Материал и методы

oncotomsk

Сибирский онкологический журнал

Siberian journal of oncology

1814-48612312-3168

Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences

10.21294/1814-4861-2024-23-5-146-156

oncotomsk-3282

Research Article

ОБЗОРЫ

REVIEWS

Участие ретроэлементов в хромоанагенезе при развитии злокачественных новообразований

Participation of retroelements in chromoanagenesis in cancer development

https://orcid.org/0000-0002-4091-382X

Мустафин

Р. Н.

Mustafin

R. N.

Мустафин Рустам Наилевич, кандидат биологических наук, доцент кафедры медицинской генетики и фундаментальной медицины,

450008, г. Уфа, ул. Ленина, 3

Rustam N. Mustafin, PhD, Associate Professor, Department of Medical Genetics and Fundamental Medicine,

3, Lenin St., Ufa, 450008

ruji79@mail.ru

ФГБОУ ВО «Башкирский государственный медицинский университет»РоссияBashkir State Medical UniversityRussian Federation

2024

15112024

235146156

2024

Мустафин Р.Н.

Mustafin R.N.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.siboncoj.ru/jour/article/view/3282

Цель исследования – определить роль ретроэлементов в механизмах хромоанагенеза при развитии злокачественных новообразований.

Материал и методы

Материал и методы. Поиск соответствующих источников проводился в системах Scopus, Web of Science, PubMed, Elibrary с включением публикаций с февраля 2002 г. по декабрь 2023 г. Из 864 найденных научных статей об эпигенетических и молекулярно-генетических механизмах хромоанагенеза 64, содержащие информацию о вовлеченности в эти процессы ретроэлементов, были использованы для написания систематического обзора.

Результаты

Результаты. Согласно полученным результатам оригинальных работ и метаанализов, причиной комплексных хромосомных перестроек при развитии злокачественных новообразований может служить патологическая активация ретроэлементов. Описаны механизмы участия в хромоанагенезе LINE1, SVA, Alu, HERV, которые вызывают двуцепочечные разрывы ДНК, инсерции в области генов супрессоров опухолей с их инактивацией и образуют мостики дистальных фрагментов ДНК. Последовательности ретроэлементов используются в качестве «молекулярных пластырей» при негомологичных соединениях концов и как промоторы. Наблюдаемые при хромоанагенезе глобальные структурные перестройки хромосом могут быть последствиями активации ретроэлементов, которые участвуют в специфическом для хромотрипсиса и хромоплексии неаллельной гомологичной рекомбинации и в характерном для хромоанасинтеза опосредованном микрогомологией соединении концов. Для определенных типов неоплазм, таких как рак толстой кишки, характерен одновременно высокий уровень хромотрипсиса и активности ретроэлементов. При плоскоклеточном раке головы и шеи специфична хромоплексия, причинами разрывов ДНК при которой служат ретроэлементы. При хромоанагенезе наблюдается активация протоонкогенов и инактивация генов супрессоров опухолей, что также является следствием патологической экспрессии ретротранспозонов. Это обусловлено наличием последовательностей ретроэлементов в промоторных областях и интронах протоонкогенов (которые становятся основой для формирования химерного онкогена) и горячих точек инсерционного мутагенеза в генах супрессоров опухолей (транспозиции в данные области инактивируют данные гены).

Полученные результаты о драйверном влиянии ретроэлементов в механизмах хромотрипсиса, хромоплексии и хромоанасинтеза, являющихся основой для формирования клональной эволюции опухолей, свидетельствуют о перспективности таргетной терапии, направленной на подавление активности специфических ретроэлементов, участвующих в онкогенезе, в комплексном лечении больных. Для этого возможно использование в качестве инструментов комплементарных ретроэлементам микроРНК, также вовлеченных в развитие опухолей.

Purpose of the study

Purpose of the study: to determine the role of retroelements in chromoanagenesis mechanisms in cancer etiopathogenesis.

Material and Methods

Material and Methods. The search for relevant sources was carried out in the Scopus, Web of Science, PubMed, Elibrary systems, including publications from February 2002 to December 2023. Of the 864 scientifc articles found, 60 were used to write a systematic review.

Results

Results. According to original works and meta-analyses results, the cause of complex chromosomal rearrangements during cancer development may be retroelement pathological activation. Chromoanagenesis involves LINE1, SVA, Alu, HERV, which cause double-stranded DNA breaks, insertions in tumor suppressor genes region, the formation of chimeric oncogenes due to retroelement use as new promoters, and function as molecular “band-aids” in non-homologous end junctions and form bridges of distal DNA fragments. Global structural rearrangements of chromosomes observed during chromoanagenesis may be consequences of retroelements activation, which participate in non-allelic homologous recombination and in microhomology-mediated joining of ends characteristic. Certain types of neoplasms, such as colon cancer, are characterized by both high levels of chromothripsis and retroelement activity. In head and neck squamous cell carcinoma, chromoplexy is specifc, the sources of sequences at the breakpoints of which are retroelements. During chromoanagenesis, activation of proto-oncogenes and inactivation of tumor suppressor genes are observed, which is also a consequence of retroelement activation. This is due to the presence of retroelement sequences in proto-oncogenes promoter regions and introns (which become the basis for chimeric oncogene formation) and hot spots of insertional mutagenesis in tumor suppressor genes (transpositions into these regions inactivate these genes).

Conclusion

Conclusion. The results obtained on the driver effect of retroelements in chromothripsis, chromoplexy and chromoanasynthesis mechanisms, which are the basis for the formation of clonal evolution of tumors, indicate promise of targeted therapy aimed at silencing the activity of retroelements in cancer patients treatment. For this purpose, it is possible to use microRNAs complementary to retroelements, which are also involved in tumor development, as tools.

ретроэлементыканцерогенезкомплексные хромосомные перестройкитранспозициихромоанагенезхромоплексияхромотрипсис

retroelementscarcinogenesiscomplex chromosomal rearrangementstranspositionschromoanagenesischromoplexychromothripsis

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