The role of genetic and epigenetic changes in the development of atypical hyperplasia and early-stage endometrial cancer

DOI

https://dx.doi.org/10.18565/aig.2021.5.48-54

Gadzhieva L.T., Pronin S.M., Pavlovich S.V., Kiselev V.I.
1) I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of Russia, Moscow, Russia; 2) Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Moscow, Russia

The paper presents the data available in the literature on the role of genetic and epigenetic changes in the development of atypical hyperplasia and early-stage endometrial cancer. Cancer of the corpus uteri in 15–39-year-old women ranks seventh in the structure of cancer incidence. In developed countries, the mean age of women at birth of first child is constantly increasing due to the tendency of women to postpone motherhood for socioeconomic reasons, and endometrioid adenocarcinoma is frequently diagnosed before implementation of their reproductive function. The oncological standard in the treatment of early-stage endometrial cancer is extirpation of the uterus with appendages, which allows a woman to cure cancer. However, this surgery in young patients rules out the possibility of implementing their reproductive function. The article evaluates the effects of the MLH1, MSH2, MSH6, PMS2, PIK3CA, KRAS, CTNNB1, PTEN, and p53 genes on endometrial carcinogenesis. The findings explain the molecular heterogeneity of both two different pathogenetic variants of endometrial cancer, and the intraspecific heterogeneity of the former pathogenetic variant.
Conclusion. The analyzed data on dysregulation of tumor suppressor genes and key proliferative signaling pathways will be able to stratify approaches to selecting patients for organ-sparing treatment.

atypical endometrial hyperplasia

endometrial cancer

organ-sparing treatment

predictive biomarkers

Full text (in Russian)

