Current views on the role of genetic disorders in the etiology and pathogenesis of endometriosis


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

The paper analyzes the data available in the literature on the results of investigating the sequences and relationships of genetic disorders in endometriosis. Hereditary predisposition to this disease is characteristic for women with clinical manifestations of endometriosis. This category of patients is noted to have epigenetic disorders in the progenitor cells and stem cells of the coelomic epithelium, endometrium, endometrial vasculature, and in other tissues of the reproductive system. Critical disorders of genome-wide DNA methylation and changes in the signaling pathways of gene expression regulation are shown to be characteristic for endometrioid stromal cells. Most of these disorders develop in the stromal cells that have the properties of stem cells and partially the characteristics of ovarian cell granules and immune cells, such as the production of estradiol, prostaglandin, and cytokines. These cells originating from the ectopic endometrium show the abnormal expression of a number of transcription factors that regulate key genes necessary for progesterone-regulated differentiation of normal endometrial stromal cells. It has been shown that the endometrial cells exhibit mutations, including driver mutations in ovarian cancer. Intense paracrine inflammatory signals, together with estrogens from epigenomically improperly programmed endometrioid cells, can lead to increased epithelial mutagenesis and activation of carcinogenesis. Conclusion. It is necessary to further study the genetic aspects of endometriosis in order to deepen our understanding of the pathogenesis of the disease and to develop promising treatment methods.

Full Text

Restricted Access

About the authors

Donna M. Kalimatova

N.I. Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation

Email: 9227707@gmail.com
Ph.D., Associate Professor of the Department of Obstetrics and Gynecology of the Faculty of Medicine

Yulia E. Dobrokhotova

N.I. Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation

Email: pr.dobrohotova@mail.ru
Dr. Med. Sci., professor, Head of the Department of Obstetrics and Gynecology of Medical Faculty

