Epstein–Barr virus LMP1 oncogene polymorphism in tatar and slavic populations in Russian Federation impacting on some malignant tumours

Objective: To compare genetic structure of the main Epstein–Barr virus (EBV) oncogene, latent membrane protein 1 (LMP1), in EBV strains circulating in two genetically distinct ethnic populations in Russian Federation, Tatars and Slavs, as well as assess an impact of diverse LMP1 variants on incidence and mortality rate for some malignant tumors partially associated with EBV infection. Materials and methods. Oral washing samples were collected from 60 ethnic Kazan Tatars and 65 ethnic Moscow Slavics. Carboxy-terminal nucleotide sequences (41 and 40 sequences, respectively) derived from hypervariable LMP1 gene region were amplified from EBV DNA samples. Next, final nucleotide sequences were translated into amino acid sequences and analyzed according to classification by Edwards et al. Results. Analysis of 41 and 40 LMP1 samples obtained from ethnic Kasan Tatars and ethnic Moscow Slavics, respectively, revealed significant difference in relevant amino acid structures. In particular, all LMP1 samples derived from Moscow Slavics were found to belong to the four protein variants: B95.8/A, Med–, China1 and NC. Among them, low-transforming variant B95.8/A was dominant (82.5%). In contrast, solely 21 out of 41 LMP1 samples derived from ethnic Tatars were classified as B95.8/A, Med– and China1 variants. Importantly, the percentage of low-transforming B95.8/A variant among ethnic Tatar samples was significantly lower compared to that one found in Moscow Slavics (29.3% vs. 82.5%). On the other hand, seven (17.1%) out of 20 other samples formed a unique protein mono group characterized by LMP1 amino acid sequence differed from that one available in the GenBank database. Such group of variants was designated as LMP1-TatK. The remaining 13 samples (31.7%) did not match either protein variants, thereby forming the “beyond classification” (LMP1-TatBC) group. Conclusion. The data obtained suggest that various LMP1 variants exist in EBV strains persisting in ethnic Tatrs and ethnic Slavics examined in Russian Federation. It was also found that EBV strains isolated from ethnic Tatars contained a unique LMP1 gene variant encoding protein LMP1-TatK lacked in EBV strains derived from ethnic Moscow Slavics. Taking into account the genealogy of Tatars, it cannot be ruled out that EBV strain bearing LMP1-TatK variant represented ethnically specific EBV strain that might circulate many centuries ago among their historical human predecessors called Mongol-Tatar tribes. In addition, it was shown that the LMP1 variants in EBV strains isolated from ethnic Kazan Tatars and ethnic Moscow Slavics did not affect the incidence and mortality of different forms of cancer consisting of EBV-associated cases

Распределение генов HLA II у больных раком носоглотки, ассоциированным с вирусом Эпштейна–Барр, и другими опухолями ротовой полости в России