Bleyer A., Barr R., Ries L., Whelan J., Andrea Ferrari A., eds. Cancer in adolescents and young adults (pediatric oncology). 2nd ed. Springer; 2016. https://dx.doi.org/10.1007/978-3-319-33679-4.
Lee N.K., Cheung M.K., Shin J.Y., Husain A., Teng N.N., Berek J.S. et al. Prognostic factors for uterine cancer in reproductive-aged women. Obstet. Gynecol. 2007; 109(3): 655-62. https://dx.doi.org/10.1097/01.AOG.0000255980.88205.15.
Tomao F., Peccatori F., Del Pup L., Franchi D., Zanagnolo V., Panici P.B., Colombo N. Special issues in fertility preservation for gynecologic malignancies. Crit. Rev. Oncol. Hematol. 2016; 97: 206-19. https://dx.doi.org/10.1016/j.critrevonc.2015.08.024.
Colombo N., Creutzberg C., Amant F., Bosse T., González-Martín A., Ledermann J. et al. ESMO-ESGO-ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up. Ann. Oncol. 2016; 27(1): 16-41. https://dx.doi.org/10.1093/annonc/mdv484.
Lajer H., Elnegaard S., Christensen R.D., Ortoft G., Schledermann D.E., Mogensen O. Survival after stage IA endometrial cancer; can follow-up be altered? A prospective nationwide Danish survey. Acta Obstet. Gynecol. Scand. 2012; 91(8): 976-82. https://dx.doi.org/10.1111/j.1600-0412.2012.01438.x.
Пронин С.М., Мацнева И.А., Новикова Е.Г. Возможности репродукции после лечения начального рака эндометрия. Акушерство и гинекология. 2018; 10: 100-4. [Pronin S.M., Matsneva I.A., Novikova E.G. Possibilities of reproduction after treatment for early endometrial cancer. Obsteterics and Gynecology. 2018; 10: 100-4. (in Russian)]. https://dx.doi.org/10.18565/aig.2018.10.100-104.
ACOG. Endometrial intraepithelial neoplasia committee opinion no. 631. 2015.
Creasman W.T. Announcement. FIGO stages: 1988 revision. Gynecol. Oncol. 1989; 35(1): 125- 7.
Alkushi A., Abdul-Rahman Z.H., Lim P., Schulzer M., Coldman A., Kalloger S.E. et al. Description of a novel system for grading of endometrial carcinoma and comparison with existing grading systems. Am. J. Surg. Pathol. 2005; 29(3):295-304. https://dx.doi.org/10.1097/01.pas.0000152129.81363.d2.
Park J.Y., Kim D.Y., Kim T.J., Kim J.W., Kim J.H., Kim Y.M. et al. Hormonal therapy for women with stage IA endometrial cancer of all grades. Obstet. Gynecol. 2013; 122(1): 7-14. https://dx.doi.org/10.1097/AOG.0b013e3182964ce3.
Koskas M., Yazbeck C., Walker F., Clouqueur E., Agostini A., Ruat S. et al. Fertility-sparing management of grade 2 and 3 endometrial adenocarcinomas. Anticancer Res. 2011; 31(9): 3047-9.
Eddib A., Allaf B., Lee J., Yeh J. Risk for advanced-stage endometrial cancer in surgical specimens from patients with complex endometrial hyperplasia with atypia. Gynecol. Obstet. Investig. 2012; 73(1): 38-42. https://dx.doi.org/10.1159/000329326.
Morice P., Leary A., Creutzberg C., Abu-Rustum N., Darai E. Endometrial cancer. Lancet. 2016; 387(10023): 1094-108. https://dx.doi.org/10.1016/S0140-6736(15)00130-0.
Giede K.C., Yen T.W., Chibbar R., Pierson R.A. Significance of concurrent endometrial cancer in women with a preoperative diagnosis of atypical endometrial hyperplasia. J. Obstet. Gynaecol. Can. 2008; 30(10): 896-901. https://dx.doi.org/10.1016/S1701-2163(16)32969-3.
Muraki Y., Banno K., Yanokura M., Kobayashi Y., Kawaguchi M., Nomura H. et al. Epigenetic DNA hypermethylation: clinical applications in endometrial cancer (Review). Oncol. Rep. 2009; 22(5): 967-72. https://dx.doi.org/10.3892/or_00000523.
Emons G., Beckmann M.W., Schmidt D., Mallmann P. New WHO classification of endometrial hyperplasias. Geburtshilfe Frauenheilkd. 2015; 75(2): 135-6. https://dx.doi.org/10.1055/s-0034-1396256.
Cухих Г.Т., Ашрафян Л.А., Байрамова Г.Р., Бабкина И.О., Чернова В.Ф., Осипьянц А.И., Королькова А.И., Полозников А.А., Асфарова Г.Р., Муллабаева С.М., Коган Е.А., Муйжнек Е.Л., Друх В.М., Киселев В.И. Метилирование гена WIF-1 при цервикальных плоскоклеточных интраэпителиальных поражениях. Акушерство и гинекология. 2017; 5: 114-23. [Sukhikh G.T., Ashrafyan L.A., Bairamova G.R., Babkina I.O., Chernova V.F., Osipyants A.I., Korolkova A.I., Poloznikov A.A., Asfarova G.R., Mullabaeva S.M., Kogan E.A., Muizhnek E.L., Drukh V.M., Kiselev V.I. WIF-1 gene methylation in cervical squamous intraepithelial lesions. Obsteterics and Gynecology. 2017; 5: 114-23 (in Russian)]. https://dx.doi.org/10.18565/aig.2017.5.114-23.
