Перспективы молекулярного профилирования при стратификации и лечении рака мочевого пузыря

Любченко Л.Н., Чернавина К.М., Казарян К.А., Заборский И.Н., Карякин О.Б. Перспективы молекулярного профилирования при стратификации и лечении рака мочевого пузыря. Современная Онкология. 2025;27(3):1–8. DOI: 10.26442/18151434.2025.3.203421

© ООО «КОНСИЛИУМ МЕДИКУМ», 2025 г.

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Lyubchenko LN, Chernavina KM, Ghazaryan KA, Zaborskiy IN, Karyakin OB. Prospects for molecular profiling in bladder cancer stratification and treatment. A review. Journal of Modern Oncology. 2025;27(3): 1–8. DOI: 10.26442/18151434.2025.3.203421

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Аннотация

Современные тенденции онкологической помощи строятся на принципах прецизионной медицины, что обусловливает необходимость идентификации прогностических и предиктивных молекулярно-генетических маркеров. Результаты геномного профилирования рака мочевого пузыря (РМП) представляют широкий спектр генов, вовлеченных в канцерогенез, однако функциональная значимость и клинический потенциал большинства из них изучены недостаточно. Цель настоящего исследования – обобщение современных научно-практических данных о тенденциях прецизионной медицины в области онкоурологии при РМП. Материалами для исследования послужили отечественные и зарубежные базы научных данных, в частности National Library of Medicine (http://www.ncbi.nlm.nih.gov/) с использованием электронного ресурса PubMed (https://pubmed.ncbi.nlm.nih.gov/), eLIBRARY.RU (https://www.elibrary.ru/) и Google Scholar (https://scholar.google.ru/schhp?hl=ru), при поиске по ключевым словам: РМП, уротелиальная карцинома, NGS, молекулярное профилирование, гены, FGFR3, TERT, PIK3CA, TP53, мутации, экспрессия. Аналитический обзор, касающийся клинических, патоморфологических и молекулярно-генетических данных по проблематике диагностики и лечения РМП, включал отчеты о доклинических экспериментальных и клинических исследованиях, метаанализы, систематические обзоры, когортные рандомизированные исследования за период 2002–2025 гг. В ряде исследований продемонстрирована связь молекулярно-генетических изменений генов, кодирующих рецепторные и внутриклеточные киназы (FGFR2/3, PIK3CA и др.), с ранними этапами канцерогенеза РМП при условии вариабельной мультифакторной прогностической значимости с учетом наличия современных молекулярно-направленных препаратов. В частности, в настоящее время для лечения распространенных форм РМП одобрен продемонстрировавший свою эффективность пан-FGFR-ингибитор – эрдафитиниб. Учитывая патогенетические механизмы, важной дальнейшей перспективой применения ингибиторов рецепторных и внутриклеточных киназ при РМП считается разработка и внедрение в клиническую практику высокоселективных системных и локально-доставляемых форм с возможностью их использованиях в клинически разнородных группах пациентов, в том числе с ранними стадиями заболевания. В свою очередь, альтерации генов, ответственных за репарацию ДНК (TP53 и др.), ассоциированы с агрессивным течением заболевания и соответствующим менее благоприятным прогнозом. В этом направлении ключевая точка приложения персонализированной терапии – разработка и применение агентов, способных модулировать активность белков системы репарации на различных этапах канцерогенеза. Таким образом, мутационный и функциональный статус генов, вовлеченных в ключевые онкогенные и репарационные пути при РМП, играет важную роль в контексте разработки прогностической модели, а также служит предиктивной мишенью для терапевтического воздействия.

Ключевые слова: рак мочевого пузыря, уротелиальная карцинома, NGS, молекулярное профилирование, гены, FGFR3, TERT, PIK3CA, TP53, мутации, экспрессия

