Differential gene expression in uterine fibroids

Capa

Citar

Texto integral

Acesso aberto Acesso aberto
Acesso é fechado Acesso está concedido
Acesso é fechado Somente assinantes

Resumo

Objective: The study of differential gene expression in fibroid nodules and myometrium to identify potential target genes for the development of personalized approaches to the diagnosis, prediction of the course, prevention and treatment of uterine fibroids (also known as leiomyomas).

Materials and methods: The total number of 133 tissue samples were examined, including 48 samples of myometrium and 85 samples of fibroid nodules. The material was obtained during surgical interventions. All samples of fibroid nodules were analyzed for the presence of somatic mutations in exon 2 of the MED12+ gene. In RNA samples, which were isolated from myometrial tissues and fibroid nodules using RT-PCR, gene expression analysis of the HMGA2, PAPPA1, GRPR, TYMS, PLAG1, VCAN, AVPR1A, ESR1, PLA2R1, RANKL, KLF11, KRT19, MMP11, ADAM12, MMP16, PCP4, STAB2, WIF1 genes was performed.

Results: Somatic mutations in the MED12 gene were found in 42 samples (MED 12+ fibroid nodules), and no mutations were found in 43 samples (MED12- fibroid nodules). Multiple fibroids were found in 19 patients among the studied patient sample, while fibroid nodules both MED12+ and MED12- were found in 9 patients. The results of our study showed statistically significant differences in gene expression levels between myometrium and fibroid nodules in 13 of 18 examined genes. At the same time, a number of genes demonstrated opposite changes in the transcription level compared to myometrium, depending on the presence of somatic mutation in the MED12 gene.

It has been shown that in the presence of somatic mutation in the MED12 gene, significantly increased gene expression of 7 genes – GRPR, TYMS, RANKL, MMP11, AVPR1A, PCP4 and ESR1 and significantly reduced gene expression of 2 genes – KRT19, KLF11 was in nodules compared to myometrium. There was significantly increased expression of only 2 genes – GRPR and TYMS in all fibroid nodules, whereas increased expression of the PAPPA1, VCAN, ESR1, RANKL, KRT19, MMP11, PCP4 and AVPR1A genes in MED12+ nodule phenotype was found compared to MED12- nodules.

Conclusion: The obtained data enabled to distinguish two molecular phenotypes of uterine fibroids in the examined sample – the associated and unassociated phenotype with somatic mutation in exon 2 of the MED12 gene. The expression of some genes alters in different molecular phenotypes of uterine fibroids, and statistically significant differences are found not only between each type of uterine fibroids and myometrium, but also between different molecular phenotypes of fibroids. The obtained results enable to consider some of the examined genes as potential targets to develop personalized approaches to diagnosis, prognosis of the course, prevention and treatment of uterine fibroids.

Sobre autores

Maria Kuznetsova

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Autor responsável pela correspondência
Email: mkarja@mail.ru
ORCID ID: 0000-0003-3790-0427

PhD (Bio.), Senior Researcher at the Laboratory of Molecular Genetic Methods of the Institute of Reproductive Genetics

Rússia, Moscow

Ekaterina Nersesyan

A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia

Email: knea_doc@icloud.com
ORCID ID: 0009-0004-6444-5962

PhD Student at the Department of Reproductive Medicine and Surgery

Rússia, Moscow

Olga Burmenskaya

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: o_bourmenskaya@oparina4.ru

Dr. Bio. Sci., Head of the Laboratory of Oncological Genetics

Rússia, Moscow

Narine Tonoyan

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: mkarja@mail.ru
ORCID ID: 0000-0002-1631-1829
Código SPIN: 8547-9399
Scopus Author ID: 57213609878

PhD, obstetrician-gynecologist at the Department of Operative Gynecology

Rússia, Moscow

Galina Mikhaylovskaya

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: galina.mikhaylovskaya@gmail.com

Biologist at the Laboratory of Molecular Genetic Methods of the Institute of Reproductive Genetics

Rússia, Moscow

Ksenia Svirepova

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: mkarja@mail.ru

Doctor of Clinical Laboratory Diagnostics

Rússia, Moscow

Leyla Adamyan

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: l_adamyan@oparina4.ru
ORCID ID: 0000-0002-3253-4512

