bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2020-65-4-444-459bloodjour-249Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESОпределение молекулярно-генетического профиля у взрослых больных острыми миелоидными лейкозами методом секвенирования нового поколенияNext-generation sequencing-based molecular genetic profiling in adults with acute myeloid leukaemiahttps://orcid.org/0000-0002-3548-8929КашлаковаА. И.KashlakovaA. I.

Кашлакова Анастасия Игоревна, клинический ординатор отделения интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения с круглосуточным стационаром

125167, Москвател.: +7 (495) 612-45-92 

Anastasia I. Kashlakova, Clinical Resident, Department of Intensive HighDose Chemotherapy for Hemoblastoses and Hematopoietic Depressions

125167, Moscowtel.: +7 (495) 612-45-92 

kashlakova.a.i@gmail.comhttps://orcid.org/0000-0001-6177-3566ПаровичниковаЕ. Н.ParovichnikovaE. N.

Паровичникова Елена Николаевна, доктор медицинских наук, руководитель отдела химиотерапии гемобластозов, депрессий кроветворения и трансплантации костного мозга

125167, Москва

Elena N. Parovichnikova, Dr. Sci. (Med.), Head of the Department of Chemotherapy for Hemoblastoses, Hematopoietic Depressions and BMT

125167, Moscow

elenap@blood.ruhttps://orcid.org/0000-0002-6253-3334БидерманБ. В.BidermanB. V.

Бидерман Белла Вениаминовна, кандидат биологических наук, старший научный сотрудник лаборатории молекулярной гематологии

125167, Москва

Bella V. Biderman, Cand. Sci. (Biol.), Senior Researcher, Laboratory of Molecular Hematology

125167, Moscow

bella_biderman@mail.ruhttps://orcid.org/0000-0003-1936-0084СидороваЮ. В.SidorovaY. V.

Сидорова Юлия Владимировна, кандидат медицинских наук, старший научный сотрудник лаборатории молекулярной гематологии

125167, Москва

Yulia V. Sidorova, Cand. Sci. (Med.), Senior Researcher, Laboratory of Molecular Hematology

125167, Moscow

iouliavl@gmail.comhttps://orcid.org/0000-0001-8044-598XЧабаеваЮ. А.ChabaevaY. A.

Чабаева Юлия Александровна, кандидат технических наук, заместитель заведующего информационно-аналитическим отделом

125167, Москва

Yulia A. Chabaeva, Cand. Sci. (Tech.), Deputy Head of the Information and Analysis Department

125167, Moscow

uchabaeva@gmail.comhttps://orcid.org/0000-0002-4827-8947ТроицкаяВ. В.TroitskayaV. V.

Троицкая Вера Витальевна, кандидат медицинских наук, заместитель генерального директора по лечебной работе, заведующая отделением интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения с круглосуточным стационаром

125167, Москва

Vera V. Troitskaya, Cand. Sci. (Med.), Deputy Director for Therapy, Head of the Department of Intensive High-Dose Chemotherapy for Hemoblastoses and Hematopoietic Depressions, Deputy Director for Medical Affairs

125167, Moscow

verat@blood.ruhttps://orcid.org/0000-0002-8337-2242ЛукьяноваИ. А.LukianovaI. A.

Лукьянова Ирина Анатольевна, кандидат медицинских наук, врач отделения интенсивной отделения интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения с дневным стационаром

125167, Москва

Irina A. Lukianova, Cand. Sci. (Med.), Physician, Department of Intensive HighDose Chemotherapy for Hemoblastoses and Hematopoietic Depressions

125167, Moscow

irina.donskova99@mail.ruhttps://orcid.org/0000-0003-0261-5941КохноА. В.KokhnoA. V.

Кохно Алина Владимировна, кандидат медицинских наук, ведущий научный сотрудник отделения интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения с круглосуточным стационаром

125167, Москва

Alina V. Kokhno, Cand. Sci. (Med.), Leading Researcher, Department of Intensive High-Dose Chemotherapy for Hemoblastoses and Hematopoietic Depressions

125167, Moscow

anilako@rambler.ruhttps://orcid.org/0000-0003-1494-7978СоколовА. Н.SokolovA. N.

Соколов Андрей Николаевич, кандидат медицинских наук, старший научный сотрудник отделения интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения с круглосуточным стационаром

125167, Москва

Andrey N. Sokolov, Cand. Sci. (Med.), Senior Researcher, Department of Intensive High-Dose Chemotherapy for Hemoblastoses and Hematopoietic Depressions

125167, Moscow

sokolov.a@blood.ruhttps://orcid.org/0000-0001-9463-9187СудариковА. Б.SudarikovA. B.

Судариков Андрей Борисович, доктор биологических наук, заведующий лабораторией молекулярной гематологии

125167, Москва

Andrey B. Sudarikov, Dr. Sci. (Biol.), Head of the Laboratory of Molecular Hematology

125167, Moscow

sudarikov.a@blood.ruhttps://orcid.org/0000-0003-1613-652XОбуховаТ. Н.ObukhovaT. N.

Обухова Татьяна Никифоровна, кандидат медицинских наук, заведующая лабораторией кариологии

125167, Москва

Tatyana N. Obukhova, Cand. Sci. (Med.), Head of the Laboratory of Karyology

125167, Moscow

obukhova.t@blood.ruhttps://orcid.org/0000-0001-8188-5557СавченкоВ. Г.SavchenkoV. G.