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Modern trends in oncological care are based on the principles of precision medicine, which necessitates the identification of prognostic and predictive molecular genetic markers. The results of genomic profiling of bladder cancer (BC) represent a wide range of genes involved in carcinogenesis, but the functional significance and clinical potential of most of them have not been sufficiently studied. The aim of this study was to summarize modern scientific and practical data on the trends in precision medicine in the field of oncourology in BC. The materials for the study were domestic and foreign scientific databases, in particular the National Library of Medicine (http://www.ncbi.nlm.nih.gov/) using the electronic resource PubMed (https://pubmed.ncbi.nlm.nih.gov/), eLIBRARY.RU (https://www.elibrary.ru/) and Google Scholar (https://scholar.google.ru/schhp?hl=ru), when searching by keywords: BC, urothelial carcinoma, NGS, molecular profiling, genes, FGFR3, TERT, PIK3CA, TP53, mutations, expression. An analytical review concerning clinical, pathomorphological and molecular genetic data on the problems of diagnosis and treatment of BC included reports on preclinical experimental and clinical studies, meta-analyses, systematic reviews, cohort randomized studies for the period 2002–2025. A number of studies have demonstrated the association of molecular genetic changes in genes encoding receptor and intracellular kinases (FGFR2/3, PIK3CA etc.) with early stages of BC carcinogenesis, provided that the multifactorial prognostic significance is variable, taking into account the availability of modern molecular-targeted drugs. In particular, a pan-FGFR inhibitor, erdafitinib, which has demonstrated its effectiveness, is currently approved for the treatment of common forms of BC. Taking into account the pathogenetic mechanisms, an important further prospect for the use of receptor and intracellular kinase inhibitors in BC is the development and introduction into clinical practice of highly selective systemic and locally delivered forms with the possibility of their use in clinically heterogeneous groups of patients, including those with early stages of the disease. In turn, alterations in genes responsible for DNA repair (TP53, etc.) are associated with an aggressive course of the disease and a corresponding less favorable prognosis. In this direction, the key point of application of personalized therapy is the development and use of agents capable of modulating the activity of proteins of the reparation system at various stages of carcinogenesis. Thus, the mutational and functional status of genes involved in key oncogenic and reparation pathways in BC plays an important role in the context of developing a prognostic model, and also serves as a predictive target for therapeutic intervention.

Keywords: bladder cancer, urothelial carcinoma, NGS, molecular profiling, gene, FGFR3, TERT, PIK3CA, TP53, mutation, expression

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71. El Azzouzi M, El Ahanidi H, Hassan I, et al. Comprehensive behavioural assessment of TERT in bladder cancer. Urol Oncol. 2024;42(12):451.e19-29. DOI:10.1016/j.urolonc.2024.06.024
72. Cheng L, Zhang S, Wang M, Lopez-Beltran A. Biological and clinical perspectives of TERT promoter mutation detection on bladder cancer diagnosis and management. Hum Pathol. 2023;133:56-75. DOI:10.1016/j.humpath.2022.06.005
73. Gupta S, Vanderbilt CM, Lin YT, et al. A Pan-Cancer Study of Somatic TERT Promoter Mutations and Amplification in 30,773 Tumors Profiled by Clinical Genomic Sequencing. J Mol Diagn. 2021;23(2):253-63. DOI:10.1016/j.jmoldx.2020.11.003
74. Agarwal N, Rinaldetti S, Cheikh BB, et al. TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer. Proc Natl Acad Sci USA. 2021;118(38):e2102423118. DOI:10.1073/pnas.2102423118
75. Huang DS, Wang Z, He XJ, et al. Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation. Eur J Cancer. 2015;51(8):969-76. DOI:10.1016/j.ejca.2015.03.010
76. Tran L, Xiao JF, Agarwal N, et al. Advances in bladder cancer biology and therapy. Nat Rev Cancer. 2021;21(2):104-21. DOI:10.1038/s41568-020-00313-1
77. Allory Y, Beukers W, Sagrera A, et al. Telomerase reverse transcriptase promoter mutations in bladder cancer: High frequency across stages, detection in urine, and lack of association with outcome. Eur Urol. 2014;65:360-6. DOI:10.1016/j.eururo.2013.08.052
78. Rachakonda PS, Hosen I, de Verdier PJ, et al. TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism. Proc Natl Acad Sci USA. 2013;110:17426-31. DOI:10.1073/pnas.1310522110
79. Batista R, Lima L, Vinagre J, et al. TERT Promoter Mutation as a Potential Predictive Biomarker in BCG-Treated Bladder Cancer Patients. Int J Mol Sci. 2020;21(3):947. DOI:10.3390/ijms21030947
80. Shuai H, Duan X, Zhou JJ, et al. Effect of the TERT mutation on the prognosis of patients with urothelial carcinoma: a systematic review and meta-analysis. BMC Urol. 2023;23(1):177. DOI:10.1186/s12894-023-01349-9
81. Wan S, Liu X, Hua W, et al. The role of telomerase reverse transcriptase (TERT) promoter mutations in prognosis in bladder cancer. Bioengineered. 2021;12(1):1495-504. DOI:10.1080/21655979.2021.1915725
82. Descotes F, Kara N, Decaussin-Petrucci M, et al. Non-invasive prediction of recurrence in bladder cancer by detecting somatic TERT promoter mutations in urine. Br J Cancer. 2017;117:583-7. DOI:10.1038/bjc.2017.210
83. Kovacs A, Sükösd F, Kuthi L, et al. Novel method for detecting frequent TERT promoter hot spot mutations in bladder cancer samples. Clin Exp Med. 2024;24(1):192. DOI:10.1007/s10238-024-01464-3
84. Zvereva M, Pisarev E, Hosen I, et al. Activating Telomerase TERT Promoter Mutations and Their Application for the Detection of Bladder Cancer. Int J Mol Sci. 2020;21(17):6034. DOI:10.3390/ijms21176034
85. Agarwal N, Zhou Q, Arya D, et al. AST-487 Inhibits RET Kinase Driven TERT Expression in Bladder Cancer. Int J Mol Sci. 2022;23(18):10819. DOI:10.3390/ijms231810819
86. Saitoh H, Mori K, Kudoh S, et al. BCG effects on telomerase activity in bladder cancer cell lines. Int J Clin Oncol. 2002;7(3):165-70. DOI:10.1007/s101470200024
87. Kailashiya C, Sharma HB, Kailashiya J. Telomerase based anticancer immunotherapy and vaccines approaches. Vaccine. 2017;35(43):5768-75. DOI:10.1016/j.vaccine.2017.09.011

