{"paper_id":"b799eaab-ef6d-4edb-9955-b4ea6abb9ec1","body_text":"Abstract\nPurpose\nTo investigate the role of epigenetic inactivation of hMLH1 during the malignant transformation of ovarian endometriosis (EMs), and to explore the relationship between the epigenetic inactivation of hMLH1 in eutopic endometria and the malignant transformation of ovarian EMs.\nMethods\nThe target tissue from 29 cases of the endometriosis-associated ovarian carcinoma (EAOC) group, 20 cases of EMs group and 16 cases of control endometrium (CEs) group was obtained by laser capture microdissection (LCM). The methylation statue of hMLH1 promoter was determined by methylation-specific PCR (MSP) and the protein expression of hMLH1 was analysed by immunohistochemistry.\nResults\nThe frequency of promoter hypermethylation of hMLH1 in the neoplastic tissue or ectopic endometria of the EAOC group was higher than that of the EMs group (p < 0.05), and the frequency of promoter hypermethylation of hMLH1 in eutopic endometria of the EAOC group was higher than that of the EMs and CEs groups (p < 0.05). In addition, the protein expression of hMLH1 in eutopic endometria of the EAOC group was lower than that of the EMs and CEs group (p < 0.05), and absence of hMLH1 protein expression was significantly correlated with promoter hypermethylation of the gene.\nConclusions\nEpigenetic inactivation of hMLH1 was an early event in the malignant transformation of ovarian EMs. Epigenetic inactivation of hMLH1 in eutopic endometria was synchronous with that in ectopic endometria and the epigenetic inactivation of hMLH1 in eutopic endometria of EMs might be a potential molecular tool for early diagnosis of the malignant transformation of ovarian EMs.\nSimilar content being viewed by others\nReferences\nNoel JC, Chapron C, Fayt I et al (2008) Lymph node involvement and lympho -vascular invasion in deep infiltrating rectosigmoid endometriosis. Fertil Steril 89(5):1069–1072\nAnaf V, El Nakadi I, Simon P et al (2004) Preferential infiltration of large bowel endometriosis along the nerves of the colon. Hum Reprod 19(4):996–1002\nSampson JA (1925) Endometrial carcinoma of the ovary, arising in endometrial tissue in that organ. Arch Surg 10:1–72\nObata K, Hoshiai H (2000) Common genetic changes between endometriosis and ovarian cancer. Gynecol Obstet Invest 50(Suppl 1):39–43\nFukunaga M, Nomura K, Ishikawa E et al (1997) Ovarian atypical endometriosis: its close association with malignant epithelial tumours. Histopathology 30:249–255\nSeidman JD (1996) Prognostic importance of hyperplasia and atypia in endometriosis. Int J Gynecol Pathol 115:2–9\nGuan H, Ji M, Hou P et al (2008) Hypermethylation of the DNA mismatch repair gene hMLH1 and its association with lymph node metastasis and T1799A BRAF mutation in patients with papillary thyroid cancer. Cancer 113(2):247–255\nLeung SY, Yuen ST, Chung LP et al (1999) hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability. Cancer Res 59:159–164\nAmemiya S, Sekizawa A, Otsuka J et al (2004) Malignant transformation of endometriosis and genetic alterations of K-ras and microsatellite instability. Int J Gynaecol Obstet 86(3):371–376\nAli-Fehmi R, Khalifeh I, Bandyopadhyay S et al (2006) Patterns of loss of heterozygosity at 10q23.3 and microsatellite instability in endometriosis, atypical endometriosis, and ovarian carcinoma arising in association with endometriosis. J Int J Gynecol Pathol 25(3):223–229\nSalvesen HB, MacDonald N, Ryan A et al (2000) Methylation of hMLH1 in a population-based series of endometrial carcinomas. Clin Cancer Res 6(9):3607–3613\nGeisler JP, Goodheart MJ, Sood AK et al (2003) Mismatch repair gene expression defects contribute to microsatellite instability in ovarian carcinoma. Cancer 98(10):2199–2206\nScott RB (1953) Malignant changes in endometriosis. J Obstet Gynecol 2:283–289\nHerman JG, Graff JR, Myöhänen S et al (1996) Methylation specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93:9821–9826\nErcoli A, Ferrandina G, Genuardi M et al (2005) Microsatellite instability is not related to response to cisplatin-based chemotherapy in cervical cancer. Int J Gynecol Cancer 15(2):308–311\nMartini M, Ciccarone M, Garganese G et al (2002) Possible involvement of hMLH1, p16(INK4a) and PTEN in the malignant transformation of endometriosis. Int J Cancer 102:398–406\nXu B, Hamada S, Kusuki I et al (2011) Possible involvement of loss of heterozygosity in malignant transformation of ovarian endometriosis. Gynecol Oncol 120(2):239–246\nDinulescu DM, Ince TA, Quade BJ et al (2005) Role of K-ras and Pten in the 6 development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med 11(1):63–70\nZanetta GM, Webb MJ, Li H et al (2000) Hyperestrogenism: a relevant risk factor for the development of cancer from endometriosis. Gynecol Oncol 79:18–22\nNoel JC, Anaf V, Fayt I et al (2006) Ureteral mullerian carcinosarcoma (mixed mullerian tumor) associated with endometriosis occurring in a patient with a concentrated soy isoflavones supplementation. Arch Gynecol Obstet 274(6):389–392\nSaylam K, Devreker F, Simon P et al (2006) Ovarian clear cell carcinoma occurring in a young patient with endometriosis and long-term ovulation stimulations. Acta Obstet Gynecol Scand 85(12):1506–1507\nVan Gorp T, Amant F, Neven P et al (2004) Endometriosis and the development of malignant tumours of the pelvis. A review of literature. Best Pract Res Clin Obstet Gynaecol 18(2):349–371\nFurlan D, Carnevali I, Marcomini B et al (2006) The high frequency of de novo promoter methylation in synchronous primary endometrial and ovarian carcinomas. Clin Cancer Res 12(11):3329–3336\nYamaguchi K, Mandai M, Toyokuni S, Hamanishi J et al (2008) Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress. Clin Cancer Res 14(1):32–40\nAcknowledgments\nThis research received support from the National Natural Science Foundation of China (No. 30471816) and the Department of Education of Liaoning Province, Shenyang, China (No. 2008671).\nConflict of interest\nWe declare that we have no conflict of interest.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nRights and permissions\nAbout this article\nCite this article\nRen, F., Wang, D., Jiang, Y. et al. Epigenetic inactivation of hMLH1 in the malignant transformation of ovarian endometriosis. Arch Gynecol Obstet 285, 215–221 (2012). https://doi.org/10.1007/s00404-011-1922-x\nReceived:\nAccepted:\nPublished:\nIssue date:\nDOI: https://doi.org/10.1007/s00404-011-1922-x","source_license":"CC0","license_restricted":false}