bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2022-67-1-75-89bloodjour-338Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESСтруктура и прогностическое значение делеции 13q14 при хроническом лимфолейкозеStructure and prognostic signifi cance of 13q14 deletion in chronic lymphocytic leukemiahttps://orcid.org/0000-0003-1613-652XОбуховаТ. Н.ObukhovaT. N.

Обухова Татьяна Никифоровна, кандидат медицинских наук, заведующая лабораторией кариологии 

125167, Москва

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

125167, Moscow

obukhova_t@mail.ruhttps://orcid.org/0000-0002-8794-0120КисловаМ. И.KislovaM. I.

Кислова Мария Игоревна, врач-ординатор направления «Гематология» 

125284, Москва

Maria I. Kislova, Resident of Hematology Department 

125284, Moscow

xkislovamariax@gmail.comhttps://orcid.org/0000-0002-2490-1263НикитинЕ. А.NikitinE. A.

Никитин Евгений Александрович, доктор медицинских наук, профессор, заведующий дневным стационаром гематологии, онкологии и химиотерапии Городского гематологического центра; заведующий кафедрой гематологии и трансфузиологии им. акад. И.А. Кассирского и А.И. Воробьева 

125284, Москва; 125993, Москва

Eugene A. Nikitin, Dr. Sci. (Med.), Professor, Head of the Day Hospital of Hematology, Oncology and Chemotherapy of the city Hematological center; Head of the Department of Hematology and Transfusiology 

125284, Moscow; 125993, Moscow

eugene_nikitin@mail.ruhttps://orcid.org/0000-0003-3337-2487КислицынаМ. А.KislitsynaM. A.

Кислицына Мария Анатольевна, врач клинической лабораторной диагностики лаборатории кариологии 

125167, Москва

Maria A. Kislitsyna, Doctor of Clinical Laboratory Diagnostics in Karyology Laboratory 

125167, Moscow

makislitsyna@gmail.comhttps://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 of Department of Molecular Hematology 

125167, Moscow

bella_biderman@mail.ruhttps://orcid.org/0000-0003-3078-2616ТагироваМ. К.TagirovaM. K.

Тагирова Миляуша Кавыевна, научный сотрудник патологического отделения 

117997, Москва

Milyausha K. Tagirova, Researcher of the Pathology Department 

117198, Moscow

tagirova81@gmail.comhttps://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 Department of Molecular Hematology 

125167, Moscow

andrey@sudarikov.nethttps://orcid.org/0000-0002-9368-6050ПтушкинВ. В.PtushkinV. V.

Птушкин Вадим Вадимович, доктор медицинских наук, профессор, заместитель главного врача по медицинской части (по гематологии); профессор кафедры гематологии и трансфузиологии им. академиков И.А. Кассирского и А.И. Воробьева; главный внештатный специалист гематолог-трансфузиолог Департамента здравоохранения Москвы 

125284, Москва; 125993, Москва

Vadim V. Ptushkin, Dr. Sci. (Med.), Professor, Deputy Chief Physician for Hematology; Professor of the Department of Hematology and Transfusiology 

125284, Moscow; 125993, Moscow

vadimvadim@inbox.ruhttps://orcid.org/0000-0001-8188-5557СавченкоВ. Г.SavchenkoV. G.

Савченко Валерий Григорьевич , доктор медицинских наук, профессор, академик РАН, генеральный директор 

125167, Москва

Valery G. Savchenko , Dr. Sci. (Med.), Professor, Academician of RAS, CEO 

125167, Moscow

director@blood.ruФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Medical Research Center for HematologyRussian FederationГБУЗ г. Москвы Городская клиническая больница имени С.П. Боткина Департамента здравоохранения города МосквыРоссияS.P. Botkin’s City Clinical HospitalRussian FederationГБУЗ г. Москвы Городская клиническая больница имени С.П. Боткина Департамента здравоохранения города Москвы; ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Министерства здравоохранения Российской Федерации РоссииРоссияS.P. Botkin’s City Clinical Hospital; Russian Medical Academy of Continuous Professional EducationRussian FederationФГБУ «Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии имени академика В.И. Кулакова» Министерства здравоохранения Российской ФедерацииРоссияNational Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. KulakovRussian Federation2022110420226717589Copyright © Обухова Т.Н., Кислова М.И., Никитин Е.А., Кислицына М.А., Бидерман Б.В., Тагирова М.К., Судариков А.Б., Птушкин В.В., Савченко В.Г., 20222022Обухова Т.Н., Кислова М.И., Никитин Е.А., Кислицына М.А., Бидерман Б.В., Тагирова М.К., Судариков А.Б., Птушкин В.В., Савченко В.Г.Obukhova T.N., Kislova M.I., Nikitin E.A., Kislitsyna M.A., Biderman B.V., Tagirova M.K., Sudarikov A.B., Ptushkin V.V., 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/338Введение

Введение. Делеция 13q14  является самым частым хромосомным нарушением при хроническом лимфолейкозе (ХЛЛ) и как единственная аберрация определяет благоприятный прогноз заболевания. По размеру утраченного хромосомного материала определены два типа делеции 13q14: короткая (I тип) с вовлечением сегмента D13S319, содержащего гены MIR15A/MIR16-1 и DLEU1, и длинная (II тип), захватывающая центромерный участок 13q14 с вовлечением гена RB1.

