vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJGB-22-09vavilov-3256Research ArticleБИОТЕХНОЛОГИЯ В ПОСТГЕНОМНУЮ ЭРУMEDICAL GENETICSАссоциация полиморфизма генов ТР53, MDM2 и NQO1 с вирусной нагрузкой среди женщин с вирусом папилломы человекаAssociation between ТР53, MDM2 and NQO1 gene polymorphisms and viral load among women with human papillomavirushttps://orcid.org/0000-0003-1520-8245АлБосалеА.Х.AlBosaleA.H.

Мосул

Mosul

abbashammadi4@gmail.comhttps://orcid.org/0000-0002-4424-9508МашкинаЕ. В.MashkinaE. V.

 Ростов-на-Дону,

Rostov-on-Don

Аль-Доур технический институт, Северный технический университет, кафедра медицинской лабораторной техники; Южный федеральный университетИракAl-Dour Technical Institute, Northern Technical University, Department of Medical Laboratory Techniques; Southern Federal UniversityIraqЮжный федеральный университетРоссияSouthern Federal UniversityRussian Federation2022010320222615964Copyright © АлБосале А., Машкина Е.В., 20222022АлБосале А., Машкина Е.В.AlBosale A., Mashkina E.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/3256

Риск рака шейки матки вызван персистирующей инфекцией вируса папилломы человека (ВПЧ). Наша цель – исследовать связь между полиморфизмами генов TP53 215C>G (Pro72Arg), MDM2 -410T>G и NQO1 609C>T с риском формирования высокой вирусной нагрузки при ВПЧ-инфекции. Восемьдесят девять женщин с высокой вирусной нагрузкой ВПЧ и 114 здоровых женщин были вовлечены в исследование случай–контроль. Генотипирование для SNP TP53 Pro72Arg и MDM2 -410T>G проводили методом аллельспецифичной ПЦР, а для NQO1 609C>T – путем анализа ПЦР в реальном времени с использованием TaqMan зондов. Количественный анализ ДНК ВПЧ выполняли с использованием тест-системы «АмплиСенс ВПЧ ВКР скрин-титр-FL». Анализ межгенных взаимодействий осуществляли с помощью алгоритма многофакторного снижения размерности (MDR). Исследование отдельных SNP генов, MDM2 -410T>G и NQO1 609C>T, не выявило статистически значимой разницы в частотах генотипов и аллелей среди женщин в двух группах. Частота аллеля 72Arg и генотипа 72Arg/Arg гена TP53 в группе ВПЧ-инфицированных женщин была значительно выше, чем в контрольной группе (OR = 1.74, 95 % CI = 1.10–2.73; p = 0.02 и OR = 1.97, 95 % CI = 1.13–3.46; p = 0.04 соответственно). MDR-анализ показал значимость межгенных взаимодействий исследуемых локусов TP53 (rs1042522) – MDM2 (rs2279744) – NQO1 (rs1800566) для формирования высокой нагрузки ВПЧ (OR = 3.05, 95 % CI = 1.73–5.46; p = 0. 0001).

The risk of cervical cancer is caused by persistent human papillomavirus (HPV) infection. Cervical cancer is the most frequent cancer among women. Our purpose was to investigate the association between TP53 215C>G (Pro72Arg), MDM2 -410T>G, and NQO1 609C>T gene polymorphisms with a high HPV load and the influence of gene-gene interactions on prolonged HPV infection. Eighty-nine women with a high HPV viral load and 114 healthy women were involved in a case–control study. Genotyping for TP53 215C>G (Pro72Arg) and MDM2 -410T>G SNPs was carried out by allele-specific PCR and genotyping for NQO1 609C>T was performed by a TaqMan assay. Quantitative analysis of HPV DNA was performed by AmpliSens® HPV HCR screen-titer-FRT test system. Gene-gene interactions were analyzed using the multifactor dimensionality reduction (MDR) method. The study of separate SNPs of MDM2 -410T>G and NQO1 609C>T genes did not reveal any statistically significant difference in genotype and allele frequencies among women within the two groups. The frequency of the 215G (72Arg) allele and 215GG (72Arg/Arg) genotype of the TP53 gene was significantly higher in the case group than in the control group (OR = 1.74, 95 % CI = 1.10–2.73; p = 0.02 and OR = 1.97, 95 % CI = 1.13–3.46; p = 0.04, respectively). MDR analysis showed the significance of intergenic interactions of the three studied loci TP53 (rs1042522) – MDM2 (rs2279744) – NQO1 (rs1800566) for the formation of a high HPV load (OR = 3.05, 95 % CI = 1.73–5.46; p = 0.0001).

