MOLECULAR GENETIC AND PHENOTYPIC CHARACTERISTICS OF PATIENTS WITH LUNG ADENOCARCINOMA AMONG INHABITANTS OF THE SOUTH OF RUSSIA

DOI: https://doi.org/None

O.I. Kit, D.I. Vodolazhsky, A.Yu. Maksimov, Yu.N. Lazutin, S.P. Pyltsin, I.A. Leyman, A.M. Makueva Rostov Research Oncological Institute, 14 line, 63, Rostov on Don, 344037, Russian Federation

Introduction. EGFR mutation and EML4-ALK fusion are the most clinically significant genetic alterations in non-small cell lung cancer. Numerous studies have been devoted to EGFR mutations and their association with phenotypic clinical and pathological characteristics, however, in the Russian oncological literature such works are rare, and in the South of Russia, no such studies had previously been carried out The purpose of the study. To study the polymorphism of 29 somatic mutations of the EGFR gene in samples of lung adenocarcinoma, establish the prevalence rate and the distribution in dependence on phenotypic features. Methods. The study included 140 patients with adenocarcinoma of the lung, inhabitants of the south of Russia, in whom the detection of mutations EGFR was performed with the use of the Real-Time PCR method. Results. EGFR mutations were detected in 26 (18,6%) patients: SNP-mutation L858R – in 53,8% of cases, deletions in exon 19 – in 38,5%, insertions in exon 20 – in 7,7%. The rate of mutations in individuals of Slavic ethnic group was 16%, representatives of the Caucasian nationalities – 25%. Phenotypically patients-carriers of mutations of the EGFR gene were statistically significantly more often women, persons who had never smoked, aged over 55 years, who had 1-3A stage of the disease. Conclusion. Thus 92,3% of the identified mutations EGFR indicate to the increased sensitivity to targeted therapy. The changing strategy for prescription of tyrosine kinase inhibitors makes the detection of EGFR mutations to be necessary, especially in patients with a specific phenotype.
Keywords: 
EGFR mutations, lung adenocarcinoma, inhabitants of south Russia
Список литературы: 
  1. Jemal A., Siegel R., Ward E., Murray T., Xu J., Smigal C., Thun M.J. Cancer statistics, 2006. CA Cancer J. Clin. 2006; 56 (2): 106–30.
  2. Fong K.M., Sekido Y., Gazdar A.F., Minna J.D. Lung cancer 9: Molecular biology of lung cancer: clinical implications. Thorax. 2003; 58 (10): 892–900.
  3. Lovly C.M., Pao W. Escaping ALK inhibition: mechanisms of and strategies to overcome resistance. Sci. Transl. Med. 2012; 4 (120): 120ps2.(75).
  4. Lynch Thomas J., Bell Daphne W., Sordella Raffaella, Gurubhagavatula Sarada, Okimoto Ross A., Brannigan Brian W., Harris Patricia L., Haserlat Sara M., Supko Jeffrey G., Haluska Frank G., Louis David N., Christiani David C., Settleman Jeff, Haber Daniel A. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 2004; 350 (21): 2129–39. (59).
  5. Rosell R., Moran T., Queralt C., Porta R., Cardenal F., Camps C., Majem M., LopezVivanco G., Isla D., Provencio M., Insa A., Massuti B., Gonzalez-Larriba J.L., Paz-Ares L., Bover I., Garcia-Campelo R., Moreno M.A., Catot S., Rolfo C., Reguart N., Palmero R., Sánchez J.M., Bastus R., Mayo C., Bertran-Alamillo J., Molina M.A., Sanchez J.J., Taron M.; Spanish Lung Cancer Group. Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med. 2009; 361 (10): 958–67.
  6. Soda M.I., Choi Y.L., Enomoto M., Takada S., Yamashita Y., Ishikawa S., Fujiwara S., Watanabe H., Kurashina K., Hatanaka H., Bando M., Ohno S., Ishikawa Y., Aburatani H., Niki T., Sohara Y., Sugiyama Y., Mano H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007; 448 (7153): 561–6.
  7. Amann J., Kalyankrishna S., Massion P.P., Ohm J.E., Girard L., Shigematsu H., Peyton M., Juroske D., Huang Y., Stuart Salmon J., Kim Y.H., Pollack J.R., Yanagisawa K., Gazdar A., Minna J.D., Kurie J.M., Carbone D.P. Aberrant Epidermal Growth Factor Receptor Signaling and Enhanced Sensitivity to EGFR Inhibitors in lung cancer. Cancer Res. 2005; 65 (1): 226–35.
  8. Ohm J.E, Amann J.M, Carbone D.P. Acquired EGFR TKI resistance associated with mutation of the EGFR. AACR Meeting Abstracts. 2004; 2004 (1): 570-b-. (60).
  9. Paez J.G., Jänne P.A, Lee J.C, Tracy S., Greulich H., Gabriel S., Herman P., Kaye F.J., Lindeman N., Boggon T.J., Naoki K., Sasaki H., Fujii Y., Eck M.J., Sellers W.R., Johnson B.E., Meyerson M.EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304 (5676): 1497–500.
  10. Pao W., Miller V., Zakowski M., Doherty J., Politi K., Sarkaria I., Singh B., Heelan R., Rusch V., Fulton L., Mardis E., Kupfer D., Wilson R., Kris M., Varmus H. 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 (36): 13306–11.
  11. Koivunen J.P., Mermel C., Zeinullahu K., Murphy C., Lifshits E., Holmes A.J., Choi H.G., Kim J., Chiang D., Thomas R., Lee J., Richards W.G., Sugarbaker D.J., Ducko C., Lindeman N., Marcoux J.P., Engelman J.A., Gray N.S., Lee Sh., Meyerson M., Jänne P.A. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin. Cancer Res, 2008; 14: 4275–83.
  12. Riely G.J., Politi K.A., Miller V.A., Pao W. Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin. Cancer Res. 2006; 12 (24): 7232–41.
  13. Ellison G., Zhu G., Moulis A., Dearden S., Speake G., McCormack R. EGFR mutation testing in lung cancer: a review of available methods and their use for analysis of tumor tissue and cytology samples. J. Clin. Pathol. 2013; 66: 79–89.
  14. Demidova I.A, Barinov A.A., Savelova V.N. Issledovanie molekulyarno- geneticheskih narusheniy u bol`nyh adenokarcinomoy legkogo. Onkologiya. Zhurnal im. P.A. Gercena. 2012; 2: 28–34. [Demidova I.A., Barinov A.A., Savelova V.N. The study of molecular-genetic disorders in patients with lung adenocarcinoma. Onkologija. Zhurnal im. P.A. Gercena. 2012; 2: 28–34 (in Russian)]
  15. Vodolazhskiy D.I., Kit O.I., Maksimov A.Yu., Antonec A.V., Dvadnenko K.V., Vladimirova L.Yu., Leyman I.A., Lazutin Yu.N. Svyaz` mutaciy gena EGFR s kliniko- patologicheskimi osobennostyami adeno- karcinomy legkogo u pacientov yuga Rossii. Klinicheskaya medicina. 2014; 7: 49–53. [Vodolazhsky D.I., Kit O.I., Maksimov A.Yu., Antonets A.V., Dvadnenko K.V., Vladimirova L.Yu., Leyman I.A., Lazutin Yu.N. The relationship of EGFR mutations with clinicopathological features of lung adenocarcinoma patients in the South of Russia. Klinicheskaya medicina. 2014; 7: 49–53 (in Russian)