Цель — оценить прогностическое значение разных вариантов делеции 13q14 при ХЛЛ.

Материалы и методы

Материалы и методы. В исследование включены две выборки больных ХЛЛ. Выборка 1 включала 256 больных, которым до начала иммунохимиотерапии выполнено FISH-исследование с ДНК-зондами на наличие делеций 13q14/D13S319, 11q23/ATM, 17p13/TP53 и трисомии 12. 101 больному с выявленной делецией 13q14/D13S319 проведен FISH-анализ с ДНК-зондом к локусу гена RB1 для определения ее размера (тип I или тип II). Выборка 2 включала 28 больных, обследованных на разных этапах заболевания, с выявленной при FISH-исследовании делецией 13q14, у которых структуру нарушений 13q изучали с помощью комбинации методов стандартной и молекулярной цитогенетики (mFISH, mBAND, arrayCGH).

Результаты

Результаты. В выборке 1 хромосомные нарушения выявлены у 75 % больных: делеция 13q — у 52 % (изолированная — 36 % всех случаев и 48 % случаев с делецией), делеция 11q — 19 %, +12–13 %, делеция 17p — 6 %. Делеция 13q14 I типа определена у 56 %, II — у 44 % больных. Выявлена ассоциация делеции II типа с наличием делеции 11q (р = 0,05). Изолированные делеции I и II типа выявлены в 61 и 39 % соответственно. Биаллельная делеция — у 12,7 % больных с делецией 13q. Получены значимые различия общей выживаемости (ОВ) в группах больных с изолированной делецией 13q14 I и II типа: медиана ОВ в группе с делецией I типа не была достигнута, в группе с делецией II типа она составила 67,5 месяца, р = 0,05. В выборке 2 при стандартном цитогенетическом исследовании (СЦИ) структурные нарушения хромосомы 13  определены в  50 % случаев: делеция 13q  — в  11  случаях; транслокации с вовлечением 13q14 — в 6 случаях. Из 5 случаев с биаллельной делецией, обнаруженной методом FISH, при СЦИ делеция 13q14 определена у 2 больных, причем только в одном аллеле.

Заключение

Заключение. Делеция 13q14 является цитогенетическим фактором благоприятного прогноза ХЛЛ, но ее структура неоднородна. Потеря гена-супрессора опухоли RB1 (делеция II типа) негативно влияет на ОВ больных на иммунохимиотерапии.

Introduction

Introduction. 13q14 deletion is the most common chromosomal abnormality in chronic lymphocytic leukemia (CLL), and as the sole abnormality determines the most favorable prognosis of the disease. Using molecular genetic methods two subtypes of 13q14 deletion were identifi ed based on the size of the lost chromosomal material: small (type I) with the involvement of the D13S319 segment containing MIR15A/MIR16-1 and DLEU1 genes and large (type II) containing centromeric region of 13q14 involving RB1 gene. Data on the impact of type I and II deletions on the course of CLL are controversial.

Aim — to evaluate the prognostic signifi cance of different variants of 13q14 deletion in CLL.

Patients and methods

Patients and methods. The study enrolled two cohorts of CLL patients. Cohort 1: 256 patients who were studied by FISH with DNA probes for detection of 13q14/D13S319, 11q23/ATM, 17p13/TP53 deletions, and trisomy 12 before immunochemotherapy. 101 patients with identifi ed 13q14/D13S319 deletion were analyzed with a DNA probe for RB1 locus for determination of deletion size (type I or type II). Cohort 2: 28 patients at different stages of the disease with deletion 13q14 detected by FISH were studied by using combination of standard and molecular cytogenetic methods (mFISH, mBAND, arrayCGH) to clarify the structure of 13q abnormalities.

Results

Results. In Cohort 1 chromosomal aberrations were detected in 75 % of patients: 13q deletion — 52 % (isolated — 36 % of all cases and 48 % of cases with deletion), 11q deletion — 19 %, +12 — 13 %, 17p deletion — 6 %. 13q14 deletion type I was detected in 56 %, type II — in 44 % of patients. Type II deletion correlated with the presence of 11q deletion (p = 0.05). Isolated deletions of type I and II were found in 61 and 39 %, respectively. Biallelic deletion was identifi ed in 12.7 % of patients with 13q deletion. Statistically signifi cant differences in OS were obtained in type I and II groups of patients with isolated 13q14 deletions: median OS was not reached and made 67.5 months, respectively, p = 0.05. In Cohort 2 structural abnormalities of chromosome 13 by conventional cytogenetic analysis (CCA) were identifi ed in 50 % of cases: 13q deletion — 11 cases; translocations involving 13q14 — 6 cases. In 5 cases with biallelic deletion identifi ed by FISH, 13q14 deletion by CCA was detected in two patients, and only in one allele.

Conclusion

Conclusion. In general, 13q14 deletion is a cytogenetic factor of favorable prognosis for CLL but its structure is heterogeneous. Loss of tumor suppressor RB1 (type II deletion) negatively affects OS in patients treated with immunochemotherapy

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