Dr. Med. Sci., Professor, Academician of the Russian Academy of Sciences, Deputy Director for Research, Head of the Gynecological Department

Rússia, Moscow

Dmitry Trofimov

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia

Email: d_trofimov@oparina4.ru
ORCID ID: 0000-0002-1569-8486

Corresponding Member of the Russian Academy of Sciences, Professor, Dr. Bio. Sci., Director of the Institute of Reproductive Genetics

Rússia, Moscow

Bibliografia

  1. Адамян Л.В., Андреева Е.Н., Артымук Н.В., Белоцерковцева Л.Д., Беженарь В.Ф., Геворкян М.А., Глухов Е.Ю., Гус А.И., Доброхотова Ю.Э., Жорданиа К.И., Зайратьянц О.В., Козаченко А.В., Киселев С.И., Коган Е.А., Кузнецова И.В., Курашвили Ю.Б., Леваков С.А., Малышкина А.И., Мальцева Л.И., Марченко Л.А., Мурватов К.Д., Пестрикова Т.Ю., Попов А.А., Протопопова Н.В., Самойлова А.В., Сонова М.М., Тихомиров А.Л., Ткаченко Л.В., Урумова Л.Т., Филиппов О.С., Хашукоева А.З., Чернуха Г.Е., Ярмолинская М.И., Яроцкая Е.Л. Миома матки: диагностика, лечение и реабилитация. Клинические рекомендации (протокол лечения). М.; 2015. [Adamyan L.V., Andreeva E.N., Artymuk N.V., Belotserkovtseva L.D., Bezhenar V.F., Gevorkyan M.A., Glukhov E.Yu., Gus A.I., Dobrokhotova Y.E., Zhordania K.I., Zayratyants O.V., Kozachenko A.V., Kiselev S.I., Kogan E.A., Kuznetsova I.V., Kurashvili Yu.B., Levakov S.A., Malyshkina A.I., Maltseva L.I., Marchenko L.A., Murvatov K.D., Pestrikova T.Yu., Popov A.A., Protopopova N.V., Samoilova A.V., Sonova M.M., Tikhomirov A.L., Tkachenko L.V., Urumova L.T., Filippov O.S., Khashukoeva A.Z., Chernukha G.E., Yarmolinskaya M.I., Yarotskaya E.L. Uterine myoma: diagnosis, treatment and rehabilitation. Clinical guidelines (treatment protocol). Moscow; 2015. (in Russian)].
  2. Савельева Г.М., Сухих Г.Т., Серов В.Н., Радзинский В.Е., Манухин И.Б., ред. Гинекология. Национальное руководство. 2-е изд. М.; ГЭОТАР-Медиа; 2020. 1044 с. [Savelyeva G.M., Sukhikh G.T., Serov V.N., Radzinsky V.E., Manukhin I.B., eds. Gynecology. National Guide. 2nd ed. Moscow; GEOTAR-Media; 2020. 1044 p. (in Russian)].
  3. Stewart E.A., Cookson C.L., Gandolfo R.A., Schulze-Rath R. Epidemiology of uterine fibroids: a systematic review. BJOG. 2017; 124(10): 1501-12. https://dx.doi.org/10.1111/1471-0528.14640.
  4. Тихомиров А.Л., Лубнин Д.М. Миома матки. М.: ООО Медицинское информационное агентство; 2006. 176 с. [Tikhomirov A.L., Lubnin D.M. Uterine myoma. M.: Medical News Agency LLC; 2006. 176 p. (in Russian)].
  5. Беженарь В.Ф., Комличенко Э.В., Ярмолинская М.И., Дедуль А.Г., Шевелева Т.С., Малушко А.В., Калинина Е.А., Зубарева Т.М., Гамзатова З.Х., Кондратьев А.А. Инновационные подходы к восстановлению репродуктивной функции у больных с миомой матки. Акушерство и гинекология. 2016; 1: 80-7. [Bezhenar V.F., Komlichenko E.V., Yarmolinskaya M.I., Dedul A.G., Sheveleva T.S., Malushko A.V., Kalinina E.A., Zubareva T.M., Gamzatova Z.Kh., Kondratyev A.A. Innovative approaches to reproductive function recovery in patients with uterine myoma. Obstetrics and Gynecology. 2016; (1): 80-7. (in Russian)]. https://dx.doi.org/10.18565/aig.2016.1.80-87.
