Journal of Clinical PracticeJournal of Clinical Practice2220-30952618-8627Eco-Vector900810.17816/clinpract848-14Research ArticleTHE ROLE OF ABERRANT METHYLATED IN GENES APC, RASSF1A AND ITGA4 FOR DIAGNOSIS OF COLORECTAL CANCERBrovkinaO Ibrov.olia@gmail.comGordievM Gmarat7925@gmail.comToropovskiyA NDmKh008@gmail.comKhodyrevD Savialn@gmail.comNikitinAu Vyacheslavovichpulmo_fmba@mail.ruAveryanovA Vinfo@fnkc-fmba.ru151220178481426062018Copyright © 2017, Brovkina O.I., Gordiev M.G., Toropovskiy A.N., Khodyrev D.S., Nikitin A.V., Averyanov A.V.2017The “gold standard” of diagnosis of colorectal cancer (CRC) is a colonoscopy. Despite the high reliability, this method is not applicable in large-scale population screening or in estimation of the disease dynamics in a particular patient. In this study, we conducted an investigation of aberrant methylation in the APC, RASSF1A and ITGA4 genes. The study included 150 pairs of tumor tissue samples with known mutation status of the RAS family genes and the surrounding histologically unchanged tissue of patients with rectal adenocarcinoma treated at the Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Tatarstan. The methylation profiles were studied using MethyLight PCR. The most difference in the methylation between tumor and healthy tissue was observed for the ITGA4 gene (sensitivity 78%, specificity 92.7%). For the APC gene sensitivity was 32%, specificity -93.3%, for the RASSF1 gene sensitivity was 85.3%, specificity - 56.7%. Previous data on the aberrant methylation of the SEPT9 and VIM genes and new data on the APC, RASSF1A and ITGA4 genes were compared with the mutations status in the KRAS and NRAS genes. The DNA of tumor samples was significantly more often methylated in the SEPT9 (P= 0.0018) and ITGA4 (P = 0.0044) genes in the group of patients carrying mutations in the KRAS or NRAS genes, in contrast to the DNA of tumor samples of non-carriers. In statistical analysis of the effectiveness of the diagnostic test system, it was shown that our model, which includes five methylation markers (APC, RASSF1A, ITGA4, SEPT9 and VIM), has the best sensitivity and specificity (82.7% and 97.3%, respectively). The obtained model of the diagnostic test system is proposed to be used for diagnostic problems.colorectal cancercolonoscopyaberrant methylationgenesколоректальный ракколоноскопияаберрантное метилированиегены[Jemal A., Center M.M., DeSantis C., Ward E.M. Global Patterns of Cancer Incidence and Mortality Rates and Trends. Cancer Epidemiol. Prev. Biomark. 2010;19:1893-1907.][Давыдов М.И., Аксель Е.М. Заболеваемость злокачественными новообразованиями населения России и стран СНГ в 2008 г. Вестник РОНЦ им. Н.Н. Блохина РАМН. 2010. Т. 21, прил.1. С. 52-86.][Шахшаль Г. 2012. Практическая колоноскопия. М.: «МЕДпресс-информ».192 с.][Khare S., Verma M. Epigenetics of Colon Cancer. In Cancer Epigenetics. 2012. Humana Press, Totowa, NJ. 177-185.][Соколова Е.А., Боярских У.А., Ширшова А.Н., Кель А.Э., Филипенко М.Л. Биомаркеры для своевременной диагностики колоректального рака. Клиническая лабораторная диагностика. 2015; 60 (12): 15-23.][Kim M.S., Lee J., Sidransky D. DNA methylation markers in colorectal cancer. Cancer Metastasis Rev. 2010; 29: 181-206.][Бровкина О.И., Гордиев М.Г., Ходырев Д.С., Никитин А.Г., Аверьянов А.В. Использование аберрантно метилированных генов SEPT9 и VIM для клинической диагностики колоректального рака. Клиническая практика. 2016; 28: 15-19.][Dammann R., Schagdarsurengin U., Strunnikova M., Rastetter M., Seidel C., Liu L., Tommasi S., Pfeifer G.P. Epigenetic inactivation of the Ras-association domain family 1 (RASSF1A) gene and its function in human carcinogenesis. Histol. Histopathol. 2003; 18:665-677.][Fodde R. 2002. The APC gene in colorectal cancer. Eur. J. Cancer Oxf. Engl. 1990; 38: 867-871.][Aoki K., Taketo M.M. Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene. J. Cell Sci. 2007; 120: 3327-3335.][Fodde R., Smits R., Clevers H. APC, Signal transduction and genetic instability in colorectal cancer. Nat. Rev. Cancer. 2001; 1: 55-67.][Gerecke C., Scholtka B., Löwenstein Y., Fait I., Gottschalk U., Rogoll D., Melcher R., Kleuser B. Hypermethylation of ITGA4, TFPI2 and VIM promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer. J. Cancer Res. Clin. Oncol. 2015; 141: 2097-2107.][Bar-Sagi D., Hall A. Ras and Rho GTPases: a family reunion. Cell. 2000; 103: 227-238.][Мазуренко Н.Н., Цыганова И.В., Гагарин И.М., Чуев Ю.В., Мочальникова В.В., Коломейцева А.А., Горбунова В.А. Мутации EGFR и KRAS, важные для таргетной терапии немелкоклеточного рака легких. Молекулярная Медицина. 2013;6: 55-59.][Писарева Е.Е., Любченко Л.Н., Коваленко C.П., Шаманин В.А. Анализ мутаций в генах KRAS и BRAF при раке толстой и прямой кишки в российской популяции. 2016; 15: 36-41.]