Background. It has been proved that for the nasopharyngeal carcinoma (NPC) the etiological agent is the Epstein–Barr virus (EBV). Being an ubiquitous infection, EBV, under certain conditions, is able to display its oncogenic potential. Among a wide range of tumors associated with EBV, the NPC occupies a special place because it is characterized by a geographically and ethnically heterogeneous distribution, suggesting that in the pathogenesis of NPC, in addition to EBV, an important role is played by other factors, such as genetic predisposition to this neoplasm. Among known genetic factors influencing the frequency of NPC development, the human leukocyte antigen (HLA) complex occupies an important place, as it plays a central role in the presentation of viral antigens to the immune system. In Russia, the association of HLA alleles with the risk of EBV associated forms of NPC development and with development of other oral cavity tumors (OOCT), not associated with the virus, has not been studied. In the literature there are contradictory information about HLA genes, which determine the predisposition to the emergence of these tumors, and their role in the initiation and formation an immune response to EBV proteins.Objective: to study the distribution of the of DQA1-, DQB1-, DRB1-HLA class II gene variants associated with respectively the risk or resistance to the development of NPC and OOCT and with a high and low level of antibody response to EBV main proteins. A group of healthy persons served as a control.Materials and methods. Blood samples from 62 patients with NPC, 44 patients with OOCT, and as control, 300 healthy individuals, were used in the study. The blood serum samples of NPC and OOCT patients were tested for the presence of immunoglobulin classes G and A antibodies to capsid and early EBV antigens by indirect immunofluorescence. All serum samples of patients and healthy individuals were genotyped on HLA-DQA1, -DQB1 and -DRB1 by the method of multi-primer amplification by sequence-specific primers by real-time polymerase chain reaction.Results. In NPC patients, an increase in the frequency of HLA-DRB1*08 was found when compared with the frequency of a similar allele in healthy individuals (5.6 % vs 1.8 %; odds ratio (OR) 3.2; 95 % confidence interval (CI) 1.1–9.1; p = 0.02), and, on the contrary, a lower HLA-DQB1*0301 frequency was detected (16.1 % vs 25.3 %; p <0.05) than in healthy individuals. The data obtained suggest that the HLA-DRB1*08 gene is associated with an increased sensitivity to NPC.In OOCT patients, HLA-DQB1*0502–4 and HLA-DRB1*16 variants were less common than in healthy individuals (1.1 % vs 6.8 %; p <0.05 and 1.1 % vs 6.7 %; OR 0.16; 95 % CI 0.01–1.08; p <0.05, respectively), suggesting that the HLA-DQB1*0301 gene is associated with resistance to NPC, and HLA-DQB1*0502–4 and HLA-DRB1*16 variants – with resistance to OOCT. It is interesting to note the difference in the frequency of HLA-DRB1*13 between NPC and OOCT patients (17.7 % vs 6.8 %; OR 2.9; 95 %CI 1.1–8.6; p <0.05). One can suggest that this difference is related to the proven involvement of EBV in the NPC development. There were no other differences in the frequencies of class II HLA genes between the groups of NPC and OOCT patients. For the first time in Russia the importance of alleles DQA1, DQB1 and DRB1 of the HLA gene for the NPC and OOCT development, malignant tumors, respectively associated and non-associated with EBV, was studied. The results of the investigation completed together with known literature data allow us to conclude that the above alleles of the HLA class II gene can serve as a factor predisposing to the development of NPC in Russia.Conclusion. However, in order to establish a strict association between a specific HLA haplotype and the NPC and OOCT incidence, the information obtained is insufficient due to the complexity and variability of the genetic control of immune responses controlling the tumor process. A comprehensive study of this issue using different immune response genes and populations of different ethnic origins will probably help to elucidate the effect of genetic polymorphism on the risk of NPC and OOCT development in Russia.Введение. Назофарингеальная карцинома (рак носоглотки, РНГ), как известно, строго ассоциирована с вирусом Эпштейна–Барр (ВЭБ). Однако ВЭБ является убиквитарной инфекцией, тогда как РНГ развивается довольно редко и характеризуется географически и этнически неоднородным распространением, что позволяет предположить важную роль других кофакторов в патогенезе РНГ, таких как окружающая среда и генетическая предрасположенность. Среди известных генетических факторов, ассоциированных с РНГ, главный комплекс гистосовместимости (лейкоцитарный антиген человека, human leukocyte antigen (HLA)) занимает важное положение, так как играет ключевую роль в презентации вирусных антигенов иммунной системы. В России изучение ассоциации аллелей HLA с риском развития РНГ, связанного с ВЭБ, не проводилось, а в литературе существуют противоречивые сведения о роли разных HLA-генов как в возникновении и развитии РНГ, так и в инициации и особенностях иммунного ответа к белкам ВЭБ.Цель исследования – изучение распределения вариантов DQA1-, DQB1-, DRB1-генов HLA класса II у больных РНГ и пациентов с другими опухолями полости рта (ДОПР), ассоциированными и не ассоциированными с ВЭБ, в группах с высоким и низким уровнем гуморального иммунного ответа к основным белкам ВЭБ по сравнению с контрольной группой здоровых лиц.Материалы и методы. Всего в исследование вошли 62 больных недифференцированным РНГ и 44 пациента с ДОПР, а также 300 здоровых лиц. Сыворотка крови всех больных была протестирована на наличие антител иммуноглобулинов классов G и А к капсидному и раннему антигенам ВЭБ методом непрямой иммунофлюоресценции. Все образцы генотипированы на HLA-DQA1, -DQB1 и -DRB1 с помощью мультипраймерной амплификации сиквенс-специфическими праймерами методом полимеразной цепной реакции в режиме реального времени.Результаты. Показано увеличение частоты HLA-DRB1*08 у пациентов с РНГ по сравнению с контролем (5,6 % против 1,8 %; отношение шансов (ОШ) 3,2; 95 % доверительный интервал (ДИ) 1,1–9,1; р = 0,02). Возможно, ген HLA-DRB1*08 ассоциирован с повышенной чувствительностью к РНГ. В то же время у пациентов с РНГ была выявлена более низкая, чем в контроле, частота HLA-DQB1*0301 (16,1 % против 25,3 %; р <0,05). Вариант HLA-DQB1*0502–4, наоборот, реже встречался у пациентов с ДОПР, чем в контроле (1,1 % против 6,8 %; р <0,05). Аналогичные наблюдения касаются HLA-DRB1*16, частота которого у пациентов с ДОПР была ниже, чем в контроле (1,1 % против 6,7 %; ОШ 0,16; 95 % ДИ 0,01–1,08; р <0,05), т. е. ген HLA-DQB1*0301 ассоциирован с резистентностью к РНГ, а варианты HLA-DQB1*0502–4 и HLA-DRB1*16 – с резистентностью к ДОПР.Интересен факт обнаружения различий в частоте HLA-DRB1*13 у пациентов с РНГ и ДОПР (17,7 % против 6,8 %; ОШ 2,9; 95 % ДИ 1,1–8,6; р <0,05). Эти различия могут быть связаны с доказанным участием ВЭБ в развитии РНГ. Других различий по частотам генов HLA класса II между группами пациентов с РНГ и ДОПР не выявлено. Впервые в России проведено изучение связи аллелей DQA1, DQB1 и DRB1 гена HLA с развитием назофарингеальной карциномы (РНГ) и ДОПР, ассоциированных и не ассоциированных с ВЭБ.Заключение. Наши исследования в совокупности с уже известными данными позволяют заключить, что имеется определенная связь генов HLA класса II c развитием РНГ, однако для установления строгой ассоциации аллелей HLA класса II с РНГ и другими опухолями области головы и шеи полученных сведений недостаточно из-за сложности и вариабельности генетического контроля иммунных реакций, контролирующих опухолевый процесс