Савченко Валерий Григорьевич, доктор медицинских наук, профессор, академик РАН, главный внештатный специалист-гематолог МЗ РФ, генеральный директор

125167, Москва

Valery G. Savchenko, Dr. Sci. (Med.), Professor, Full Member of the Russian Academy of Sciences, Director, National Research Center for Hematology; Chief Non-staff Hematologist, Ministry of Health of the Russian Federation

125167, Moscow

svg@blood.ruФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Research Center for HematologyRussian Federation202010122020654444459Copyright © Кашлакова А.И., Паровичникова Е.Н., Бидерман Б.В., Сидорова Ю.В., Чабаева Ю.А., Троицкая В.В., Лукьянова И.А., Кохно А.В., Соколов А.Н., Судариков А.Б., Обухова Т.Н., Савченко В.Г., 20202020Кашлакова А.И., Паровичникова Е.Н., Бидерман Б.В., Сидорова Ю.В., Чабаева Ю.А., Троицкая В.В., Лукьянова И.А., Кохно А.В., Соколов А.Н., Судариков А.Б., Обухова Т.Н., Савченко В.Г.Kashlakova A.I., Parovichnikova E.N., Biderman B.V., Sidorova Y.V., Chabaeva Y.A., Troitskaya V.V., Lukianova I.A., Kokhno A.V., Sokolov A.N., Sudarikov A.B., Obukhova T.N., Savchenko V.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.htjournal.ru/jour/article/view/249Введение

Введение. У больных острыми миелоидными лейкозами (ОМЛ) выявляются множественные драйверные мутации. Прогностическая значимость выявляемых мутаций в настоящее время до конца не изучена.

Цель

Цель: оценить частоту мутаций различных генов и их влияние на прогноз заболевания у взрослых больных ОМЛ.

Материалы и методы

Материалы и методы. В исследование включены 90 взрослых больных с впервые установленным диагнозом ОМЛ, из них 76 больных моложе 60 лет и 14 больных в возрасте от 60 лет и старше. В качестве индукции ремиссии у больных моложе 60 лет использовали программу химиотерапии (ХТ) «7+3», у больных старшей возрастной группы различные программы низкодозной ХТ с гипометилирующими агентами. Определение молекулярно-генетического статуса больных проводилось с использованием метода секвенирования нового поколения; авторская панель содержала гены ASXL1, BCOR, DNMT3, FLT3, IDH1, IDH2, PIGA, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53 и U2AF2.

Результаты

Результаты. Нуклеотидные замены были обнаружены в генах DNMT3, TET2, TP53, SETBP1, BCOR, RUNX1, IDH2, IDH1, FLT3, U2AF2, SF3B1 у 57,8 % больных (n = 52), при этом у 17,8 % больных (n = 16) были выявлены сочетанные мутации в двух или трех генах. Эффективность лечения и долгосрочные результаты терапии оценивали в зависимости от возраста, группы риска по ELN 2017 и наличия мутаций в генах TP53, RUNX1, IDH1, IDH2 и DNMT3. При оценке долгосрочных результатов терапии были выявлены достоверные различия в общей выживаемости (ОВ) в зависимости от наличия мутаций генов TP53 и RUNX1: у больных с мутациями TP53 ОВ составила 30 %, у больных без мутаций 53,4 % (p = 0,0037). Схожие результаты были получены для мутаций гена RUNX1 — у больных с мутациями ОВ составила 20 %, в то время как у больных без — 54 % (p = 0,0466).

Заключение

Заключение. При диагностике ОМЛ определяют мутации в генах FLT3-ITD, NPM1 и CEBPA, однако генетическая гетерогенность группы больных ОМЛ диктует необходимость детального изучения их молекулярно-генетического статуса, что необходимо для уточнения прогноза заболевания и выбора оптимальной тактики терапии.

Introduction

Introduction. Acute myeloid leukaemia (AML) is associated with multiple driver mutations, which prognostic value remains understudied.

Aim

Aim. Assessment of the frequency of mutations in various genes and their impact on acute myeloid leukaemia outcome in adults.

Materials and methods

Materials and methods. The study included 90 adult patients with newly diagnosed AML; 76 were aged under 60, 14 were 60 and more years old. Patients under 60 had chemotherapy (CT) “7+3” as induction, the elder cohort had variant low-dose CT with hypomethylating agents. The molecular genetic status of patients was determined using next-generation sequencing; the in-house gene panel included ASXL1, BCOR, DNMT3, FLT3, IDH1, IDH2, PIGA, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53 and U2AF2.

Results

Results. Nucleotide substitutions were identified in genes DNMT3, TET2, TP53, SETBP1, BCOR, RUNX1, IDH2, IDH1, FLT3, U2AF2, SF3B1 in 57.8 % of the patients (n = 52), with 17.8 % (n = 16) having compound mutations in two or three genes. Treatment efficacy and long-term outcomes were assessed against age, ELN-2017 risk groups and mutations in genes TP53, RUNX1, IDH1, IDH2 and DNMT3. In the long term, a reliable variation was revealed in the overall survival (OS) rate with respect to mutations in genes TP53 and RUNX1. Patients with mutant TP53 had 30 % OS, those with the intact gene — 53.4 % (p = 0.0037). Similar results were obtained with RUNX1: mutations marked 20 % OS, intact patients had 54% OS (p = 0.0466).

Conclusion

Conclusion. Mutations in genes FLT3-ITD, NPM1 and CEBPA are proxy to AML. However, a more accurate prognosis and optimal choice of therapy require detailed molecular profiling due to genetic heterogeneity of AML patients.

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