References

  1. Адамян Л.В., Андреева И.А., Беженарь В.Ф., Геворкян М.А., Гус А.И., Демидов В.Н., Калинина Е.А., Леваков С.А., Марченко Л.А., Попов А.А., Сонова М.М., Филиппов О.С., Хашукоева А.З., Чернуха Г.Е., Яроцкая Е.Л., Доброхотова Ю.Э., Гаспарян С.А., Малышкина А.И., Файзуллин И.Ф., Штыров С.В. Эндометриоз. Клинические рекомендации. М.; 2016. 37 с. [Adamyan L.V., Andreeva I.A., Bezhenar V.F., Gevorkyan M.A., Gus A.I., Demidov V.N., Kalinina E.A., Levakov S.A., Marchenko L A.A., Popov A.A., Sonova M.M., Filippov O.S., Khashukoeva A.Z., Chernukha G.E., Yarotskaya E.L., Dobrokhotova Yu.E., Gasparyan S.A., Malyshkina A.I., Faizullin I.F. et al. Endometriosis. Clinical guidelines. M., 2016. 37 р. (in Russian)].
  2. Tanbo T., Fedorcsak P. Endometriosis-associated infertility: aspects of pathophysiological mechanisms and treatment options. Acta Obstet. Gynecol. Scand. 2017; 96(6): 659-67. https://dx.doi.org/10.1111/aogs.13082.
  3. Доброхотова Ю.Э., Ганковская Л.В., Боровкова Е.И., Зайдиева З.С., Скальная В.С. Модулирование локальной экспрессии факторов врожденного иммунитета у пациенток с хроническим эндометритом и бесплодием. Акушерство и гинекология. 2019; 5: 125-32. [Dobrokhotova Yu.E., Gankovskaya L.V., Borovkova E.I., Zaydieva Z.S., Skalnaya V.S. Modulation of local expression of innate immunity factors in patients with chronic endometritis and infertility. Obstetrics and gynecology. 2019; 5: 125-32. (in Russian)]. https://dx.doi.org/10.18565/ aig.2019.5.125-132.
  4. Bulun S.E., Wan Y., Matei D. Epithelial mutations in endometriosis: link to ovarian cancer. Endocrinology. 2019; 160(3): 626-38. https:// dx.doi.org/10.1210/en.2018-00794.
  5. Baranov V., Malysheva O., Yarmolinskaya M. Pathogenomics of endometriosis development. Int. J. Mol. Sci. 2018; 19(7): 1852. https://dx.doi.org/10.3390/ ijms19071852.
  6. Баранов В.С. Эндометриоз и миома матки с позиции системной генетики. Журнал акушерства и женских болезней. 2016; 65 (Спецвыпуск): 5-7. [Baranov V.S. Endometriosis and uterine fibroids from the perspective of systemic genetics. Journal of Obstetrics and Women's Diseases. 2016; 65 (Special Issue): 5-7. (in Russian)].
  7. Bulun S.E., Yilmaz В.D., Sison C., Miyazaki K., Bernardi L., Liu S. et al. Endometriosis. Endocr. Rev. 2019; 40(4): 1048-79. https://dx.doi. org/10.1210/er.2018-00242.
  8. Vercellini P., Vigano P., Somigliana E., Fedele L. Endometriosis: pathogenesis and treatment. Nat. Rev. Endocrinol. 2014; 10(5): 261-75. https://dx.doi. org/10.1038/nrendo.2013.255.
  9. Vercellini P., Somigliana E., Vigano P., Abbiati A., Barbara G., Fedele L. “Blood on the Tracks” from corpora lutea to endometriomas. BJOG. 2009; 116(3): 366-71. https://dx.doi.org/10.1111/j.1471-0528.2008.02055.x.
  10. Anglesio M.S., Papadopoulos N., Ayhan A., Nazeran T.M., Noe M., Horlings H.M. et al. Cancer-associated mutations in endometriosis without cancer. N. Engl. J. Med. 2017; 376(19): 1835-48. https://dx.doi.org/10.1056/NEJMoa1614814.
  11. Suda K., Nakaoka H., Yoshihara K., Ishiguro T., Tamura R., Mori Y. et al. Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Rep. 2018; 24(7): 1777-89. https://dx.doi. org/10.1016/j.celrep.2018.07.037.
  12. Li X., Zhang Y., Zhao L., Wang L., Wu Z., Mei Q. et al. Whole-exome sequencing of endometriosis identifies frequent alterations in genes involved in cell adhesion and chromatin-remodeling complexes. Hum. Mol. Genet. 2014; 23(22): 6008-21. https://dx.doi.org/10.1093/hmg/ddu330.
  13. Simpson J.L., Elias S., Malinak L.R., Buttram V.C.Jr. Heritable aspects of endometriosis. I. Genetic studies. Am. J. Obstet. Gynecol. 1980; 137(3): 327-31. https://dx.doi.org/10.1016/0002-9378(80)90917-5.
  14. Treloar S.A., O’Connor D.T., O’Connor V.M., Martin N.G. Genetic influences on endometriosis in an Australian twin sample. Fertil. Steril. 1999; 71(4): 701-10. https://dx.doi.org/10.1016/s0015-0282(98)00540-8.
  15. Rahmioglu N., Missmer S.A., Montgomery G.W., Zondervan K.T. Insights into assessing the genetics of endometriosis. Curr. Obstet. Gynecol. Rep. 2012; 1(3): 124-37. https://dx.doi.org/10.1007/s13669-012-0016-5.
  16. Treloar S.A., Zhao Z.Z., Le L., Zondervan K.T., Martin N.G., Kennedy S. et al. Variants in EMX2 and PTEN do not contribute to risk of endometriosis. Mol. Hum. Reprod. 2007; 13(8): 587-94. https://dx.doi.org/10.1093/molehr/gam023.
  17. Lin J., Zong L., Kennedy S.H., Zondervan K.T. Coding regions of INHBA, SFRP4 and HOXA10 are not implicated in familial endometriosis linked to chromosome 7p13-15. Mol. Hum. Reprod. 2011; 17(10): 605-11. https://dx.doi.org/10.1093/ molehr/gar035.