Вирус Эпштейна-Барр у адыгейцев и славян в России: типы вируса, варианты LMP1 и злокачественные новообразования

Introduction. It is known that the structural features of the Epstein-Barr virus (EBV) affect the manifestation of its biological properties. Based on differences in the sequences of the EBNA2, EBNA3A, -B, and -C genes, two types of the virus, EBV-1 and EBV-2, have been identified that have different ability to transform B cells in vitro and possibly playing certain role in the development of EBV-associated neoplasms.Aim. To study the prevalence of EBV-1 and EBV-2 in two ethnic groups, Аdygeans and Slavs, as well as the contribution of EBV-associated tumors to the overall incidence of malignant neoplasms certain organs and tissues.Materials and methods. DNA samples were extracted from 59 oral lavages of ethnic Аdygeans from Republic of Adygea and 40 such from oral cavity of ethnic Slavs of Moscow city. These samples were used for amplification of EBV DNA, determination of the concentration of viral DNA copies per 1 cell washout, as well as for amplification of EBV LMP1 followed by sequencing of the resulting gene samples and determination of their protein variant (LMP1).Results. Studies have shown that among the representatives of the Аdygeans the 2nd EBV type prevails, and among the Slavs, the 1st one. Epstein-Barr virus isolates in representatives of the two ethnic groups also differed in the structure of LMP1. Among the Slavs, a set of its LMP1 variants (B95.8/A, China, Med- and NC) was identified. However, among the Adygeans, the only variant - B95.8 and its subtype - B95.8/A was identified. EBV-1, which prevails among the representatives of the Slavs and has the ability to transform B-cells, was projected onto a higher incidence of tumors of the pharynx, stomach, Hodgkin's and non-Hodgkin's lymphomas (where EBV-associated cases cam occur) in the population of Moscow than in the population of the Republic of Adygea. However, the differences between incidence rates for these neoplasms (with the exception for the stomach tumors) were not statistically significant (p >0.5). A higher and statistically significantly different incidence rate of stomach cancer in residents of Moscow city, compared with that in residents of the Republic of Adygea, in our opinion, is not due to EBV-1 type and/or LMP1 variants, but rather is associated with a genetic predisposition the population of Moscow city to this tumor.Conclusion. The fact that two ethnic groups of Russia were found to be prevails by different types of EBV raises the question of their ethno-geographical association and their role in the induction of EBV-associated tumors. To resolve this issue additional studies in other geographical regions of Russia among representatives of different ethnic groups are required.Введение. Известно, что структурные особенности вируса Эпштейна-Барр (ВЭБ) влияют на проявление его биологических свойств. На основе различий в последовательностях генов EBNA2, EBNA3A, -B и -C идентифицированы 2 типа вируса, 1-й (ВЭБ-1) и 2-й (ВЭБ-2), обладающие разной способностью трансформировать В-клетки in vitro и, возможно, играющие определенную роль в возникновении ВЭБ-ассоциированных новообразований.Цель исследования - изучение распространенности ВЭБ-1 и вЭБ-2 у 2 этносов, адыгейцев и славян, а также вклада ассоциированных с ВЭБ случаев в общую заболеваемость злокачественными новообразованиями определенных органов и тканей.Материалы и методы. Из 59 смывов полости рта этнических адыгейцев Республики Адыгея и 40 таковых этнических славян Москвы экстрагировали образцы ДНК. Эти образцы использовали для амплификации ДНК ВЭБ, определения концентрации копий вирусной ДНК на 1 клетку смыва, а также для амплификации LMP1 ВЭБ с последующим секвенированием полученных образцов гена и выявления их белкового варианта (LMP1).Результаты. Исследования показали, что у представителей адыгейцев преобладает ВЭБ-2, а у славян - ВЭБ-1. изоляты ВЭБ у представителей 2 этносов также различались по структуре его LMP1: у славян выявлен целый набор его белковых вариантов ( В95.8/А, China, Med- и NC), а у адыгейцев - единственный вариант - B95.8 и его подтип -B95.8/A. доминирующий у представителей славян ВЭБ-1, обладающий способностью трансформировать в-клетки, проецировался на более высокую у населения Москвы, чем у населения Республики Адыгея, заболеваемость опухолями глотки, желудка, лимфомой Ходжкина и неходжкинскими лимфомами, в которых встречаются ВЭБ-ассоциированные случаи. Однако различия между показателями заболеваемости для указанных патологий (за исключением данных для желудка) были статистически недостоверными (p >0,5). Более высокий и статистически достоверно отличающийся показатель заболеваемости раком желудка у жителей Москвы по сравнению с таковым у жителей Республики Адыгея, по нашему мнению, не обусловлен ВЭБ-1 и/или вариантами LMP1, а скорее связан с генетической предрасположенностью к этой опухоли населения Москвы.Заключение. Факт обнаружения у 2 этносов России превалирования различных типов ВЭБ поднимает вопрос об их этногеографической ассоциации и роли в индукции ВЭБ-ассоциированных новообразований. для решения этого вопроса необходимо проведение дополнительных исследований в других географических регионах России у представителей разных этносов

Вирус Эпштейна–Барр у этнических татар: инфицированность и сиквенсные варианты онкогена LMP1

Objective of the investigation was to study the infection of ethnic Tatars with the Epstein–Barr virus (EBV) and to analyze the genetic structure of the oncogene of the virus, the latent membrane protein 1 (LMP1), in the virus strains of Tatar origin. Materials and methods. The materials for the study were samples of boucle flushes of 60 students from the Kazan State Medical University who are ethnic Tatars (Tatars no less than in the 3rd generation). Amplified from DNA of boucle flushes the nucleotide sequences of the LMP1 samples translated into DNA amino acid sequences, have undergone classification based on the well-known and widely used in literature the R.H. Edwards et al. classification. Results. The analysis of nucleotide and deductive amino acid sequences of the 41 LMP1 amplicons revealed their homology with only three gene variants from the R.H. Edwards et al. classification (1999): 95.8/A (29.3 %; 12/41), Med– (14.6 %; 6/41) and China1 (7.3 %, 3/41). Such variants of LMP1 as Alaskan, Med+, Chinа2, China3 and NC, were not found. Among the LMP1 samples of Tatar origin in 20 cases (48.8 %), the composition of the mutations found did not allow them to be assigned to any of the oncogene variants listed above. Out of this number, in 7 (17.1 %) cases a mono group of LMP1 samples was found, differing not only from representatives of the Slavs, inhabitants of the European part of Russia, but also from other Kazan samples, and was designated as LMP1-TatK. The remaining 13 samples of LMP1 (31.7 %), not belonging to any of the known classifications, formed the group designated by us as an LMP1 group beside the classification (LMP1BC). Conclusion. Continuation of the study of the molecular-biological and functional properties of LMP1 in TatK and BC groups, which constitute 48.8 % of the number of gene samples studied, and an analysis of the peculiarities of the ethnic Tatar genotype, will probably help to clarify whether certain EBV strains influence morbidity and mortality in Tatar population with malignant neoplasms, which include EBVassociated cases.Цель исследования – изучение инфицированности вирусом Эпштейна–Барр (ВЭБ) этнических татар и анализ генетической структуры онкогена вируса, латентного мембранного белка 1 (LMP1), в штаммах вируса татарского происхождения. Материалы и методы. Материалом для исследования служили буккальные смывы 60 студентов Казанского государственного медицинского университета, являющихся этническими татарами (не менее чем в III поколении). Выделенную из смывов ДНК использовали для амплификаци LMP1. Амплифицированные из ДНК буккальных смывов нуклеотидные последовательности образцов LMP1, транслированные в аминокислотные последовательности, подверглись классификации на основании известной и широко используемой в литературе классификации R.H. Edwards и соавт. Результаты. Анализ нуклеотидных и транслированных аминокислотных последовательностей 41-го ампликона LMP1 выявил их гомологию только с 3 вариантами гена из классификации R.H. Edwards и соавт.: 95.8/А (29,3 %; 12/41), Med– (14,6 %; 6/41) и China1 (7,3 %; 3/41). Такие варианты LMP1, как Alaskan, Med+, Chinа2, China3 и NC, не обнаружены. В остальных 20 случаях (48,8 %) спектр обнаруженных мутаций в образцах LMP1 татарского происхождения не позволил их отнести ни к одному из перечисленных выше вариантов онкогена. Из них в 7 случаях (17,1 % всех исследованных образцов) обнаружена моногруппа вариантов LMP1, отличающаяся не только от представителей славян, жителей европейской части России, но и от других казанских образцов, и обозначенная нами, как LMP1-TatK. Остальные 13 образцов LMP1 (31,7 %), не относящихся ни к одной из известных классификаций, сформировали группу, обозначенную нами, как группа LMP1 вне классификации (LMP1ВК). Заключение. Дальнейшее изучение молекулярно-биологических и функциональных свойств LMP1 в группах ВК и TatK, составляющих 48,8 % от числа изученных образцов онкобелка, и анализ особенностей генотипа этнических татар, вероятно, позволят выяснить, оказывают ли определенные штаммы ВЭБ влияние на показатели заболеваемости и смертности злокачественными новообразованиями, в состав которых входят ВЭБ-ассоциированные случаи, у татарского населения

HLA II genes distribution in Epstein–Barr virus-associated nasopharyngeal carcinoma and other tumors of the oral cavity patients in Russia