  6. Серов В.Н., Сухих Г.Т., ред. Клинические рекомендации. Акушерство и гинекология. 4-е изд. М: ГЭОТАР-Медиа; 2014. 1024 с. [Serov V.N., Sukhikh G.T., eds. Clinical guidelines. Obstetrics and gynecology. 4th ed. Moscow: GEOTAR-Media; 2014. 1024 p. (in Russian)].
  7. Vidal-Mazo C., Forero-Diaz C., Lopez-Gonzalez E., Yera-Gilabert M., Machancoses F.H. Clinical recurrence of submucosal myoma after a mechanical hysteroscopic myomectomy: Review after 5 years follow up. Eur. J. Obstet. Gynecol. Reprod. Biol. 2019; 243: 41-5. https://dx.doi.org/10.1016/ j.ejogrb.2019.10.014.
  8. Marugo M., Centonze M., Bernasconi D., Fazzuoli L., Berta S., Giordano G. Estrogen and progesterone receptors in uterine leiomyomas. Acta Obstet. Gynecol. Scand. 1989; 68(8): 731-5. https://dx.doi.org/10.3109/00016348909006147.
  9. Wise L.A., Laughlin-Tommaso S.K. Epidemiology of uterine fibroids – from menarche to menopause. Clin. Obstet. Gynecol. 2016; 59(1): 2-24. https://dx.doi.org/10.1097/GRF.0000000000000164.
  10. Sparic R., Mirkovic L., Malvasi A., Tinelli A. Epidemiology of uterine myomas: a review. Int. J. Fertil. Steril. 2016; 9(4): 424-5. https://dx.doi.org/10.22074/ijfs.2015.4599.
  11. Manta L., Suciu N., Toader O., Purcărea R.M., Constantin A., Popa F. The etiopathogenesis of uterine fibromatosis. J. Med. Life. 2016; 9(1): 39-45.
  12. McWilliams M.M., Chennathukuzhi V.M. Recent advances in uterine fibroid etiology. Semin. Reprod. Med. 2017; 35(2): 181-9. https://dx.doi.org/ 10.1055/s-0037-1599090.
  13. Markowski D.N., Bartnitzke S., Löning T., Drieschner N., Helmke B.M., Bullerdiek J. MED12 mutations in uterine fibroids--their relationship to cytogenetic subgroups. Int. J. Cancer. 2012; 131(7): 1528-36. https:// dx.doi.org/10.1002/ijc.27424.
  14. Narayanan D.L., Phadke S.R. A novel variant in MED12 gene: further delineation of phenotype. Am. J. Med. Genet. A. 2017; 173(8): 2257-60. https://dx.doi.org/10.1002/ajmg.a.38295.
  15. Mittal P., Shin Y.H., Yatsenko S.A., Castro C.A., Surti U., Rajkovic A. Med12 gain-of-function mutation causes leiomyomas and genomic instability. J. Clin. Invest. 2015; 125(8): 3280-4. https://dx.doi.org/10.1172/ JCI81534.
  16. Navarro A., Yin P., Monsivais D., Lin S.M., Du P., Wei J.-J., Bulun S.E. Genome-wide DNA methylation indicates silencing of tumor suppressor genes in uterine leiomyoma. PLoS One. 2012; 7(3): e33284. https://dx.doi.org/10.1371/journal.pone.0033284.
  17. Maekawa R., Sato S., Yamagata Y., Asada H., Tamura I., Lee L. et al. Genome-wide DNA methylation analysis reveals a potential mechanism for the pathogenesis and development of uterine leiomyomas. PLoS One. 2013; 8(6): e66632. https://dx.doi.org/10.1371/journal.pone.0066632.
  18. Maekawa R., Sato S., Tamehisa T., Sakai T., Kajimura T., Sueoka K. et al. Different DNA methylome, transcriptome and histological features in uterine fibroids with and without MED12 mutations. Sci. Rep. 2022; 12(1): 8912. https://dx.doi.org/10.1038/s41598-022-12899-7.
  19. Mehine M., Kaasinen E., Heinonen H.R., Makinen N., Kampjarvi K., SarvilinnaN. et al. Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers. Proc. Natl. Acad. Sci. U. S. A. 2016; 113(5): 1315-20. https://dx.doi.org/10.1073/pnas.1518752113.