полиморфизмвирус папилломы человекавирусная нагрузкаTP53MDM2NQO1polymorphismhuman papillomavirusviral loadTP53MDM2NQO1ReferencesAtia A., Abdullah A. NQO1 enzyme and its role in cellular protection; an insight. Iberoam. J. Med. 2020;2(4):306-313. DOI 10.5281/ zenodo.3877528.Atia A., Abdullah A. NQO1 enzyme and its role in cellular protection; an insight. Iberoam. J. Med. 2020;2(4):306-313. DOI 10.5281/ zenodo.3877528.Aubrey B.J., Strasser A., Kelly G.L. Tumor-suppressor functions of the TP53 pathway. Cold Spring Harb. Perspect. Med. 2016;6(5): a026062. DOI 10.1101/cshperspect.a026062.Aubrey B.J., Strasser A., Kelly G.L. Tumor-suppressor functions of the TP53 pathway. Cold Spring Harb. Perspect. Med. 2016;6(5): a026062. DOI 10.1101/cshperspect.a026062.Balasubramaniam S.D., Balakrishnan V., Oon C.E., Kaur G. Key molecular events in cervical cancer development. Medicina (Kaunas). 2019;55(7):384. DOI 10.3390/medicina55070384.Balasubramaniam S.D., Balakrishnan V., Oon C.E., Kaur G. Key molecular events in cervical cancer development. Medicina (Kaunas). 2019;55(7):384. DOI 10.3390/medicina55070384.Basyar R., Saleh A.Z., Sastradinata I., Yuwono Y. p53 gene codon 72 polymorphisms among cervical carcinoma patients. Indones. J. Obstet. Gynecol. 2016;3(3):165-169. DOI 10.32771/inajog.v3i3.48.Basyar R., Saleh A.Z., Sastradinata I., Yuwono Y. p53 gene codon 72 polymorphisms among cervical carcinoma patients. Indones. J. Obstet. Gynecol. 2016;3(3):165-169. DOI 10.32771/inajog.v3i3.48.Bond G.L., Hu W., Bond E.E., Robins H., Lutzker S.G., Arva N.C. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119(5):591-602. DOI 10.1016/j.cell. 2004.11.022.Bond G.L., Hu W., Bond E.E., Robins H., Lutzker S.G., Arva N.C. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119(5):591-602. DOI 10.1016/j.cell. 2004.11.022.Bordignon V., Di Domenico E., Trento E., D’Agosto G., Cavallo I., Pontone M. How human papillomavirus replication and immune evasion strategies take advantage of the host DNA damage repair machinery. Viruses. 2017;9(12):390. DOI 10.3390/v9120390.Bordignon V., Di Domenico E., Trento E., D’Agosto G., Cavallo I., Pontone M. How human papillomavirus replication and immune evasion strategies take advantage of the host DNA damage repair machinery. Viruses. 2017;9(12):390. DOI 10.3390/v9120390.Chansaenroj J., Theamboonlers A., Junyangdikul P., Swangvaree S., Karalak A., Chinchai T. Polymorphisms in TP53 (rs1042522), p16 (rs11515 and rs3088440) and NQO1 (rs1800566) genes in Thai cervical cancer patients with HPV 16 infection. Asian Pac. J. Cancer. Prev. 2013;14(1):341-346. DOI 10.7314/APJCP.2013.14.1.341.Chansaenroj J., Theamboonlers A., Junyangdikul P., Swangvaree S., Karalak A., Chinchai T. Polymorphisms in TP53 (rs1042522), p16 (rs11515 and rs3088440) and NQO1 (rs1800566) genes in Thai cervical cancer patients with HPV 16 infection. Asian Pac. J. Cancer. Prev. 2013;14(1):341-346. DOI 10.7314/APJCP.2013.14.1.341.Diao J., Bao J., Peng J., Mo J., Ye Q., He J. Correlation between NAD(P)H: quinone oxidoreductase 1 C609T polymorphism and increased risk of esophageal cancer: evidence from a meta-analysis. Ther. Adv. Med. Oncol. 2017;9(1):13-21. DOI 10.1177/175883401 6668682.Diao J., Bao J., Peng J., Mo J., Ye Q., He J. Correlation between NAD(P)H: quinone oxidoreductase 1 C609T polymorphism and increased risk of esophageal cancer: evidence from a meta-analysis. Ther. Adv. Med. Oncol. 