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68. Liu M, Zhang Y, Jian Y, et al. The regulations of telomerase reverse transcriptase (TERT) in cancer. Cell Death Dis. 2024;15(1):90. DOI:10.1038/s41419-024-06454-7
69. Selivanova LS, Volganova KS, Abrosimov AIu. Telomerase reverse transcriptase (TERT) promoter mutations in the tumors of human endocrine organs: Biological and prognostic value. Archive of Pathology. 2016;78(1):62-9 (in Russian). DOI:10.17116/patol201678162-68
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71. El Azzouzi M, El Ahanidi H, Hassan I, et al. Comprehensive behavioural assessment of TERT in bladder cancer. Urol Oncol. 2024;42(12):451.e19-29. DOI:10.1016/j.urolonc.2024.06.024
72. Cheng L, Zhang S, Wang M, Lopez-Beltran A. Biological and clinical perspectives of TERT promoter mutation detection on bladder cancer diagnosis and management. Hum Pathol. 2023;133:56-75. DOI:10.1016/j.humpath.2022.06.005
73. Gupta S, Vanderbilt CM, Lin YT, et al. A Pan-Cancer Study of Somatic TERT Promoter Mutations and Amplification in 30,773 Tumors Profiled by Clinical Genomic Sequencing. J Mol Diagn. 2021;23(2):253-63. DOI:10.1016/j.jmoldx.2020.11.003
74. Agarwal N, Rinaldetti S, Cheikh BB, et al. TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer. Proc Natl Acad Sci USA. 2021;118(38):e2102423118. DOI:10.1073/pnas.2102423118
75. Huang DS, Wang Z, He XJ, et al. Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation. Eur J Cancer. 2015;51(8):969-76. DOI:10.1016/j.ejca.2015.03.010
76. Tran L, Xiao JF, Agarwal N, et al. Advances in bladder cancer biology and therapy. Nat Rev Cancer. 2021;21(2):104-21. DOI:10.1038/s41568-020-00313-1
77. Allory Y, Beukers W, Sagrera A, et al. Telomerase reverse transcriptase promoter mutations in bladder cancer: High frequency across stages, detection in urine, and lack of association with outcome. Eur Urol. 2014;65:360-6. DOI:10.1016/j.eururo.2013.08.052
78. Rachakonda PS, Hosen I, de Verdier PJ, et al. TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism. Proc Natl Acad Sci USA. 2013;110:17426-31. DOI:10.1073/pnas.1310522110
79. Batista R, Lima L, Vinagre J, et al. TERT Promoter Mutation as a Potential Predictive Biomarker in BCG-Treated Bladder Cancer Patients. Int J Mol Sci. 2020;21(3):947. DOI:10.3390/ijms21030947
80. Shuai H, Duan X, Zhou JJ, et al. Effect of the TERT mutation on the prognosis of patients with urothelial carcinoma: a systematic review and meta-analysis. BMC Urol. 2023;23(1):177. DOI:10.1186/s12894-023-01349-9
81. Wan S, Liu X, Hua W, et al. The role of telomerase reverse transcriptase (TERT) promoter mutations in prognosis in bladder cancer. Bioengineered. 2021;12(1):1495-504. DOI:10.1080/21655979.2021.1915725
82. Descotes F, Kara N, Decaussin-Petrucci M, et al. Non-invasive prediction of recurrence in bladder cancer by detecting somatic TERT promoter mutations in urine. Br J Cancer. 2017;117:583-7. DOI:10.1038/bjc.2017.210
83. Kovacs A, Sükösd F, Kuthi L, et al. Novel method for detecting frequent TERT promoter hot spot mutations in bladder cancer samples. Clin Exp Med. 2024;24(1):192. DOI:10.1007/s10238-024-01464-3
84. Zvereva M, Pisarev E, Hosen I, et al. Activating Telomerase TERT Promoter Mutations and Their Application for the Detection of Bladder Cancer. Int J Mol Sci. 2020;21(17):6034. DOI:10.3390/ijms21176034
85. Agarwal N, Zhou Q, Arya D, et al. AST-487 Inhibits RET Kinase Driven TERT Expression in Bladder Cancer. Int J Mol Sci. 2022;23(18):10819. DOI:10.3390/ijms231810819
86. Saitoh H, Mori K, Kudoh S, et al. BCG effects on telomerase activity in bladder cancer cell lines. Int J Clin Oncol. 2002;7(3):165-70. DOI:10.1007/s101470200024
87. Kailashiya C, Sharma HB, Kailashiya J. Telomerase based anticancer immunotherapy and vaccines approaches. Vaccine. 2017;35(43):5768-75. DOI:10.1016/j.vaccine.2017.09.011

Авторы

Л.Н. Любченко*^1,2, К.М. Чернавина³, К.А. Казарян⁴, И.Н. Заборский⁵, О.Б. Карякин⁵

¹ФГБУ «Национальный медицинский исследовательский центр радиологии» Минздрава России, Москва, Россия;
²Научно-исследовательский институт урологии и интервенционной радиологии им. Н.А. Лопаткина – филиал ФГБУ «Национальный медицинский исследовательский центр радиологии» Минздрава России, Москва, Россия;
³Московский научно-исследовательский онкологический институт им. П.А. Герцена – филиал ФГБУ «Национальный медицинский исследовательский центр радиологии» Минздрава России, Москва, Россия;
⁴ФГАОУ ВО «Российский университет дружбы народов им. Патриса Лумумбы», Москва, Россия;
⁵Медицинский радиологический научный центр им. А.Ф. Цыба – филиал ФГБУ «Национальный медицинский исследовательский центр радиологии» Минздрава России, Обнинск, Россия
*clingen@mail.ru

________________________________________________

Liudmila N. Lyubchenko*^1,2, Karina M. Сhernavina³, Koryun A. Ghazaryan⁴, Ivan N. Zaborskiy⁵, Oleg B. Karyakin⁵

¹National Medical Research Radiological Centre, Moscow, Russia;
²Lopatkin Scientific Research Institute of Urology and Interventional Radiology – branch of the National Medical Research Radiological Centre, Moscow, Russia;
³Hertsen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre, Moscow, Russia;
⁴Peoples' Friendship University of Russia named after Patrice Lumumba, Moscow, Russia;
⁵Tsyb Medical Radiological Research Centre – branch of the National Medical Research Radiological Centre, Obninsk, Russia
*clingen@mail.ru

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