Сухих Г.Т., Ашрафян Л.А., Киселев В.И., Аполихина И.А., Мальцева Л.И., Сутурина Л.В., Селиванов С.П., Леонидова Т.Н., Цхай В.Б., Радзинский В.Е., Ордиянц И.М., Бебнева Т.Н., Евтушенко И.Д., Удут В.В., Кулагина Н.В., Баранов А.Н., Хасанов Р.Ш., Гурьева В.А., Шамина И.В., Карахалис Л.Ю., Муйжнек Е.Л. Исследование эффективности и безопасности препарата на основе дииндолметана у пациенток с цервикальной интраэпителиальной неоплазией (CIN 1–2). Акушерство и гинекология. 2018; 9: 91-8. [Sukhikh G.T., Ashrafyan L.A., Kiselev V.I., Apolikhina I.A., Maltseva L.I., Suturina L.V., Selivanov S.P., Leonidova T.N., Tskhai V.B., Radzinsky V.E., Ordiyants I.M., Bebneva T.N., Evtushenko I.D., Udut V.V., Kulagina N.V., Baranov A.N., Khasanov R.Sh., Guryeva V.A., Shamina I.V., Karakhalis L.Yu., Muyzhnek E.L. Investigation of the efficacy and safety of a diindolylmethane-based drug in patients with cervical intraepithelial neoplasia grades 1–2 (CIN 1–2). Obsteterics and Gynecology. 2018; 9: 91-8. (in Russian)]. https://dx.doi.org/10.18565/aig.2018.9.91-98.
Киселев В.И., Муйжнек Е.Л., Ашрафян Л.А., Сухих Г.Т. Новая парадигма прогрессии цервикальных неоплазий: от фундаментальных знаний – к практической гинекологии. Акушерство и гинекология. 2019; 1: 5-12. [Kiselev V.I., Muyzhnek E.L., Ashrafyan L.A., Sukhikh G.T. A new paradigm in cervical neoplasia progression: from fundamental knowledge to practical gynecology. Obsteterics and Gynecology. 2019; 1: 5-12. (in Russian)]. https: // dx.doi.org/10.18565/aig.2019.1.5-12.
Kurman R.J., Kaminski P.F., Norris H.J. The behavior of endometrial hyperplasia. A long-term study of "untreated" hyperplasia in 170 patients. Cancer. 1985; 56(2): 403-12. https://dx.doi.org/10.1002/1097-0142(19850715)56:2<403::aid-cncr2820560233>3.0.co;2-x.
Di Domenico M., Santoro A., Ricciardi C., Iaccarino M., Iaccarino S., Freda M. et al. Epigenetic fingerprint in endometrial carcino- genesis: the hypothesis of a uterine field cancerization. Cancer Biol. Ther. 2011; 12(5): 447-57. https://dx.doi.org/10.4161/cbt.12.5.15963.
Widra E.A., Dunton C.J., McHugh M., Palazzo J.P. Endometrial hyperplasia and the risk of carcinoma. Int. J. Gynecol. Cancer. 1995; 5(3): 233-5. https://dx.doi.org/10.1046/j.1525-1438.1995.05030233.x.
Karamursel B.S., Guven S., Tulunay G., Kucukali T., Ayhan A. Which surgical procedure for patients with atypical endometrial hyperplasia? Int. J. Gynecol. Cancer. 2005: 15(1): 127-31. https://dx.doi.org/10.1111/j.1048-891X.2005.15013.x.
Trimble C.L., Kauderer J., Zaino R., Silverberg S., Lim P.C., Burke J.J. et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer. 2006; 106(4): 812-9. https://dx.doi.org/10.1002/cncr.21650.
Ашрафян Л.А., Киселев В.И. Современная онкология, молекулярная биология и перспективы эффективной терапии. М.: Молодая гвардия; 2015. 95с. [Ashrafyan L.A., Kiselev V.I. Modern oncology, molecular biology and prospects of effective therapy. Moscow: Molodaya Gvardiya; 2015. 95 p. (in Russian)].
Киселев В.И., Ляшенко А.А. Молекулярные механизмы регуляции гиперпластических процессов. М.: Димитрейд График Групп; 2005. 348с. [Kiselev V.I., Lyashenko A.A. Molecular mechanisms of regulation of hyperplastic processes. Moscow: Dimitreid Graph Group; 2005. 348 p. (in Russian)].
Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013; 497(7447): 67-73. https://dx.doi.org/10.1038/nature12113.
Billingsley C.C., Cohn D.E., Mutch D.G., Stephens J.A., Suarez A.A., Goodfellow P.J. Polymerase ɛ (POLE) mutations in endometrial cancer: clinical outcomes and implications for lynch syndrome testing. Cancer. 2015; 121(3): 386-94. https://dx.doi.org/10.1002/cncr.29046.
Church D.N., Briggs S.E.W., Palles C., Enric Domingo S.J., Kearsey J.M., Grimes M.G. et al. DNA polymerase ɛ and δ exonuclease domain mutations in endometrial cancer. Hum. Mol. Genet. 2013; 22(14): 2820-8. https://dx.doi.org/10.1093/hmg/ddt131.
