tumorsMalignant tumoursMalignant tumours2224-50572587-6813Rosoncoweb10.18027/2224-5057-2025-054tumors-1490Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL REPORTSМутационный профиль мышечно-инвазивной уротелиальной карциномы и его взаимосвязь с течением опухолевого процессаThe mutational profile of muscle-invasive urothelial carcinoma and its association with the course of the diseasehttps://orcid.org/0000-0002-4673-1031ХмельковаД. Н.KhmelkovaD. N.

Хмелькова Дарья Николаевна

119333 Москва, ул. Губкина, 3, корп. 1 

115093 Москва, наб. Космодамианская, 4 / 22 б 

Khmelkova Daria Nikolaevna

Build 1, 3 Gubkina St., Moscow 119333

4/22b Kosmodamianskaya Emb., Moscow 115093

https://orcid.org/0000-0001-7754-6624ВолковаМ. И.VolkovaM. I.

Волкова Мария Игоревна

117152 Москва, Загородное шоссе, 18А 

125993 Москва, ул. Баррикадная, 2 / 1, стр. 1 

Volkova Maria Igorevna

18A Zagorodnoe Shosse, Moscow 117152

Build. 1,2/1 Barrikadnaya St., Moscow 125993

https://orcid.org/0000-0002-9015-2002ГридневаЯ. В.GridnevaYa. V.

Гриднева Яна Владимировна  

117152 Москва, Загородное шоссе, 18А 

119991 Москва, ул. Трубецкая, 8, стр. 2 

Gridneva Yana Vladimirovna

18A Zagorodnoe Shosse, Moscow 117152

Build. 2, 8 Trubetskaya St., Moscow 119991

Gridnevyana@mail.ruhttps://orcid.org/0000-0002-8732-0300БлагодатскихК. А.BlagodatskikhK. A.

Благодатских Константин Александрович

119333 Москва, ул. Губкина, 3, корп. 1 

Blagodatskikh Konstantin Aleksandrovich

Center of Genetics and Reproductive Medicine “GENETICO”;

МироноваИ. В.MironovaI. V.

119333 Москва, ул. Губкина, 3, корп. 1 

Build 1, 3 Gubkina St., Moscow 119333

https://orcid.org/0000-0002-8433-0837СеменоваА. Б.SemenovaA. B.

Семенова Анна Борисовна

117152 Москва, Загородное шоссе, 18А 

Semenova Anna Borisovna

18A Zagorodnoe Shosse, Moscow 117152

https://orcid.org/0009-0003-4372-6135ВещевайловА. А.VeshchevaylovA. A.

Вещевайлов Александр Александрович

117152 Москва, Загородное шоссе, 18А 

Veshchevaylov Alexander Alexandrovich

18A Zagorodnoe Shosse, Moscow 117152

https://orcid.org/0000-0001-5485-5803БабкинаА. В.BabkinaA. V.

Бабкина Александра Владимировна

117152 Москва, Загородное шоссе, 18А 

Babkina Alexandra Vladimirovna

18A Zagorodnoe Shosse, Moscow 117152

https://orcid.org/0009-0000-6205-3106БондаревС. А.BondarevS. A.

Бондарев Сергей Анатольевич

117152 Москва, Загородное шоссе, 18А 

Sergey Anatolyevich Bondarev

18A Zagorodnoe Shosse, Moscow 117152

https://orcid.org/0000-0002-6619-6179ГалкинВ. Н.GalkinV. N.

Галкин Всеволод Николаевич

117152 Москва, Загородное шоссе, 18А 

125993 Москва, ул. Баррикадная, 2 / 1, стр. 1 

Vsevolod Nikolaevich Galkin

18A Zagorodnoe Shosse, Moscow 117152

Build. 1,2/1 Barrikadnaya St., Moscow 125993

ПАО «Центр генетики и репродуктивной медицины «ГЕНЕТИКО» ; ООО «АйТиДжен Лабс»РоссияCenter of Genetics and Reproductive Medicine “GENETICO” ; ITGen Labs LLCRussian FederationОнкологический центр № 1 Городской клинической больницы имени С. С. Юдина Департамента здравоохранения города Москвы ; ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава РоссииРоссияOncology Center No. 1 of the City Clinical Hospital named after S. S. Yudin of the Moscow Department of Health ; Russian Medical Academy of Continuing Professional Education, Ministry of Health of RussiaRussian FederationОнкологический центр № 1 Городской клинической больницы имени С. С. Юдина Департамента здравоохранения города Москвы ; ФГАОУ ВО «Первый Московский государственный медицинский университет им. И. М. Сеченова» Минздрава России (Сеченовский Университет)РоссияOncology Center No. 1 of the City Clinical Hospital named after S. S. Yudin of the Moscow Department of Health ; I. M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University)Russian FederationПАО «Центр генетики и репродуктивной медицины «ГЕНЕТИКО»РоссияCenter of Genetics and Reproductive Medicine “GENETICO”Russian FederationОнкологический центр № 1 Городской клинической больницы имени С. С. Юдина Департамента здравоохранения города МосквыРоссияOncology Center No. 1 of the City Clinical Hospital named after S. S. Yudin of the Moscow Department of HealthRussian Federation2025301020251531728Copyright © Хмелькова Д.Н., Волкова М.И., Гриднева Я.В., Благодатских К.А., Миронова И.В., Семенова А.Б., Вещевайлов А.А., Бабкина А.В., Бондарев С.А., Галкин В.Н., 20252025Хмелькова Д.Н., Волкова М.И., Гриднева Я.В., Благодатских К.А., Миронова И.В., Семенова А.Б., Вещевайлов А.А., Бабкина А.В., Бондарев С.А., Галкин В.Н.Khmelkova D.N., Volkova M.I., Gridneva Y.V., Blagodatskikh K.A., Mironova I.V., Semenova A.B., Veshchevaylov A.A., Babkina A.V., Bondarev S.A., Galkin 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://www.malignanttumors.org/jour/article/view/1490

Цель исследования: Первичной целью исследования являлась оценка мутационного профиля мышечно-инвазивной уротелиальной карциномы (МИУК) с помощью секвенирования нового поколения (next generation sequencing, NGS). Вторичная цель заключалась в выделении мутаций, обеспечивающих потенциальные мишени противоопухолевой терапии, исследовательская цель — в выявлении взаимосвязей мутационного профиля с течением опухолевого процесса.Материал: в исследовании использованы опухолевая ткань и медицинские данные 50 пациентов с МИУК мочевого пузыря (48 (96,0 %)) или почечной лоханки (2 (4,0 %)). В клетках, выделенных из опухоли с гистологически подтвержденной инвазивной УК, изучались альтерации в ДНК и РНК путем проведения NGS с использованием панели из 523 генов.Результаты: медиана возраста — 72 (51–87) года, мужчин — 43 (86,0 %). У всех больных верифицирована МИУК, выявленная de novo (Т2–Т4а — 32 (64,0 %) пациента, включая 2 (4,0 %) больных раком почечной лоханки) или развившаяся вследствие опухолевой прогрессии немышечно-инвазивного рака мочевого пузыря (Тis-T1–18 (36,0 %) пациентов). Регионарные метастазы диагностированы у 8 (16,0 %), отдаленные — у 5 (10,0 %) больных. В 44 (88,0 %) образцов верифицирована УК high grade (в том числе, сопутствующая carcinoma in situ — в 4 (8,0 %) случаях). Медиана мутационной нагрузки (tumor mutational burden, TMB) составила 10,9 (0,0–49,6) мут / Мб (высокая TMB (≥ 10 мут / Мб) — 30 (60,0 %) из 50 случаев). Во всех образцах уровень микросателлитной нестабильности был низким. В 50 образцах выявлено 244 терапевтически значимых и онкогенных мутации в 84 генах (медиана — 5 (1–11) мутаций в образце). Патогенные мутации 1–2 уровня обнаружены в 13 генах 29 (58,0 %) образцов (в ≥ 1 гене — в 13 (26,0 %)), с частотой ≥ 10 % — в генах FGFR3 (9 (18,0 %)), TSC1 (9 (18,0 %)), PIK3CA (7 (14,0 %)), ERBB2 (6 (12,0 %)). Мутации 3–4 уровня выделены в 12 генах 33 (66,0 %) образцов (в ≥ 1 гене — в 15 (10,0 %)), с частотой ≥ 10 % — в генах KDM6A (19 (38,0 %)), ARID1A (12 (24,0 %)) и MDM2 (7 (14,0 %)). Онкогенные мутации выявлены в 63 генах 46 (92,0 %) образцов (в ≥ 1 гене — в 37 (74,0 %)), с частотой ≥ 10 % — в генах TP53 (25 (50,0 %)), FGF4 (5 (10,0 %)), RB1 (6 (12,0 %)), CDKN1A, STAG2, FGF3, CCND1 (по 5 (10,0 %) образцов с мутациями каждый). Инвазивная УК de novo по сравнению с рецидивной ассоциирована с большей частотой высокой TMB (71,9 % vs. 38,9 %, р = 0,024) и большей частотой мутаций генов сигнального пути PI3K (46,8 % vs. 16,7 %, р = 0,031).Заключение: МИУК характеризуется высокой TMB и низкой частотой микросателлитной нестабильности. Самыми частыми мутациями, предоставляющими потенциальные терапевтические мишени, являются альтерации генов FGFR3, TSC1, PIK3CA и ERBB2. МИУК de novo ассоциирована с большей частотой высокой TMB и увеличением частоты мутаций генов сигнального пути PI3K по сравнению с инвазивными рецидивами немышечно-инвазивной УК.

