ymjЯкутский медицинский журналYakut Medical Journal1813-19052312-1017ЯНЦ КМП10.25789//YMJ.2021.73.01ymj-461Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHЧастота гетерозиготного носительства мутаций в генах Notch-сигнального пути у пациентов со светлоклеточным раком почки и в популяциях Волго-Уральского регионаFrequency of heterozygous carriage of mutations in the genes of Notch signal path in patients with clear cell kidney cancer and in the populations of the Volga-Ural regionГилязоваИ. Р.GilyazovaI. R.

Гилязова Ирина Ришатовна – к.б.н., с.н.с.

г. Уфа

Ufa, Prospect Oktyabrya 71, 450054

ИвановаЕ. А.IvanovaE. A.

Иванова Елизавета Алексеевна – к.б.н., н.с.

г. Уфа

Ufa, Prospect Oktyabrya 71, 450054

ХуснутдиноваЭ. К.KhusnutdinovaE. K.

Хуснутдинова Эльза Камилевна – д.б.н., проф., директор

г. Уфа

Ufa, Prospect Oktyabrya 71, 450054

ИзмайловА. А.IzmailovA. A.

Измайлов Адель Альбертович – д.м.н., проф.

г. Уфа

Ufa, Lenina 3, 450008

СултановИ. М.SultanovI. M.

Султанов Ильнур Миндиахметович – врач-уролог

г. Уфа

Ufa, Lenina 3, 450008

СафиуллинР. И.SafiullinR. I.

Сафиуллин Руслан Ильясович – д.м.н., проф.

г. Уфа

Ufa, Lenina 3, 450008

ГилязоваГ. Р.GilyazovaG. R.

Гилязова Гульшат Руслановна – студент

г. Уфа

Ufa, Lenina 3, 450008

ПавловВ. Н.PavlovV. N.

Павлов Валентин Николаевич – д.м.н., проф.

г. Уфа

Ufa, Lenina 3, 450008

ФГБУН Институт биохимии и генетики УФИЦ РАНРоссияInstitute of Biochemistry and Genetics, Ufa Federal Research Centre, Russian Academy of SciencesRussian FederationГБОУ ВО БГМУ Минздрава РоссииРоссияBashkir State Medical UniversityRussian Federation2021270420250157Copyright © Гилязова И.Р., Иванова Е.А., Хуснутдинова Э.К., Измайлов А.А., Султанов И.М., Сафиуллин Р.И., Гилязова Г.Р., Павлов В.Н., 20252025Гилязова И.Р., Иванова Е.А., Хуснутдинова Э.К., Измайлов А.А., Султанов И.М., Сафиуллин Р.И., Гилязова Г.Р., Павлов В.Н.Gilyazova I.R., Ivanova E.A., Khusnutdinova E.K., Izmailov A.A., Sultanov I.M., Safiullin R.I., Gilyazova G.R., Pavlov V.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://ymj.elpub.ru/jour/article/view/461

В статье представлены результаты анализа частоты изменений нуклеотидной последовательности генов сигнального пути Notch (DLL4 (rs35748882), HEY2 (rs61737181), JAG1 (rs1801140, rs1801139, rs45575136), NOTCH1 (rs61751542), NOTCH2 (rs3795666), NOTCH4 (rs8192576, rs8192579, rs8192585)) у пациентов со светлоклеточным раком почки и здоровых индивидов из популяционного контроля. Было обнаружено, что частота выявленных изменений у пациентов в среднем была выше общепопуляционных значений. Полученные в настоящем исследовании результаты могут свидетельствовать о вкладе изученных изменений нуклеотидной последовательности генов сигнального пути Notch в патогенез светлоклеточного рака почки, а также о возможности их использования при создании панели молекулярных маркеров для диагностики и прогноза течения заболевания.

The article presents the results of frequency analysis in the nucleotide sequence of genes of the signal path Notch (DLL4 (rs35748882), HEY2 (rs61737181), JAG1 (rs1801140, rs1801139, rs45575136), NOTCH1 (rs61751542), NOTCH2 (rs3795666), NOTCH4 (rs8192576, rs8192579, rs8192585)) at patients with clear cell kidney cancer and healthy individuals from the population control. It was found that the frequency of detected changes in patients was on average higher than the general population values. The results of this study may indicate the contribution of the studied changes in the nucleotide sequence of genes of Notch signaling pathway to the pathogenesis of clear cell kidney cancer, as well as the possibility of their use while creating a panel of molecular markers for diagnosis and prognosis of the course of the disease.

светлоклеточный рак почкисигнальный путь Notchоднонуклеотидные заменыclear cell kidney cancerNotch signaling pathuninucleotide substitutionsРабота выполнена при поддержке Министерства образования и науки Российской Федерации [№AAA-A16-116020350032-1] и за счет средств гранта СПбГУ [ID № 60238366/№ проекта 60257092]. В работе использованы образцы ДНК из «Коллекции биологических материалов человека» ИБГ УФНЦ РАН при поддержке Программы коллекций биоресурсов ФАСО России [Соглашение № 007-030164/2].This work was supported by the Ministry of Education and Science of the Russian Federation [No.AAA-A16-116020350032-1] and a grant from St. Petersburg State University [ID No. 60238366 / Project No. 60257092]. We used DNA samples from the "Collection of Human Biological Materials" of the IBG UFSC RAS with the support of the Bioresource Collections Program of the FASO Russia [Agreement No. 007-030164 / 2].ReferencesAssociations of multiple NOTCH4 exonic variants with systemic sclerosis/ X. Zhou, H. Li, S. Guo et al. // J. Rheumatol. - 2019. - V. 46. - № 2. - P. 184–189. 10.3899/jrheum.180094Zhou X, Li H, Guo S, et al. Associations of multiple NOTCH4 exonic variants with systemic sclerosis. J Rheumatol. 2019, V.46, №2, p:184-189. doi:10.3899/jrheum.180094He, Y., Wang, X. Identification of molecular features correlating with tumor immunity in gastric cancer by multi-omics data analysis/ Y. He, X. Wang. // Ann. Transl. Med. - 2020. - V. 8. - № 17. - P. 1050–1050. doi:10.21037/atm-20-922He Y, Wang X. Identification of molecular features correlating with tumor immunity in gastric cancer by multi-omics data analysis. Ann Transl Med. 2020, V.8, №17, p:1050-1050. doi:10.21037/atm-20-922Hyperprogression to a dual immune blockade followed by subsequent response with cabozantinib in metastatic poor-risk clear cell renal cell carcinoma with NOTCH mutation/ J. Molina-Cerrillo, T. Alonso-Gordoa, A. Carrato et al. // Oncotarget. - 2020. - V. 11. - № 22. - P. 2137–2140. doi:10.18632/oncotarget.27598Molina-Cerrillo J, Alonso-Gordoa T, Carrato A, Grande E. Hyperprogression to a dual immune blockade followed by subsequent response with cabozantinib in metastatic poor-risk clear cell renal cell carcinoma with NOTCH mutation. Oncotarget. 