Background. It has been proved that for the nasopharyngeal carcinoma (NPC) the etiological agent is the Epstein–Barr virus (EBV). Being an ubiquitous infection, EBV, under certain conditions, is able to display its oncogenic potential. Among a wide range of tumors associated with EBV, the NPC occupies a special place because it is characterized by a geographically and ethnically heterogeneous distribution, suggesting that in the pathogenesis of NPC, in addition to EBV, an important role is played by other factors, such as genetic predisposition to this neoplasm. Among known genetic factors influencing the frequency of NPC development, the human leukocyte antigen (HLA) complex occupies an important place, as it plays a central role in the presentation of viral antigens to the immune system. In Russia, the association of HLA alleles with the risk of EBV associated forms of NPC development and with development of other oral cavity tumors (OOCT), not associated with the virus, has not been studied. In the literature there are contradictory information about HLA genes, which determine the predisposition to the emergence of these tumors, and their role in the initiation and formation an immune response to EBV proteins.Objective: to study the distribution of the of DQA1-, DQB1-, DRB1-HLA class II gene variants associated with respectively the risk or resistance to the development of NPC and OOCT and with a high and low level of antibody response to EBV main proteins. A group of healthy persons served as a control.Materials and methods. Blood samples from 62 patients with NPC, 44 patients with OOCT, and as control, 300 healthy individuals, were used in the study. The blood serum samples of NPC and OOCT patients were tested for the presence of immunoglobulin classes G and A antibodies to capsid and early EBV antigens by indirect immunofluorescence. All serum samples of patients and healthy individuals were genotyped on HLA-DQA1, -DQB1 and -DRB1 by the method of multi-primer amplification by sequence-specific primers by real-time polymerase chain reaction.Results. In NPC patients, an increase in the frequency of HLA-DRB1*08 was found when compared with the frequency of a similar allele in healthy individuals (5.6 % vs 1.8 %; odds ratio (OR) 3.2; 95 % confidence interval (CI) 1.1–9.1; p = 0.02), and, on the contrary, a lower HLA-DQB1*0301 frequency was detected (16.1 % vs 25.3 %; p <0.05) than in healthy individuals. The data obtained suggest that the HLA-DRB1*08 gene is associated with an increased sensitivity to NPC.In OOCT patients, HLA-DQB1*0502–4 and HLA-DRB1*16 variants were less common than in healthy individuals (1.1 % vs 6.8 %; p <0.05 and 1.1 % vs 6.7 %; OR 0.16; 95 % CI 0.01–1.08; p <0.05, respectively), suggesting that the HLA-DQB1*0301 gene is associated with resistance to NPC, and HLA-DQB1*0502–4 and HLA-DRB1*16 variants – with resistance to OOCT. It is interesting to note the difference in the frequency of HLA-DRB1*13 between NPC and OOCT patients (17.7 % vs 6.8 %; OR 2.9; 95 %CI 1.1–8.6; p <0.05). One can suggest that this difference is related to the proven involvement of EBV in the NPC development. There were no other differences in the frequencies of class II HLA genes between the groups of NPC and OOCT patients. For the first time in Russia the importance of alleles DQA1, DQB1 and DRB1 of the HLA gene for the NPC and OOCT development, malignant tumors, respectively associated and non-associated with EBV, was studied. The results of the investigation completed together with known literature data allow us to conclude that the above alleles of the HLA class II gene can serve as a factor predisposing to the development of NPC in Russia.Conclusion. However, in order to establish a strict association between a specific HLA haplotype and the NPC and OOCT incidence, the information obtained is insufficient due to the complexity and variability of the genetic control of immune responses controlling the tumor process. A comprehensive study of this issue using different immune response genes and populations of different ethnic origins will probably help to elucidate the effect of genetic polymorphism on the risk of NPC and OOCT development in Russia

Epstein–Barr virus in the ethnic Tatars population: the infection and sequence variants of LMP1 oncogene

Objective of the investigation was to study the infection of ethnic Tatars with the Epstein–Barr virus (EBV) and to analyze the genetic structure of the oncogene of the virus, the latent membrane protein 1 (LMP1), in the virus strains of Tatar origin. Materials and methods. The materials for the study were samples of boucle flushes of 60 students from the Kazan State Medical University who are ethnic Tatars (Tatars no less than in the 3rd generation). Amplified from DNA of boucle flushes the nucleotide sequences of the LMP1 samples translated into DNA amino acid sequences, have undergone classification based on the well-known and widely used in literature the R.H. Edwards et al. classification. Results. The analysis of nucleotide and deductive amino acid sequences of the 41 LMP1 amplicons revealed their homology with only three gene variants from the R.H. Edwards et al. classification (1999): 95.8/A (29.3 %; 12/41), Med– (14.6 %; 6/41) and China1 (7.3 %, 3/41). Such variants of LMP1 as Alaskan, Med+, Chinа2, China3 and NC, were not found. Among the LMP1 samples of Tatar origin in 20 cases (48.8 %), the composition of the mutations found did not allow them to be assigned to any of the oncogene variants listed above. Out of this number, in 7 (17.1 %) cases a mono group of LMP1 samples was found, differing not only from representatives of the Slavs, inhabitants of the European part of Russia, but also from other Kazan samples, and was designated as LMP1-TatK. The remaining 13 samples of LMP1 (31.7 %), not belonging to any of the known classifications, formed the group designated by us as an LMP1 group beside the classification (LMP1BC). Conclusion. Continuation of the study of the molecular-biological and functional properties of LMP1 in TatK and BC groups, which constitute 48.8 % of the number of gene samples studied, and an analysis of the peculiarities of the ethnic Tatar genotype, will probably help to clarify whether certain EBV strains influence morbidity and mortality in Tatar population with malignant neoplasms, which include EBVassociated cases