2017;9(1):13-21. DOI 10.1177/175883401 6668682.Fernandes J.V., De Medeiros T.A.A., De Azevedo J.C.V., Cobucci R.N.O., De Carvalho M.G.F., Andrade V.S. Link between chronic inflammation and human papillomavirus-induced carcinogenesis (Review). Oncol. Lett. 2015;9(3):1015-1026. DOI 10.3892/ol.2015. 2884.Fernandes J.V., De Medeiros T.A.A., De Azevedo J.C.V., Cobucci R.N.O., De Carvalho M.G.F., Andrade V.S. Link between chronic inflammation and human papillomavirus-induced carcinogenesis (Review). Oncol. Lett. 2015;9(3):1015-1026. DOI 10.3892/ol.2015. 2884.Gheit T. Mucosal and cutaneous human papillomavirus infections and cancer biology. Front. Oncol. 2019;9:355. DOI 10.3389/fonc.2019. 00355.Gheit T. Mucosal and cutaneous human papillomavirus infections and cancer biology. Front. Oncol. 2019;9:355. DOI 10.3389/fonc.2019. 00355.Hu X., Zhang Z., Ma D., Huettner P.C., Massad L.S., Nguyen L. TP53, MDM2, NQO1, and susceptibility to cervical cancer. Cancer Epidemiol. Biomarkers Prev. 2010;19(3):755-761. DOI 10.1158/1055- 9965.EPI-09-0886.Hu X., Zhang Z., Ma D., Huettner P.C., Massad L.S., Nguyen L. TP53, MDM2, NQO1, and susceptibility to cervical cancer. Cancer Epidemiol. Biomarkers Prev. 2010;19(3):755-761. DOI 10.1158/1055- 9965.EPI-09-0886.Karni-Schmidt O., Lokshin M., Prives C. The roles of MDM2 and MDMX in сancer. Annu. Rev. Pathol. 2016;11:617-644. DOI 10.1146/annurev-pathol-012414-040349.Karni-Schmidt O., Lokshin M., Prives C. The roles of MDM2 and MDMX in сancer. Annu. Rev. Pathol. 2016;11:617-644. DOI 10.1146/annurev-pathol-012414-040349.Khoury R., Sauter S., Butsch Kovacic M., Nelson A., Myers K., Mehta P. Risk of human papillomavirus infection in cancer-prone individuals: What we know. Viruses. 2018;10(1):47. DOI 10.3390/ v10010047.Khoury R., Sauter S., Butsch Kovacic M., Nelson A., Myers K., Mehta P. Risk of human papillomavirus infection in cancer-prone individuals: What we know. Viruses. 2018;10(1):47. DOI 10.3390/ v10010047.Litwin T., Clarke M., Dean M., Wentzensen N. Somatic host cell alterations in HPV carcinogenesis. Viruses. 2017;9(8):206. DOI 10.3390/ v9080206.Litwin T., Clarke M., Dean M., Wentzensen N. Somatic host cell alterations in HPV carcinogenesis. Viruses. 2017;9(8):206. DOI 10.3390/ v9080206.Malagón T., Louvanto K., Ramanakumar A.V., Koushik A., Coutlée F., Franco E.L. Viral load of human papillomavirus types 16/18/31/33/45 as a predictor of cervical intraepithelial neoplasia and cancer by age. Gynecol. Oncol. 2019;155(2):245-253. DOI 10.1016/ j.ygyno.2019.09.010.Malagón T., Louvanto K., Ramanakumar A.V., Koushik A., Coutlée F., Franco E.L. Viral load of human papillomavirus types 16/18/31/33/45 as a predictor of cervical intraepithelial neoplasia and cancer by age. Gynecol. Oncol. 2019;155(2):245-253. DOI 10.1016/ j.ygyno.2019.09.010.McBride A.A., Warburton A. The role of integration in oncogenic progression of HPV-associated cancers. PLoS Pathog. 2017;13(4): e1006211. DOI 10.1371/journal.ppat.1006211.McBride A.A., Warburton A. The role of integration in oncogenic progression of HPV-associated cancers. PLoS Pathog. 2017;13(4): e1006211. DOI 10.1371/journal.ppat.1006211.Mendoza M., Mandani G., Momand J. The MDM2 gene family. Biomol. Concepts. 2014;5(1):9-19. DOI 10.1515/bmc-2013-0027.Mendoza M., Mandani G., Momand J. The MDM2 gene family. Biomol. Concepts. 