  18. Treloar S.A., Wicks J., Nyholt D.R., Montgomery G.W., Bahlo M., Smith V. et al. Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26. Am. J. Hum. Genet. 2005; 77(3): 365-76. https://dx.doi.org/10.1086/432960.
  19. Painter J.N., Anderson C.A., Nyholt D.R., Macgregor S., Lin J., Lee S.H. et al. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat. Genet. 2011; 43(1): 51-4. https://dx.doi.org/10.1038/ng.731.
  20. Mwinyi J., Cavaco I., Pedersen R.S., Persson A., Burkhardt S., Mkrtchian S. et al. Regulation of CYP2C19 expression by estrogen receptor a: implications for estrogen-dependent inhibition of drug metabolism. Mol. Pharmacol. 2010; 78(5): 886-94. https://dx.doi.org/10.1124/mol.110.065540.
  21. Uno S., Zembutsu H., Hirasawa A., Takahashi A., Kubo M., Akahane T. et al. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nat. Genet. 2010; 42(8): 707-10. https://dx.doi.org/10.1038/ng.612.
  22. Nyholt D.R., Low S.K., Anderson C.A., Painter J.N., Uno S., Morris A.P. et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat. Genet. 2012; 44(12): 1355-9. https://dx.doi.org/10.1038/ng.2445.
  23. Rahmioglu N., Nyholt D.R., Morris A.P., Missmer S.A., Montgomery G.W., Zondervan K.T. Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets. Hum. Reprod. Update. 2014; 20(5): 702-16. https://dx.doi.ois/10.1093/humupd/dmu015.
  24. Sapkota Y., Steinthorsdottir V., Morris A.P., Fassbender A., Rahmioglu N., De Vivo I. et al. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat. Commun. 2017; 8: 15539. https://dx.doi.org/10.1038/ncomms15539.
  25. Bulun S.E. Physiology and pathology of the female reproductive axis. In: Melmed S., Polonsky K., Larsen P., Kronenberg H., eds. Williams textbook of endocrinology. 13th ed. Elsevier; 2016: 627-63.
  26. Hodgkinson K., Forrest L.A., Vuong N., Garson K., Djordjevic B., Vanderhyden B.C. GREB1 is an estrogen receptor-regulated tumour promoter that is frequently expressed in ovarian cancer. Oncogene. 2018; 37(44): 5873-86. https://dx.doi. org/10.1038/s41388-018-0377-y.
  27. Doherty J.A., Rossing M.A., Cushing-Haugen K.L., Chen C., Van Den Berg D.J., Wu A.H. et al. ESR1/SYNE1 polymorphism and invasive epithelial ovarian cancer risk: an Ovarian Cancer Association Consortium study. Cancer Epidemiol. Biomarkers Prev. 2010; 19(1): 245-50. https://dx.doi.ojs/10.1158/1055-9965. EPI-09-0729.
  28. Dyson M.T., Kakinuma T., Pavone M.E., Monsivais D., Navarro A., Malpani S.S. et al. Aberrant expression and localization of deoxyribonucleic acid methyltransferase 3B in endometriotic stromal cells. Fertil. Steril. 2015; 104(4): 953-63. e2. https:// dx.doi.org/10.1016/j.fertnstert.2015.06.046.
  29. Veeraraghavan J., Tan Y., Cao X.X., Kim J.A., Wang X., Chamness G. C. et al. Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers. Nat. Commun. 2014; 5: 4577. https://dx.doi. org/10.1038/ncomms5577.
  30. Bernardi L.A., Dyson M.T., Tokunaga H., Sison C., Oral M., Robins J.C. et al. The essential role of GATA6 in the activation of estrogen synthesis in endometriosis. Reprod. Sci. 2019; 26(1): 60-9. https://dx.doi.org/10.1177/1933719118756751.
  31. Barragan F., Irwin J.C., Balayan S., Erikson D.W., Chen J.C., Houshdaran S. et al. Human endometrial fibroblasts derived from mesenchymal progenitors inherit progesterone resistance and acquire an inflammatory phenotype in the endometrial niche in endometriosis. Biol. Reprod. 2016; 94(5): 118. https:// dx.doi.org/10.1095/biolreprod.115.136010.
  32. Lala D.S., Rice D.A., Parker K.L. Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. Mol. Endocrinol. 1992; 6(8): 1249-58. https://dx.doi.org/10.1210/ mend.6.8.1406703.
  33. Xue Q., Lin Z., Yin P., Milad M.P., Cheng Y.H., Confino E. et al. Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5’ CpG island in endometriosis. J. Clin. Endocrinol. Metab. 2007; 92(8): 3261-7. https://dx.doi. org/10.1210/jc.2007-0494.
  34. Utsunomiya H., Cheng Y.H., Lin Z., Reierstad S., Yin P., Attar E. et al. Upstream stimulatory factor-2 regulates steroidogenic factor-1 expression in endometriosis. Mol. Endocrinol. 2008; 22(4): 904-14. https://dx.doi.org/10.1210/ me.2006-0302.
  35. Tsai S.J., Wu M.H., Lin C.C., Sun H.S., Chen H.M. Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells. J. Clin. Endocrinol. Metab. 2001; 86(12): 5765-73. https:// dx.doi.org/10.1210/jcem.86.12.8082.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies