Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press70410.17650/2313-805X-2024-11-3-8-23REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИGermline and somatic alterations in NBN and their putative impact on the pathogenesis of malignant neoplasmsГерминативные и соматические нарушения гена NBN и их возможная роль в патогенезе злокачественных новообразованийhttps://orcid.org/0000-0002-0207-2724KrivtsovaO. M.КривцоваО. М.
Russian Federation

Olga Mikhailovna

4 Kashirskoe Shosse, Moscow 115522

Ольга Михайловна Кривцова

115552 Москва, Каширское шоссе, 24

o.krivtsova@ronc.ruhttps://orcid.org/0009-0005-2450-8452OzerovaD. D.ОзероваД. Д.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

115552 Москва, Каширское шоссе, 24

https://orcid.org/0000-0001-9560-1383LazarevichN. L.ЛазаревичН. Л.
Russian Federation

24 Kashirskoe Shosse, Moscow 115522

GSP-1, Leninskie Gory, Moscow 119991

115552 Москва, Каширское шоссе, 24

119991 Москва, Ленинские горы, 1, стр. 12

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава РоссииLomonosov Moscow State UniversityФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова»150920241138231010202410102024Copyright ©; 2024, Krivtsova O.M., Ozerova D.D., Lazarevich N.L.Copyright ©; 2024, Кривцова О.М., Озерова Д.Д., Лазаревич Н.Л.2024Krivtsova O.M., Ozerova D.D., Lazarevich N.L.Кривцова О.М., Озерова Д.Д., Лазаревич Н.Л.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/704

Disruption of mechanisms that maintain genome stability is an essential factor of tumor progression. Accordingly, predisposition to the development of neoplasms is often associated with germline mutations in genes involved in DNA damage detection and repair. At the same time, impairment of DNA repair systems may be a predictor of antitumor treatment efficacy while overexpression of genes involved in DNA repair is a frequent event in various types of malignancies that can lead to development of tumor cells’ resistance to chemo- and radiotherapy. NBN (nibrin) gene encodes the subunit of the MRN complex which acts as a sensor of double-strand DNA breaks and participates in their repair by homologous recombination. Germline variants in NBN which are associated with increased risk of tumor development are generally represented by frameshift mutations that lead to the synthesis of truncated protein as well as by nonsense and some missense mutations which occur in functionally significant domains. These germline mutations result in partial loss of nibrin function and in increased frequency of spontaneous and induced chromosomal aberrations in the cells of the carriers. On the contrary, amplification of NBN locus is a predominant type of somatic mutations affecting this gene, which indicates a dual role of NBN protein in tumor progression. The results of several studies demonstrate the influence of NBN expression level and its mutational status on anti-tumor drug resistance in particular types of tumor cells and on the survival rate of patients. These data indicate that an in-depth study of different variants and their functional significance is necessary since NBN status may be essential for the choice of treatment tactics for some types of tumors.

Нарушение механизмов поддержания стабильности генома является важным условием опухолевой прогрессии. По этой причине предрасположенность к развитию новообразований нередко связана с носительством герминативных мутаций в генах систем детекции и репарации повреждений ДНК. Вместе с тем нарушение систем репарации может служить фактором прогноза эффективности противоопухолевой терапии, а гиперэкспрессия отвечающих за репарацию ДНК генов является частым событием в различных типах новообразований, которое может приводить к приобретению опухолевыми клетками устойчивости к химио- и радиотерапии. Ген NBN (нибрин) кодирует субъединицу MRN-комплекса, являющегося сенсором двунитевых разрывов ДНК и участвующего в их репарации путем гомологичной рекомбинации. Ассоциированные с повышенным риском развития опухолей герминативные мутации NBN, представленные в первую очередь инделами, приводящими к сдвигу рамки считывания и синтезу укороченных форм белка, а также нонсенс- и некоторыми миссенс-мутациями в функционально значимых доменах, обусловливают частичную утрату нибрином своих функций и увеличение числа спонтанных и индуцированных хромосомных аберраций в клетках носителей. Среди соматических мутаций, затрагивающих NBN в опухолевых клетках, преобладают амплификации локуса этого гена, что указывает на двойственную роль белка NBN в опухолевой прогрессии. Результаты немногочисленных исследований влияния уровня экспрессии NBN и его мутационного статуса на устойчивость конкретных типов опухолевых клеток к применяемым в терапии злокачественных новообразований препаратам и выживаемость пациентов указывают на необходимость углубленного исследования функциональной значимости различных вариантов, поскольку статус NBN может иметь значение при выборе тактики лечения некоторых типов опухолей.

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