Molecular-genetic background of endometriosis: diagnostic potential of heritable and expressed factors

Cover Page

Abstract


Endometriosis (EM) is a common disease in women of reproductive and perimenopausal age, characterized by the formation of ectopic foci of endometrial proliferation. The pathogenesis of the disease is multifactorial and has not been fully studied. Non-invasive examination methods have relative diagnostic value; therefore, current therapeutic approaches frequently do not provide a complete recovery. This situation determines the interest in studying the molecular and genetic background of EM and in searching for new diagnostic and prognostic markers.

In this review, we briefly discuss the prevailing theories of EM etiology, taking into consideration modern scientific concepts. A separate chapter highlights the data of the genome-wide associative studies (GWAS) that indicate the possibilities of involving a number of genes in the pathogenesis of EM (WNT4, CDKN2BAS, FN1). The main part of the review is focused on the analysis of the gene expression studies comparing the ectopic and eutopic endometrium of women with EM. Considering the clinical significance, the results of three studies comparing expression profile of the eutopic endometrium of healthy women versus patients with EM are presented in detail. In conclusion, the prospects of the development and clinical application of heritable and expressed EM markers are assessed.


Veronika V. Marzhevskay

North-Western State Medical University named after I.I. Mechnikov

Author for correspondence.
Email: marzhevskayav@inbox.ru

Russian Federation, Saint Petersburg

MD, Post-Graduate Student. The Department of Obstetrics and Gynecology

Tatiana S. Prisyazhnaya

North-Western State Medical University named after I.I. Mechnikov

Email: tprisyazhnay@yandex.ru

Russian Federation, Saint Petersburg

MD, Post-Graduate Student

Valeria I. Zhamoydik

Saint Petersburg City Hospital No 38 named after N.A. Semashko

Email: valerigam@mail.ru

Russian Federation, Saint Petersburg

MD, the Head of the Obstetric Division

Igor V. Berlev

N.N. Petrov National Medical Research Center of Oncology

Email: iberlev@gmail.com

Russian Federation, Saint Petersburg

MD, PhD, DSci (Medicine), Professor, the Head of the Oncogynecology Scientific Department

Anastasia V. Malek

N.N. Petrov National Medical Research Center of Oncology

Email: anastasia@malek.com

Russian Federation, Saint Petersburg

MD, PhD, the Head of the Scientific Laboratory of Oncoendocrinology

  • Ярмолинская М.И., Айламазян Э.К. Генитальный эндометриоз. Различные грани проблемы. - СПб.: Эко-Вектор, 2017. [Yarmolinskaya MI, Aylamazyan EK. Genital endometriosis. Different aspects of the problem. Saint Petersburg: Eko-Vektor; 2017. (In Russ.)]
  • Российское общество акушеров-гинекологов. Эндометриоз: диагностика, лечение и реабилитация: федеральные клинические рекомендации по ведению больных. - М., 2013. [Russian Society of Obstetricians and Gynecologists. Endometriosis: diagnosis, treatment and rehabilitation: federal clinical guidelines for managing patients. Moscow; 2013. (In Russ.)]
  • Leyendecker G, Wildt L, Mall G. The pathophysiology of endometriosis and adenomyosis: tissue injury and repair. Arch Gynecol Obstet. 2009;280(4):529-538. doi: 10.1007/s00404-009-1191-0.
  • Leyendecker G, Wildt L. A new concept of endometriosis and adenomyosis: tissue injury and repair (TIAR). Horm Mol Biol Clin Investig. 2011;5(2):125-142. doi: 10.1515/HMBCI.2011.002.
  • Leyendecker G, Bilgicyildirim A, Inacker M, et al. Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study. Arch Gynecol Obstet. 2015;291(4):917-932. doi: 10.1007/s00404-014-3437-8.
  • Магало И.Ш. Сочетание аденомиоза и эндометриоза среди пациенток гинекологического стационара // Світ медицини та біології. - 2011. - № 4. - C. 106-110. [Magalo IS. The combination of adenomyosis and endometriosis among gynecological patients. Svіt meditsini ta bіologіi. 2011;(4):106-110. (In Russ.)]
  • Liu X, Shen M, Qi Q, et al. Corroborating evidence for platelet-induced epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis. Hum Reprod. 2016;31(4):734-749. doi: 10.1093/humrep/dew018.
  • Capobianco A, Rovere-Querini P. Endometriosis, a disease of the macrophage. Front Immunol. 2013;4:9. doi: 10.3389/fimmu.2013.00009.
  • Herington JL, Bruner-Tran KL, Lucas JA, Osteen KG. Immune interactions in endometriosis. Expert Rev Clin Immunol. 2011;7(5):611-626. doi: 10.1586/eci.11.53.
  • Saha R, Pettersson HJ, Svedberg P, et al. Heritability of endometriosis. Fertil Steril. 2015;104(4):947-952. doi: 10.1016/j.fertnstert.2015.06.035.
  • Zondervan KT, Rahmioglu N, Morris AP, et al. Beyond Endometriosis Genome-Wide Association Study: From Genomics to Phenomics to the Patient. Semin Reprod Med. 2016;34(4):242-254. doi: 10.1055/s-0036-1585408.
  • Li Y, Hao N, Wang YX, Kang S. Association of Endometriosis-Associated Genetic Polymorphisms From Genome-Wide Association Studies With Ovarian Endometriosis in a Chinese Population. Reprod Sci. 2016. doi: 10.1177/1933719116650753.
  • Matalliotakis M, Zervou MI, Matalliotaki C, et al. The role of gene polymorphisms in endometriosis. Mol Med Rep. 2017;16(5):5881-5886. doi: 10.3892/mmr.2017.7398.
  • de Mattos RM, Pereira PR, Barros EG, et al. Aberrant levels of Wnt/beta-catenin pathway components in a rat model of endometriosis. Histol Histopathol. 2016;31(8):933-942. doi: 10.14670/HH-11-730.
  • Holdsworth-Carson SJ, Fung JN, Luong HT, et al. Endometrial vezatin and its association with endometriosis risk. Hum Reprod. 2016;31(5):999-1013. doi: 10.1093/humrep/dew047.
  • Matalliotakis M, Zervou MI, Matalliotaki C, et al. Genetic association study in a three-generation family with seven members with endometriosis. Mol Med Rep. 2017;16(5):6077-6080. doi: 10.3892/mmr.2017.7337.
  • Chegini N, Roberts M, Ripps B. Differential expression of Interleukins (IL)-13 and IL-15 in ectopic and eutopic endometrium of women with endometriosis and normal fertile women. Am J Reprod Immunol. 2003;49(2):75-83. doi: 10.1034/j.1600-0897.2003.00028.x.
  • Sbracia M, Valeri C, Antonini G, et al. Fas and Fas-ligand in eutopic and ectopic endometrium of women with endometriosis: The possible immune privilege of ectopic endometrium. Reprod Sci. 2016;23(1):81-86. doi: 10.1177/1933719115594019.
  • Hapangama DK, Raju RS, Valentijn AJ, et al. Aberrant expression of metastasis-inducing proteins in ectopic and matched eutopic endometrium of women with endometriosis: implications for the pathogenesis of endometriosis. Hum Reprod. 2012;27(2):394-407. doi: 10.1093/humrep/der412.
  • Borghese B, Barbaux S, Mondon F, et al. Research resource: genome-wide profiling of methylated promoters in endometriosis reveals a subtelomeric location of hypermethylation. Mol Endocrinol. 2010;24(9):1872-1885. doi: 10.1210/me.2010-0160.
  • Dyson MT, Roqueiro D, Monsivais D, et al. Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLoS Genet. 2014;10(3):e1004158. doi: 10.1371/journal.pgen.1004158.
  • Wei S, Xu H, Kuang Y. Systematic enrichment analysis of microRNA expression profiling studies in endometriosis. Iran J Basic Med Sci. 2015;18(5):423-429.
  • Альмова И.К., Бобров М.Ю., Чупрынин В.Д., и др. Диагностическая роль микроРНК как биологических маркеров наружного (ретроцервикального) эндометриоза // Акушерство и гинекология. - 2017. - № 8. - C. 34-40. [Almova IK, Bobrov MY, Chuprynin VD, et al. The diagnostic role of microRNAs as biological markers of external (retrocervical) endometriosis. Akush Ginekol (Mosk). 2017;(8):34-40. (In Russ.)]. doi: 10.18565/aig.2017.8.34-40.
  • Brosens I, Brosens JJ, Benagiano G. The eutopic endometrium in endometriosis: are the changes of clinical significance? Reprod Biomed Online. 2012;24(5):496-502. doi: 10.1016/j.rbmo.2012.01.022.
  • Zhao L, Gu C, Ye M, et al. Identification of global transcriptome abnormalities and potential biomarkers in eutopic endometria of women with endometriosis: A preliminary study. Biomed Rep. 2017;6(6):654-662. doi: 10.3892/br.2017.902.
  • Herndon CN, Aghajanova L, Balayan S, et al. Global transcriptome abnormalities of the eutopic endometrium from women with adenomyosis. Reprod Sci. 2016;23(10):1289-1303. doi: 10.1177/1933719116650758.
  • Nothnick WB. MicroRNAs and endometriosis: distinguishing drivers from passengers in disease pathogenesis. Semin Reprod Med. 2017;35(2):173-180. doi: 10.1055/s-0037-1599089.
  • Ahn SH, Singh V, Tayade C. Biomarkers in endometriosis: challenges and opportunities. Fertil Steril. 2017;107(3):523-532. doi: 10.1016/j.fertnstert.2017.01.009.
  • Laudanski P, Charkiewicz R, Kuzmicki M, et al. MicroRNAs expression profiling of eutopic proliferative endometrium in women with ovarian endometriosis. Reprod Biol Endocrinol. 2013;11:78. doi: 10.1186/1477-7827-11-78.
  • Hu H, Li H, He Y. MicroRNA-17 downregulates expression of the PTEN gene to promote the occurrence and development of adenomyosis. Exp Ther Med. 2017;14(4):3805-3811. doi: 10.3892/etm.2017.5013.
  • Guo Y, Lang X, Lu Z, et al. MiR-10b directly targets ZEB1 and PIK3CA to curb adenomyotic epithelial cell invasiveness via upregulation of E-Cadherin and inhibition of akt phosphorylation. Cell Physiol Biochem. 2015;35(6):2169-2180. doi: 10.1159/000374022.
  • Bashti O, Noruzinia M, Garshasbi M, Abtahi M. miR-31 and miR-145 as potential non-invasive regulatory biomarkers in patients with endometriosis. Cell J. 2018;20(1):84-89. doi: 10.22074/cellj.2018.4915.
  • Maged AM, Deeb WS, El Amir A, et al. Diagnostic accuracy of serum miR-122 and miR-199a in women with endometriosis. Int J Gynaecol Obstet. 2018;141(1):14-19. doi: 10.1002/ijgo.12392.
  • Jia SZ, Yang Y, Lang J, et al. Plasma miR-17-5p, miR-20a and miR-22 are down-regulated in women with endometriosis. Hum Reprod. 2013;28(2):322-330. doi: 10.1093/humrep/des413.
  • Rekker K, Saare M, Roost AM, et al. Circulating miR-200-family micro-RNAs have altered plasma levels in patients with endometriosis and vary with blood collection time. Fertil Steril. 2015;104(4):938-946 e932. doi: 10.1016/j.fertnstert.2015.06.029.

Supplementary files

Supplementary Files Action
1. Fig. 1. Supervised hierarchical clustering analysis of 72 differentially expressed genes between the 13 eutopic endometrium samples from eight endometriosis patients (EU 11, 19, 6, 1, 21, 7, 18, 5) and five healthy control subjects (N 16, 8, 12, 2, 19). The expression levels are indicated using colors. Reproduced by the authors with the consent of the publisher and subject to license agreements from [25] View (287KB) Indexing metadata
2. Fig. 2. Principal component analysis of eutopic endometrium in eight patients with adenomyosis (red, n = 3) in comparison to normal controls (blue, n = 5). Reproduced by the authors with the consent of the publisher and subject to license agreements from [26] View (41KB) Indexing metadata
3. Fig. 3. Supervised hierarchical clustering analysis of eleven differentially expressed miRNAs between the seven eutopic endometrium samples from four endometriosis patients and three healthy control subjects. The expression levels are indicated using colors. Reproduced by the authors with the consent of the publisher and subject to license agreements from [29] View (130KB) Indexing metadata

Views

Abstract - 89

PDF (Russian) - 40

PlumX


Copyright (c) 2018 Marzhevskay V.V., Prisyazhnaya T.S., Zhamoydik V.I., Berlev I.V., Malek A.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.