2014;5(1):9-19. DOI 10.1515/bmc-2013-0027.Mittal S., Banks L. Molecular mechanisms underlying human papillomavirus E6 and E7 oncoprotein-induced cell transformation. Mutat. Res. Rev. Mutat. Res. 2017;772:23-35. DOI 10.1016/j.mrrev.2016. 08.001.Mittal S., Banks L. Molecular mechanisms underlying human papillomavirus E6 and E7 oncoprotein-induced cell transformation. Mutat. Res. Rev. Mutat. Res. 2017;772:23-35. DOI 10.1016/j.mrrev.2016. 08.001.Moschonas G.D., Tsakogiannis D., Lamprou K.A., Mastora E., Dimitriou T.G., Kyriakopoulou Z. Association of codon 72 polymorphism of p53 with the severity of cervical dysplasia, E6-T350G and HPV16 variant lineages in HPV16-infected women. J. Med. Microbiol. 2017;66(9):1358-1365. DOI 10.1099/jmm.0.000563.Moschonas G.D., Tsakogiannis D., Lamprou K.A., Mastora E., Dimitriou T.G., Kyriakopoulou Z. Association of codon 72 polymorphism of p53 with the severity of cervical dysplasia, E6-T350G and HPV16 variant lineages in HPV16-infected women. J. Med. Microbiol. 2017;66(9):1358-1365. DOI 10.1099/jmm.0.000563.Niwa Y., Hirose K., Nakanishi T., Nawa A., Kuzuya K., Tajima K. Association of the NAD(P)H: quinone oxidoreductase C609T poly morphism and the risk of cervical cancer in Japanese subjects. Gynecol. Oncol. 2005;96(2):423-429. DOI 10.1016/j.ygyno.2004.10.015.Niwa Y., Hirose K., Nakanishi T., Nawa A., Kuzuya K., Tajima K. Association of the NAD(P)H: quinone oxidoreductase C609T poly morphism and the risk of cervical cancer in Japanese subjects. Gynecol. Oncol. 2005;96(2):423-429. DOI 10.1016/j.ygyno.2004.10.015.Oliner J.D., Saiki A.Y., Caenepeel S. The role of MDM2 amplification and overexpression in tumorigenesis. Cold Spring Harb. Perspect. Med. 2016;6(6):a026336. DOI 10.1101/cshperspect.a026336.Oliner J.D., Saiki A.Y., Caenepeel S. The role of MDM2 amplification and overexpression in tumorigenesis. Cold Spring Harb. Perspect. Med. 2016;6(6):a026336. DOI 10.1101/cshperspect.a026336.Rampias T., Sasaki C., Psyrri A. Molecular mechanisms of HPV induced carcinogenesis in head and neck. Oral. Oncol. 2014;50(5): 356-363. DOI 10.1016/j.oraloncology.2013.07.011.Rampias T., Sasaki C., Psyrri A. Molecular mechanisms of HPV induced carcinogenesis in head and neck. Oral. Oncol. 2014;50(5): 356-363. DOI 10.1016/j.oraloncology.2013.07.011.Ross D., Siegel D. NAD(P)H:quinone oxidoreductase 1 (NQO1, DT-diaphorase), functions and pharmacogenetics. Methods Enzymol. 2004;382:115-144. DOI 10.1016/S0076-6879(04)82008-1.Ross D., Siegel D. NAD(P)H:quinone oxidoreductase 1 (NQO1, DT-diaphorase), functions and pharmacogenetics. Methods Enzymol. 2004;382:115-144. DOI 10.1016/S0076-6879(04)82008-1.Roura E., Travier N., Waterboer T., de Sanjosé S., Bosch F.X., Pawlita M. The influence of hormonal factors on the risk of developing cervical Cancer and pre-Cancer: results from the EPIC cohort. PLoS One. 2016;11(1):e0147029. DOI 10.1371/journal.pone.0147029.Roura E., Travier N., Waterboer T., de Sanjosé S., Bosch F.X., Pawlita M. The influence of hormonal factors on the risk of developing cervical Cancer and pre-Cancer: results from the EPIC cohort. PLoS One. 2016;11(1):e0147029. DOI 10.1371/journal.pone.0147029.Saadatzadeh M., Elmi A., Pandya P., Bijangi-Vishehsaraei K., Ding J., Stamatkin C. The role of MDM2 in promoting genome stability versus instability. Int. J. Mol. Sci. 2017;18(10):2216. DOI 10.3390/ ijms18102216.Saadatzadeh M., Elmi A., Pandya P., Bijangi-Vishehsaraei K., Ding J., Stamatkin C. The role of MDM2 in promoting