer patients. Cancer Sci. 2012; 4: 791–6.
Nie Q, Yang X, An S, Zhang XC, Yang JJ. CYP1A1*2A polymorphism as a predictor of clinical outcome in advanced lung cancer patients treated with EGFR-TKI and its combined effects with EGFR intron 1 (CA) polymorphism. Eur J Cancer. 2011; 13: 1962–70.
Krohn V, Wiegand S, Werner JA, Mandic R. EGFR codon 497 polymorphism-implications for receptor sensitivity to inhibitors in HNSCC cell lines. Anticancer Res. 2011; 1: 59–65.
Liu Z, Liu L, Li M, Feng L, Zhang Q. Epidermal growth factor receptor mutation in gastric cancer. Pathology. 2011; 3: 234–8.
Sasaki H, Okuda K, Takada M, Kawahara M, Kitahara N. A novel EGFR mutation D1012H and polymorphism at exon 25 in Japanese lung cancer. J Cancer Res Clin Oncol. 2008; 12: 1371–6.