Hussein Y.R., Britta Weigelt D.A., Levine J.K.S., Dao L.N., Balzer B.L., Liles G. et al. Clinicopathological analysis of endometrial carcinomas harboring somatic POLE exonuclease domain mutations. Mod. Pathol. 2015; 28(4): 505-14. https://dx.doi.org/10.1038/modpathol.2014.143.
Meng B., Hoang L.N., McIntyre J.B., Duggan M.A., Nelson G.S., Lee C.H., Köbel M. POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium. Gynecol. Oncol. 2014; 134(1): 15-9. https://dx.doi.org/10.1016/j.ygyno.2014.05.006.
Кекеева Т.В., Жевлова А.И., Подистов Ю.И., Соловьева Ю.В., Залетаев Д.В., Немцова М.В. Аномальное метилирование генов-супрессоров опухолевого роста и микросателлитная нестабильность в предраковых состояниях шейки матки. Молекулярная биология. 2006; 40(2): 224-30. [Kekeeva T.V., Zhevlova A.I., Podistov Yu.I., Solovyova Yu.V., Zaletaev D.V., Nemtsova M.V. Abnormal methylation of tumor growth suppressor genes and microsatellite instability in precancerous cervical states. Molecular biology. 2006; 40(2):224-30. (in Russian)].
Копнин Б.П. Механизмы действия онкогенов и опухолевых супрессоров. Российский онкологический научный центр им. Н.Н. Блохина РАМН. Москва. Available at: https://medport.info/onkologiya/mexanizmy-dejstviya-onkogenov-i-opuxolevyx-supressorov.html [Copnin B.P. Mechanisms of action of oncogenes and tumor suppressors. Research Institute of Carcinogenesis, Russian Cancer Scientific Center, RAMS, Moscow. (in Russian)].
Kanaya T., Kyo S., Maida Y., Yatabe N., Tanaka M., Nakamura M., Inoue M. Frequent hypermethylation of MLH1 promoter in normal endometrium of patients with endometrial cancers. Oncogene. 2003; 22(15): 2352-60. https://dx.doi.org/10.1038/sj.onc.1206365.
Kariola R., Abdel-Rahman W.M., Ollikainen M., Butzow R., Peltomäki P., Nyström M. APC and beta-catenin protein expression patterns in HNPCC-related endometrial and colorectal cancers. Cancer Res. 2005; 4(2): 187-90. https://dx.doi.org/10.1007/s10689-004-6130-4.
Lu K.H., Dinh M., Kohlmann W., Watson P., Green J., Syngal S. et al. Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet. Gynecol. 2005; 105(3): 569-74. https://dx.doi.org/10.1097/01.AOG.0000154885.44002.ae.
Basil J.B., Goodfellow P.J., Rader J.S., Mutch D.G., Herzog T.J. Clinical significance of microsatellite instability in endometrial carcinoma. Cancer. 2000; 89(8): 1758-64. https://dx.doi.org/10.1002/1097-0142(20001015)89:8<1758::aid-cncr16>3.0.co;2-a.
Cheung L.W.T., Hennessy B.T., Li J., Yu S., Myers A.P., Djordjevic B. et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mecha- nism for regulation of PTEN protein stability. Cancer Discov. 2011; 1: 170-85.
Slomovitz B.M., Coleman R.L. The PI3K/AKT/mTOR pathway as a therapeutic target in endo- metrial cancer. Clin. Cancer Res. 2012; 18(21): 5856-64. https://dx.doi.org/10.1158/1078-0432.CCR-12-0662.
Velasco A., Bussaglia E., Pallares J., Dolcet X., Llobet D., Encinas M. et al. PIK3CA gene mutations in endometrial carcinoma: correlation with PTEN and K-RAS alterations. Hum. Pathol. 2006; 37(11): 1465-72. https://dx.doi.org/10.1016/j.humpath.2006.05.007.
Levine R.L., Cargile C.B., Blazes M.S., van Rees B., Kurman R.J., Ellenson L.H. PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma. Cancer Res. 1998; 58(15): 3254-8.
Oda K., Stokoe D., Taketani Y., McCormick F. High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res. 2005; 65(23): 10669-73. https://dx.doi.org/10.1158/0008-5472.CAN-05-2620.
Vos M.D., Ellis C.A., Bell A., Birrer M.J., Clark G.J. Ras uses the novel tumor suppressor RASSF1 as an effector to mediate apoptosis. Biol. Chem. 2000; 275(46): 35669-72. https://dx.doi.org/10.1074/jbc.C000463200.
Pijnenborg J.M.A., Dam-de Veen G.C., Kisters N., Delvoux B., van Engeland M., Herman J.G., Groothuis P.G. RASSF1A methylation and K-ras and B-raf mutations and recurrent endometrial cancer. Ann. Oncol. 2007; 18(3): 491-7. https://dx.doi.org/10.1093/annonc/mdl455.
Suehiro Y., Okada Е, Okada T., Anno K., Okayama N., Ueno K. et al. Aneuploidy predicts outcome in patients with endometrial carcinoma and is related to lack of CDH13 hypermethylation. Clin. Cancer Res. 2008; 14(11): 3354-61. https://dx.doi.org/10.1158/1078-0432.CCR-07-4609.