Маркеры вируса Эпштейна–Барр в оценке клинического состояния российских больных раком носоглотки

Introduction. Epstein–Barr virus (EBV) is equally widespread in the endemic and non-endemic world regions for nasopharyngeal cancer (NPC). High incidence of NPC in endemic countries and low in non-endemic countries suggest there are different mechanisms and conditions for tumor occurrence and, possibly, different clinical significance of EBV-associated markers. However, significance of these markers for determining NPC in non-endemic regions is still poorly understood. Objective – to determine clinical significance of titers of IgG/IgA antibodies to EBV capsid antigen and concentrations of the viral DNA in patients’ blood plasma as diagnostic and monitoring markers for NPC in a non-endemic region of Russia. Materials and methods. Titers of EB-specific antibodies were determined by indirect immunofluorescence, and concentration of the viral DNA in plasma was measured using a quantitative polymerase chain reaction in real time. Study group included patients with NPC (n = 96), and control group – blood donors (n = 171) and patients with other head and neck tumors (n = 33).Results. Titers of IgG/IgA antibodies to EBV capsid antigen, being an important diagnostic marker of nasopharyngeal cancer, did not always correlate with patients’ clinical condition. Humoral response to emerging events often delayed due to inertia of the immune system. Concentration of EBV DNA in patients’ blood plasma clearly reflected the dynamics of the pathological process: it decreased to background values in remission and increased while the disease progressed. In contrast to endemic regions, we did not find any correlation between the studied EBV markers and clinical manifestations of the disease, evaluated in accordance with the TNM classification (Tumor, Nodus and Metastasis).Conclusion. In non-endemic countries, such as Russia, serological and molecular markers of EBV can be successfully used for the primary diagnosis of NPC. However, for the disease monitoring, it is preferable to use the value of the concentrations of circulating EBV DNA, which, in contrast to the values of IgG/IgA antibody titers to VCA EBV, more accurately reflect the patient’s clinical condition.Введение. В эндемичных и неэндемичных по раку носоглотки (РНГ) регионах мира в одинаковой степени широко распространено инфицирование населения вирусом Эпштейна–Барр (ВЭБ). Высокие показатели заболеваемости РНГ в эндемичных странах и низкие в неэндемичных предполагают наличие различных механизмов и условий возникновения опухоли и, возможно, различную клиническую значимость ВЭБ-ассоциированных маркеров для данного новообразования. Однако значимость этих маркеров для определения РНГ в неэндемичных регионах до сих пор остается малоизученной.Цель исследования – определить клиническую значимость титров IgG/IgA-антител к капсидному антигену ВЭБ и концентраций ДНК этого вируса в плазме крови больных в качестве диагностических и мониторинговых маркеров РНГ в неэндемичном регионе России.Материалы и методы. титры ВЭБ-специфических антител определяли методом непрямой иммунофлуоресценции, а концентрацию вирусной ДНК в плазме измеряли с помощью количественной полимеразной цепной реакции в реальном времени. Объектами исследования стали больные РНГ (n = 96), а в группы контроля вошли доноры крови (n = 171) и пациенты с другими опухолями головы и шеи (n = 33).Результаты. титры IgG/IgA-антител к капсидному антигену ВЭБ, являясь важным диагностическим маркером рака носоглотки, не всегда коррелировали с клиническим состоянием больных. Гуморальный ответ на возникающие события часто запаздывал из-за инерции иммунной системы. показатели же концентрации ДНК ВЭБ в плазме крови пациентов четко отражали динамику патологического процесса, снижались до фоновых значений в состоянии ремиссии и возрастали при прогрессировании заболевания. В отличие от эндемичных регионов корреляция между изучаемыми маркерами ВЭБ и клиническими проявлениями болезни, оцениваемыми в соответствии с классификацией TNM (Tumor, Nodus and Metastasis), нами не обнаружена.Заключение. В неэндемичных странах, таких как Россия, серологические и молекулярные маркеры ВЭБ могут быть с успехом использованы для первичной диагностики РНГ. Однако для мониторинга заболевания лучше применять показатели концентрации циркулирующей ДНК ВЭБ, которые в отличие от значений титров IgG/IgA-антител к капсидному антигену ВЭБ более точно отражают клиническое состояние пациентов