genome stability versus instability. Int. J. Mol. Sci. 2017;18(10):2216. DOI 10.3390/ ijms18102216.Sen P., Ganguly P., Ganguly N. Modulation of DNA methylation by human papillomavirus E6 and E7 oncoproteins in cervical cancer (Review). Oncol. Lett. 2017;15(1):11-22. DOI 10.3892/ol.2017.7292.Sen P., Ganguly P., Ganguly N. Modulation of DNA methylation by human papillomavirus E6 and E7 oncoproteins in cervical cancer (Review). Oncol. Lett. 2017;15(1):11-22. DOI 10.3892/ol.2017.7292.So K.A., Lee I.H., Lee K.H., Hong S.R., Kim Y.J., Seo H.H. Human papillomavirus genotype-specific risk in cervical carcinogenesis. J. Gynecol. Oncol. 2019;30(4):e52. DOI 10.3802/jgo.2019.30.e52.So K.A., Lee I.H., Lee K.H., Hong S.R., Kim Y.J., Seo H.H. Human papillomavirus genotype-specific risk in cervical carcinogenesis. J. Gynecol. Oncol. 2019;30(4):e52. DOI 10.3802/jgo.2019.30.e52.Storey A., Thomas M., Kalita A., Harwood C., Gardiol D., Mantovani F. Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature. 1998;393(6682):229-234. DOI 10.1038/30400.Storey A., Thomas M., Kalita A., Harwood C., Gardiol D., Mantovani F. Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature. 1998;393(6682):229-234. DOI 10.1038/30400.Tasic D., Lazarevic I., Knezevic A., Tasic L., Pikula A., Perisic Z. The impact of environmental and behavioural cofactors on the development of cervical disorders in HR-HPV-infected women in Serbia. Epidemiol. Infect. 2018;146(13):1714-1723. DOI 10.1017/S09502 68818001668.Tasic D., Lazarevic I., Knezevic A., Tasic L., Pikula A., Perisic Z. The impact of environmental and behavioural cofactors on the development of cervical disorders in HR-HPV-infected women in Serbia. Epidemiol. Infect. 2018;146(13):1714-1723. DOI 10.1017/S09502 68818001668.Thomas M., Kalita A., Labrecque S., Pim D., Banks L., Matlashewski G. Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol. Cell Biol. 1999;19(2):1092-1100. DOI 10.1128/MCB.19.2.1092.Thomas M., Kalita A., Labrecque S., Pim D., Banks L., Matlashewski G. Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol. Cell Biol. 1999;19(2):1092-1100. DOI 10.1128/MCB.19.2.1092.Tsvetkov P., Reuven N., Shaul Y. Ubiquitin-independent p53 proteasomal degradation. Cell Death Differ. 2010;17(1):103-108. DOI 10.1038/cdd.2009.67.Tsvetkov P., Reuven N., Shaul Y. Ubiquitin-independent p53 proteasomal degradation. Cell Death Differ. 2010;17(1):103-108. DOI 10.1038/cdd.2009.67.Vonsky M., Shabaeva M., Runov A., Lebedeva N., Chowdhury S., Palefsky J.M. Carcinogenesis associated with human papillomavirus infection. Mechanisms and potential for immunotherapy. Biochemistry. 2019;84(7):782-799. DOI 10.1134/S000629791907 0095.Vonsky M., Shabaeva M., Runov A., Lebedeva N., Chowdhury S., Palefsky J.M. Carcinogenesis associated with human papillomavirus infection. Mechanisms and potential for immunotherapy. Biochemistry. 2019;84(7):782-799. DOI 10.1134/S000629791907 0095.Yang S., Zhao J., Li L. NAD(P)H: quinone oxidoreductase 1 gene rs1800566 polymorphism increases the risk of cervical cancer in a Chinese Han sample. Medicine (Baltimore). 2020;99(20):e19941. DOI 10.1097/MD.0000000000019941.Yang S., Zhao J., Li L. NAD(P)H: quinone oxidoreductase 1 gene rs1800566 polymorphism increases the risk of cervical cancer in a Chinese Han sample. Medicine (Baltimore). 2020;99(20):e19941. DOI 10.1097/MD.0000000000019941.

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