  20. Yin P., Ono M., Moravek M.B., Coon J.S., Navarro A., Monsivais D. et al. Human uterine leiomyoma stem/progenitor cells expressing CD34 and CD49b initiate tumors in vivo. J. Clin. Endocrinol. Metab. 2015; 100(4): E601-6. https://dx.doi.org/10.1210/jc.2014-2134.
  21. Бурменская О.В., Трофимов Д.Ю., Кометова В.В., Сергеев И.В., Маерле А.В., Родионов В.В., Сухих Г.Т. Разработка и опыт использования транскрипционной сигнатуры генов в диагностике молекулярных подтипов рака молочной железы. Акушерство и гинекология. 2020; 2: 132-40. [Burmenskaya O.V., Trofimov D.Yu., Kometova V.V., Sergeev I.V., Maerle A.V., Rodionov V.V., Sukhikh G.T. Development and experience of using the transcriptional gene signature in the diagnosis of molecular breast cancer subtypes. Obstetrics and Gynecology. 2020; (2): 132-40. (in Russian)]. https://dx.doi.org/10.18565/aig.2020.2.132-140.
  22. Schmittgen T.D., Zakrajsek B.A., Mills A.G., Gorn V., Singer M.J., Reed M.W. Quantitative reverse transcription-polymerase chain reaction to study mRNA decay: comparison of endpoint and real-time methods. Anal. Biochem. 2000; 285(2): 194-204. https://dx.doi.org/10.1006/abio.2000.4753.
  23. Zhang H., Qi L., Cai Y., Gao X. Gastrin-releasing peptide receptor (GRPR) as a novel biomarker and therapeutic target in prostate cancer. Ann. Med. 2024; 56(1): 2320301. https://dx.doi.org/10.1080/07853890.2024.2320301.
  24. Yunchu Y., Miyanaga A., Matsuda K., Kamio K., Seike M. Exploring effective biomarkers and potential immune related gene in small cell lung cancer. Sci. Rep. 2024; 14(1): 7604. https://dx.doi.org/10.1038/s41598-024-58454-4.
  25. Schaper-Gerhardt K., Gutzmer R., Angela Y., Zimmer L., Livingstone E., Schadendorf D. et al. The RANKL inhibitor denosumab in combination with dual checkpoint inhibition is associated with increased CXCL-13 serum concentrations. Eur. J. Cancer. 2024; 202: 113984. https://dx.doi.org/10.1016/ j.ejca.2024.113984.
  26. Кузнецова М.В., Тоноян Н.М., Свирепова К.А., Адамян Л.В., Трофимов Д.Ю. Роль метилирования генов в развитии миомы матки. Проблемы репродукции. 2023; 29(1): 33-8. [Kuznetsova M.V., Tonoyan N.M., Svirepova K.A., Adamyan L.V., Trofimov D.Yu. The role of gene methylation in the development of fibroids. Russian Journal of Human Reproduction. 2023; 29(1): 33-8. (in Russian)]. https://dx.doi.org/10.17116/repro20232901133.
  27. Pan L., Zhang L., Fu J., Shen K., Zhang G. Integrated transcriptome sequencing and weighted gene co-expression network analysis reveals key genes of papillary thyroid carcinomas. Heliyon. 2024; 10(7): e27928. https://dx.doi.org/10.1016/ j.heliyon.2024.e27928.
  28. Sarangi J., Das P., Ahmad A., Sulaiman M., Ghosh S., Gupta B. et al. Methylation study of tumor suppressor genes in human aberrant crypt foci, colorectal carcinomas, and normal colon. J. Cancer Res. Ther. 2024; 20(1): 268-74. https://dx.doi.org/10.4103/jcrt.jcrt_1573_22.
  29. Klemke M., Meyer A., Nezhad M.H., Bartnitzke S., Drieschner N., Frantzen C. et al. Overexpression of HMGA2 in uterine leiomyomas points to its general role for the pathogenesis of the disease. Genes Chromosomes Cancer. 2009; 48(2): 171-8. https://dx.doi.org/10.1002/gcc.20627.

Este site utiliza cookies

Ao continuar usando nosso site, você concorda com o procedimento de cookies que mantêm o site funcionando normalmente.

Informação sobre cookies