Fiegl H., Gattringer C., Widschwendter A., Schneitter A., Ramoni A., Sarlay D. et al. Methylated DNA collected by tampons-A to detect endometrial new tool cancer. Cancer Epidemiol. Biomarkers Prev. 2004; 13(5):882-8.
Liu Y., Patel L., Mills G.B., Lu K.H., Sood A.K., Ding L. et al. Clinical significance of CTNNB1 mutation and Wnt pathway activation in endometrioid endometrial carcinoma. J. Natl. Cancer Inst. 2014; 106(9): dju245. https://dx.doi.org/10.1093/jnci/dju245.
Шалькова М.Ю. Эпигенетические нарушения функции генов hMLH1 и АРС у больных раком тела матки. Медицина сьогодні і завтра (Харків). 2006; 3-4: 168-70. [Shal’kova M.Yu. Epigenetic dysfunctions of the hMLH1 and APC genes in patients with uterine cancer. Medicine today and tomorrow. 2006; 3-4: 168-70. (in Ukraine)].
Cornel K.M.C., Wouters K., Van de Vijver K.K., van der Wurff A.A.M., van Engeland M., Kruitwagen R.F.P.M., Pijnenborg J.M.A. Gene promoter methylation in endometrial carcinogenesis. Pathol. Oncol. Res. 2019; 25(2): 659-67. https://dx.doi.org/10.1007/s12253-018-0489-2.
Banno K., Yanokura M., Susumu N., Kawaguchi M., Hirao N., Hirasawa A. et al. Relationship of the aberrant DNA hyper- methylation of cancer-related genes with carcinogenesis of endometrial cancer. Oncol. Rep. 2006; 16(6): 1189-96.
Salvesen H.B., Das S., Akslen L.A. Loss of nuclear p16 protein expression is not associated with promoter methylation but defines a subgroup of aggressive endometrial carcinomas with poor prognosis. Clin. Cancer Res. 2000; 6(1): 153-9.
Weigelt B., Banerjee S. Molecular targets and targeted therapeutics in endometrial cancer. Curr. Opin. Oncol. 2012; 24(5): 554-63. https://dx.doi.org/10.1097/CCO.0b013e328354e585.
Lee E.J., Kim T.J., Kim D.S., Choi C.H., Lee J.W., Lee J.H. et al. p53 alteration independently predicts poor outcomes in patients with endometrial cancer: a clinicopathologic study of 131 cases and literature review. Gynecol. Oncol. 2010; 116(3): 533-8. https://dx.doi.org/10.1016/j.ygyno.2009.11.018.
Tashiro H., Isacson C., Levine R., Kurman R.J., Cho K.R., Hedrick L. p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am. J. Pathol. 1997; 150(1): 177-85.
Santin A.D., Bellone S., Gokden M., Palmieri M., Dunn D., Agha J. et al. Overexpression of HER-2/neu in uterine serous papillary cancer. Clin. Cancer Res. 2002; 8(5): 1271-9.
Morrison C., Zanagnolo V., Ramirez N., Cohn D.E., Kelbick N., Copeland L. et al. HER-2 is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of surgically staged patients. J. Clin. Oncol. 2006; 24(15): 2376-85. https://dx.doi.org/10.1200/JCO.2005.03.4827.
Zeimet A.G., Reimer D., Huszar M., Winterhoff B., Puistola U., Azim S.A. et al. L1CAM in early-stage type I endometrial cancer: results of a large multicenter evaluation. J. Natl. Cancer Inst. 2013; 105(15): 1142-50. https://dx.doi.org/10.1093/jnci/djt144.
Doberstein K., Harter P.N., Haberkorn U., Bretz N.P., Arnold B., Carretero R. et al. Antibody therapy to human L1CAM in a transgenic mouse model blocks local tumor growth but induces EMT. Int. J. Cancer. 2015; 136(5): E326-39. https://dx.doi.org/10.1002/ijc.29222.
Huszar M., Pfeiffer M., Schirmer U., Kiefel H., Konecny G.E., Ben-Arie A. et al. Up-regulation of L1CAM is linked to loss of hormone receptors and E-cadherin in aggressive subtypes of endometrial carcinomas. J. Pathol. 2010; 220(5):551-61. https://dx.doi.org/10.1002/path.2673.
Stelloo E., Nout R.A., Osse E.M., Jurgenliemk-Schulz I.J., Jobsen J.J., Lutgens L.C. et al. Improved risk assessment by integrating molecular and clinicopath- ological factors in early-stage endometrial cancer - combined analysis of PORTEC cohorts. Clin. Cancer Res. 2016; 22(16): 421-24. https://dx.doi.org/10.1158/1078-0432.
Stelloo E., Bosse T., Nout R.A., MacKay H.J., Church D.N., Nijman H.W. et al. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. Mod. Pathol. 2015; 28(6): 836-44. https://dx.doi.org/10.1038/ modpathol.2015.43.
Westin S.N., Bryan F., Sun C.C., Broaddus R.R., Woodall M.L., Pal N. et al. Prospective phase II trial of levonorgestrel intrauterine device: nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer. Am. J. Obstet. Gynecol. 2021; 224(2): 191. e1-191. e15. https://dx.doi.org/10.1016/j.ajog.2020.08.032.