Study aim

Study aim: The primary aim of the study was to evaluate the mutational profile of muscle-invasive urothelial car­cinoma (MIUC) using next generation sequencing (NGS). A secondary aim was to identify mutations that provide potential targets for anticancer therapy, while an exploratory aim was to identify the associations between the mutational profile and the course of the disease.

Materials

Materials: The study used tumor tissue and medical data from 50 patients with MIUC of the bladder (48 (96.0 %)) or renal pelvis (2 (4.0 %)). DNA and RNA alterations were studied in cells isolated from tumors with histologically confirmed invasive UC using NGS with a panel of 523 genes.

Results

Results: The median age was 72 (51-87) years; the study sample included 43 men (86.0 %). MIUC was confirmed in all patients, either de novo (T2-T4a in 32 (64.0 %) patients, including 2 (4.0 %) patients with renal pelvis cancer) or as a result of progression of non-muscle-invasive bladder cancer (Tis-Tl in 18 (36.0 %) patients). Regional metastases were diagnosed in 8 (16.0 %) subjects, and distant metastases in 5 (10.0 %) patients. High grade UC was confirmed for 44 (88.0 %) samples (including concomitant carcinoma in situ in 4 (8.0 %) cases). The median tumor mutational burden (TMB) was 10.9 (0.0-49.6) muts / Mb (high TMB (> 10 muts / Mb) in 30 (60.0 %) out of 50 cases). The level of microsatellite instability was low in all samples; 244 therapeutically significant and oncogenic mutations in 84 genes were detected in 50 samples (median: 5 (1-11) mutations per sample). Level 1-2 pathogenic mutations were detected in 13 genes of 29 (58.0 %) samples (in > 1 gene in 13 cases (26.0 %)), with a frequency of>10% in the FGFR3 (9 (18.0 %)), TSC1 (9 (18.0 %)), PIK3CA (7 (14.0 %)), ERBB2 (6 (12.0 %)) genes. Level 3-4 mutations were identified in 12 genes of 33 (66.0 %) samples (in > 1 gene in 15 (10.0 %) cases), with a frequency of>10% in the KDM6A (19 (38.0 %)), ARID1A (12 (24.0%)) and MDM2 (7 (14.0%)) genes. Oncogenic mutations were detected in 63 genes of 46 (92.0%) samples (in > 1 gene in 37 (74.0 %) cases), with a frequency of >10% in the TP53 (25 (50.0 %)), FGF4 (5 (10.0 %)), RBI (6 (12.0 %)), CDKN1A, STAG2, FGF3, CCND1 genes (5 (10.0 %) samples with mutations for each). Invasive de novo UC is associated with a higher incidence of high TMB compared with recurrent UC (71.9 % vs. 38.9 %,p = 0.024) and a higher frequency of mutations in the PI3K signaling pathway genes (46.8 % vs. 16.7 %,p = 0.031).

Conclusion

Conclusion: MIUC is characterized by high TMB and low frequency of microsatellite instability. The most common mutations providing potential therapeutic targets are alterations of the FGFR3, TSC1, PIK3CA, and ERBB2 genes. De novo MIUC is associated with a higher frequency of high TMB and an increased frequency of mutations in the PI3K signaling pathway genes compared with invasive recurrence of non-muscle-invasive UC.

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