2020, V.11, №22, p:2137-2140. doi:10.18632/oncotarget.27598Incidence and mortality of kidney cancer and its relationship with HDI (Human Development Index) in the world in 2012/ M. Mohammadian, R. Pakzad, F. Towhidi et al. // Clujul Med. - 2017. - V. 90. - № 3. - P. 286–293. doi: 10.15386/cjmed-691Mohammadian M., Pakzad R., Towhidi F. et al. Incidence and mortality of kidney cancer and its relationship with HDI (Human Development Index) in the world in 2012. Clujul Med. 2017, V.90, №3, p:286-293. doi:10.15386/cjmed-691Integrated molecular analysis of clear-cell renal cell carcinoma/ Y. Sato, T. Yoshizato, Y. Shiraishi et al. // Nat. Genet. - 2013. - V. 45. - № 8. - P. 860–867. . doi: 10.1038/nature12222Sato Y, Yoshizato T, Shiraishi Y, et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet. 2013, V.45, №8, p:860-867. doi:10.1038/ng.2699Notch pathway is activated via genetic and epigenetic alterations and is a therapeutic target in clear cell renal cancer/ T.D. Bhagat, Y. Zou, S. Huang et al. // J. Biol. Chem. - 2017. - V. 292. - № 3. - P. 837–846. DOI: 10.1074/jbc.M116.745208Bhagat TD, Zou Y, Huang S, et al. Notch pathway is activated via genetic and epigenetic alterations and is a therapeutic target in clear cell renal cancer. J Biol Chem. 2017, V.292, №3, p:837-846. doi:10.1074/jbc.M116.745208NOTCH4 is a novel prognostic marker that correlates with colorectal cancer progression and prognosis/ G. Wu, Z. Chen, J. Li, et al. // J. Cancer. - 2018. - V. 9. - № 13. - P. 2374–2379. doi: 10.7150/jca.26359Wu G, Chen Z, Li J, et al. NOTCH4 is a novel prognostic marker that correlates with colorectal cancer progression and prognosis. J Cancer. 2018, V.9, №13, p:2374-2379. doi:10.7150/jca.26359Notch-4 silencing inhibits prostate cancer growth and EMT via the NF-κB pathway/ J. Zhang, Y. Kuang, Y. Wang et al. // Apoptosis. - 2017. - V. 22. - № 6. - P. 877–884. . doi: 10.1007/s10495-017-1368-0.Zhang J, Kuang Y, Wang Y, Xu Q, Ren Q. Notch-4 silencing inhibits prostate cancer growth and EMT via the NF-κB pathway. Apoptosis. 2017, V.22, №6, p:877-884. doi:10.1007/s10495-017-1368-0P2Y2R has a significant correlation with Notch-4 in patients with breast cancer/ D.C. Kim, H. Jin, J.S. Lee et al. // Oncol. Lett. - 2020. - V. 20. - № 1. - P. 647–654. doi:10.3892/ol.2020.11630Kim DC, Jin H, Lee JS, Son E, Lee GW, Kim HJ. P2Y2R has a significant correlation with Notch-4 in patients with breast cancer. Oncol Lett. 2020, V.20, №1, p:647-654. doi:10.3892/ol.2020.11630Saini, N., Sarin, A. Nucleolar localization of the Notch4 intracellular domain underpins its regulation of the cellular response to genotoxic stressors/ N. Saini, A. Sarin. // Cell Death Discov. - 2020. - V. 6. - № 1. - P. 7. doi:10.1038/s41420-020-0242-ySaini N, Sarin A. Nucleolar localization of the Notch4 intracellular domain underpins its regulation of the cellular response to genotoxic stressors. Cell Death Discov. 2020, V.6, №1, p.7. doi:10.1038/s41420-020-0242-ySuppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo/ J. Sjölund, M. Johansson, S. Manna et al. // J. Clin. Invest. - 2008. - V. 118. - № 1. - P. 217–228. doi: 10.1172/JCI32086Sjölund J, Johansson M, Manna S, et al. Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo. J Clin Invest. 2008, V.118, №1, p:217-228. doi:10.1172/JCI32086Vincze, T. NEBcutter: a program to cleave DNA with restriction enzymes / T. Vincze, J. Posfai, and R.J. Roberts // Nucleic Acids Res. - 2003. - V.31. – P.3688-3691. doi: 10.1093/nar/gkg526.Vincze T, Posfai J, Roberts RJ. NEBcutter: A program to cleave DNA with restriction enzymes. Nucleic Acids Res. 2003, V.31, №13, p:3688-3691. doi:10.1093/nar/gkg526Yu J. Recent genetic studies of mouse kidney development / J. Yu, A.P. McMahon, M.T.Valerius // Curr. Opin. Genet. Dev. - 2004. - V. 14. P. 550–557. doi: 10.1016/j.gde.2004.07.009.Yu J, McMahon AP, Valerius MT. Recent genetic studies of mouse kidney development. Curr Opin Genet Dev. 2004, V.14, №5, p:550-557. doi:10.1016/j.gde.2004.07.009

The authors declare that there are no conflicts of interest present.