Received 19.11.2020

Accepted 01.02.2021

Lyubov T. Gadzhieva, obstetrician-gynecologist, postgraduate of the Department of Obstetrics, Gynecology, Perinatology and Reproduction, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University), on the base of V.I. Kulakov NMRC OG&P, Ministry of Health of Russia.
E-mail: amor-amor93@bk.ru. 117997, Russia, Moscow, Oparina str., 4.
Stanislav M. Pronin, MD, oncologist, obstetrician-gynecologist, senior researcher, Department of Innovative Oncology and Gynecology, V.I. Kulakov NMRC OG&P,
Ministry of Health of Russia. E-mail: psm_doc@mail.ru. 117997, Russia, Moscow, Oparina str., 4.
Stanislav V. Pavlovich, MD, Ph.D., associate professor, professor of the Department of Obstetrics, Gynecology, Perinatology and Reproduction, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University); Scientific Secretary, V.I. Kulakov NMRC OG&P, Ministry of Health of Russia.
E-mail: st.pavlovich@mail.ru. 117997, Russia, Moscow, Oparina str., 4.
Vsevolod I. Kiselev, Dr. Bio. Sci., Corresponding Member of the RAS, Deputy Director of the Institute of Oncogynecology and Mammology, V.I. Kulakov NMRC OG&P, Ministry of Health of Russia. Tel.: +7(495)531-44-44. E-mail: vkis10@mail.ru. 117997, Russia, Moscow, Oparina str., 4.

For citation: Gadzhieva L.T., Pronin S.M., Pavlovich S.V., Kiselev V.I. The role of genetic and epigenetic changes in the development of atypical hyperplasia and early-stage endometrial cancer.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2021; 5: 48-54 (in Russian)
https://dx.doi.org/10.18565/aig.2021.5.48-54

The role of genetic and epigenetic changes in the development of atypical hyperplasia and early-stage endometrial cancer

Gadzhieva L.T., Pronin S.M., Pavlovich S.V., Kiselev V.I.

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