bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.25837/HAT.2019.35.62.003bloodjour-104Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESИЗМЕНЕНИЯ В НЕКОДИРУЮЩИХ ПОСЛЕДОВАТЕЛЬНОСТЯХ ГЕНА ТР53 ПРИ ДИФФУЗНОЙ B-КРУПНОКЛЕТОЧНОЙ ЛИМФОМЕСHANGES IN NON-CODING SEQUENCES OF THE TP53 GENE IN DIFFUSE LARGE B-CELL LYMPHOMAhttps://orcid.org/0000-0001-7542-7285ВоропаеваЕ. Н.VoropaevaE. N.

д.  м.  н., ст. н. с. лаборатории молекулярно-генетических исследований терапевтических заболеваний,

г. Новосибирск

Novosibirsk

vena.81@mail.ruhttps://orcid.org/0000-0002-1261-5470ПоспеловаТ. И.PospelovaT. I.

доктор медицинских наук, профессор, заведующая кафедрой терапии, гематологии и трансфузиологии ФПК и ППВ,

 

Novosibirsk

post_gem@mail.ruhttps://orcid.org/0000-0001-9425-413XВоеводаМ. И.VoevodaM. I.

член-корреспондент РАМН, доктор медицинских наук, профессор, директор,

г. Новосибирск

Novosibirsk

office@iimed.ruhttps://orcid.org/0000-0002-7165-4496МаксимовВ. Н.MaksimovV. N.

доктор медицинских наук, профессор, заведующий лабораторией молекулярно-генетических методов исследования терапевтических заболеваний,

г. Новосибирск

Novosibirsk

medik11@mail.ruНИИ терапии и профилактической медицины — филиал ИЦИГ СО РАН; Новосибирский государственный медицинский университет Минздрава РоссииРоссияResearch Institute of Internal and Preventive Medicine — Branch of Federal Research Center Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences; Novosibirsk State Medical University of the Ministry of Health of RussiaRussian FederationНовосибирский государственный медицинский университет Минздрава РоссииРоссияNovosibirsk State Medical University of the Ministry of Health of RussiaRussian Federation201807062019633239249Copyright © Воропаева Е.Н., Поспелова Т.И., Воевода М.И., Максимов В.Н., 20192019Воропаева Е.Н., Поспелова Т.И., Воевода М.И., Максимов В.Н.Voropaeva E.N., Pospelova T.I., Voevoda M.I., Maksimov 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.htjournal.ru/jour/article/view/104Введение

Введение. В настоящее время углубленный анализ результатов секвенирования вне кодирующих последовательностей гена ТР53 отсутствует, количество и функциональные эффекты выявляемых в них аберраций недооценены. Целью данного исследования было выявить изменения в некодирующих участках ТР53 в опухолевой ткани диффузной B-крупноклеточной лимфомы (ДВККЛ) и провести прогнозирование возможных последствий этих изменений.

Материал и методы

Материал и методы. Геномную ДНК выделяли из парафиновых блоков биоптатов опухолевых лимфоузлов и экстранодальных очагов поражения 92 больных с ДВККЛ. Методом прямого капиллярного секвенирования по Сенгеру определена нуклеотидная последовательность кодирующей области ТР53 (экзоны 5—10) и примыкающих участков интронов, а также фрагмента 3’-нетранслируемой последовательности (НТП) гена, содержащего сигнал полиаденилирования. Теоретическое прогнозирование возможных последствий обнаруженных интронных мутаций проводилось с помощью программы NetGene2.

Результаты

Результаты. В опухолевом материале от 74  больных ДВККЛ выявлены 12 типов мутаций в интронных участках: g.7675266A>G, g.7675010C>A, g.7674988A>G, g.7674326C>G, g.7674153C>G, g.7673691G>T, g.7673681T>C, g.7673664T>C и g.7673523A>G. Мутация g.7674326C>G, имеющая доказанную биологическую значимость по данным экспериментов in vitro, согласно информации из базы данных «The Human Cancer Mutation Database» относится к изменениям, влияющим на сплайсинг. Согласно прогнозу программы NetGene2, из выявленных нами в группе больных ДВККЛ интронных замен замена g.7675010C>A приводит к образованию дополнительного акцепторного сайта сплайсинга, что может приводить к включению в последовательность мРНК части интрона  5. В 5 из 9 случаев выявления rs78378222 в образцах опухолевой ткани ДВККЛ определен гомозиготный минорный генотип С/С, свидетельствующий о потере гетерозиготности в данном локусе, что способствует значительному приросту злокачественного потенциала клеток.

Заключение

Заключение. Таким образом, полученные данные свидетельствуют о функциональной селекции на этапах опухолевой прогрессии ДВККЛ изменений не только в экзонах, но и в интронах и в 3’-НТП гена ТР53. 

Background

Background. Currently, in-depth analysis of the results of sequencing outside the coding sequences of the ТР53 gene is absent, the number and functional effects of aberrations detected in them are underestimated. The purpose of this study was to identify changes in non-coding regions of ТР53 in tumor tissue of diffuse large B-cell lymphoma (DLBCL) and to predict the possible consequences of these changes.

Material and methods

Material and methods. Genomic DNA was isolated from paraffin blocks of biopsies of tumor lymph nodes and extranodal lesions of 92 patients with DLBCL. The nucleotide sequence of the coding region of ТР53 (exons 5—10) and adjacent introns, as well as the fragment of the 3’-UTR gene sequence containing the polyadenylation signal, was determined by direct capillary sequencing by Sanger method. Theoretical prediction of possible consequences of detected intron mutations was carried out using the program NetGene2.

Results

Results. In tumor material from 74 patients with DLBCL, 12 types of mutations in intron sites were identified: g.7675266A>G, g.7675010C>A, g.7674988A>G, g.7674326C>G, g.7674153C>G, g.7673691G>T, g.7673681T>C, g.7673664T>C and g.7673523A>G. The mutation  I g.7674326C>G, which has proven biological significance from in vivo experiments, according to The Human Cancer Mutation Database refers to changes that affect splicing. According to the prognosis of NetGene2, from intron replacements revealed by us in the group of patients, g.7675010C>A leads to the formation of an additional acceptor site for splicing, which may result in the incorporation of a part of the intron 5 into the mRNA sequence. In 5/9 cases of detection of rs78378222 in samples of tumor tissue of DLBCL, a homozygous minor genotype C/C was determined, which indicated the loss of heterozygosity in this locus, which contributes to a significant increase in malignant cell potential.

Conclusions

Conclusions. Thus, the data obtained by us testify to the functional selection at the stages of the tumor progression of DLBCL changes not only in the coding but also introns and 3’-UTR ТР53 gene. 

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