{"paper_id":"9ef28972-7b39-4070-ad60-3d9bb14a19cc","body_text":"http://dx.doi.org/10.14336/AD.2023.1109  \n \n*Correspondence should be addressed to:  Dr. Jalid Sehouli, Department of Gynecology (CBF), European Competence Center for \nOvarian Cancer, Charite, Berlin, Germany. Email: Jalid.Sehouli@charite.de \n \nCopyright: © 2023 Kordowitzki P. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution \nLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. \n \nISSN: 2152-5250                                                                                                                                                                                   2331 \n                  \n \n  \nCorrespondence \n \nARID1a Gene as a Potential Early Marker to Tackle \nEndometriosis-Associated Ovarian Cancer \n \nPawel Kordowitzki1,2, Sylvia Mechsner2, Jalid Sehouli2* \n \n1Department of Preclinical and Basic Sciences, Nicolaus Copernicus University, Torun, Poland.  \n2Department of Gynecology including Center of Oncological Surgery (CVK) and Department of Gynecology \n(CBF), European Competence Center for Ovarian Cancer, Charite, Berlin, Germany.  \n \n  [Received September 20, 2023; Revised October 26, 2023; Accepted November 9, 2023] \n \nABSTRACT: The worries of women with endometriosis – a chronic gynecological disease affecting \napproximately 10% of women of childbearing age - about the increased risk of ovarian cancer are present \nworldwide. Endometriosis is a common, often painful, but benign gynecological disease that affects women. \nHowever, the pathogenesis remains elusive but is certainly multifactorial. Interestingly, endometriosis s hares \nsimilarities with cancer. Therefore, women suffering from endometriosis fear an increased risk of ovarian \ncancer. In addition, these patients suffer from anxiety and depression. Previous studies have provided evidence \nthat epithelial mutations in end ometriosis or in the endometrium include certain inactivating mutations \nresponsible for ovarian cancer, such as in the ARID1A gene. \n \nKey words: endometriosis, epithelial ovarian cancer, endometrioid ovarian cancer, ARID1A mutation \n \n \n \nThe fear and concerns of women with endometriosis, a \nchronic gynecological condition affecting approximately \n176 million (~10%) women of reproductive age \nworldwide, about the increased ovarian cancer risk are \nstill up to date [1 -3]. Endometriosis is a prevalent, often \npainful, but benign gynecological disorder that affects \nwomen of reproductive age. Its pathogenesis remains \nelusive but is surely multifactorial [3]. However, \nendometriosis shares features with cancer. Consequently, \nwomen suffering from endometriosis are concerned about \nthe increased ovarian cancer risk, and endometriosis -\nassociated ovarian cancer is challenging for clinicians [1-\n3]. Moreover, the patients are suffering from anxiety and \ndepression, impacting their psychological and social \nfunctioning. These psychiatric issues should not be \nneglected since they again influence the level of the \nseverity of endometriosis symptoms thus leading to a \nvicious cycle [4]. Furthermore, exposure to pain during  \nendometriosis was estimated to be a primary factor for an \nelevated incidence of depression. As numerous patients \nreport frequently, it is very hard to live with chronic pain \nsince it affects performing all-day duties, hobbies, or tasks \nrelated to women’s jobs. Interestingly, the risk in women \nsuffering from endometriosis to develop ovarian cancer is \nlower than 2%, compared to the 1 -3% risk of ovarian \ncancer in the entire female population. Based on this, for \nwomen with endometriosis, the ovarian cancer ris k is \nrelatively low which should reduce women’s fear of \novarian cancer [3]. ARID1A is described as an epigenetic \ntumor suppressor, a component of the so-called SWI/SNF \nchromatin remodeling complexes, and very frequently - \ninactivating mutations of this gene  are present in more \nthan 50% of ovarian clear cell carcinomas, and \napproximately 30% of ovarian endometrioid carcinomas \n[5, 6].  Noteworthy, previous studies provided evidence \nthat epithelial mutations in endometriosis or endometrium \nincluded distinct driver mutations for ovarian cancer such \nas in the  ARID1A gene [1 -3]. At first glance, these \nfindings were puzzling because the direct observation of \nthe malignant transformation of endometriotic lesions, \n    Volume 15, Number 6; 2331-2333, December 2024 \n\n\n Kordowitzki P., et al.                                                              ARID1a gene and endometriosis-associated ovarian cancer\n   \nAging and Disease • Volume 15, Number 6, December 2024                                                                        2332 \n \nparticularly in the extra ovarian locations, has rarely been \nreported in the literature [1]. As mentioned above, \nARID1A mutation is considered one of the most \nimportant driver events in endometriosis -associated \novarian cancer [2,3]. This raises the questio n regarding \nthe significance of mutations in the ARID1A gene as an \nearlier biomarker in endometriosis patients to tackle \novarian cancer initiation, as partial loss of BAF250a \nexpression has been found in lesions of patients with \nendometriosis [7]. In consequence, a patient with a history \nof endometriosis has a significantly increased risk of \nclear-cell and endometrioid ovarian cancer, which \nunderlines the importance of deciphering the code for \ncomorbidity. However, one should keep in mind that most \nwomen with endometriosis will rarely develop high-grade \novarian cancer, and that serous borderline tumours from \nwhich invasive low -grade serous ovarian cancers are \nbelieved to arise are not necessarily associated with a \nhistory of endometriosis [7]. Another possib le \nexplanation is that several molecular, local \nenvironmental, or epigenetic factors might give rise to \ninvasive low -grade ovarian cancer, and endometriosis's \neffect is entirely independent of the association with \nserous borderline tumours. Results of mole cular studies \nhave highlighted the presence of ARID1A gene mutations \nin 46% of clear -cell and 30% of endometrioid ovarian \ncancers and in areas of endometriosis that are contiguous \nwith these cancers [8,9]. In this regard, it appears worth \nsuggesting ovaria n cancer screening for those patients \nwith an endometriosis history to shed light on the \npathogenesis of endometriosis-associated ovarian cancer. \nImportantly though, biomarker research, including \nmutation analyses of the ARID1A gene, early detection of \nactivated oncogenes, and the silencing of tumor \nsuppressors are strongly advised. In conclusion, we \nsuggest that doctors should reassure women suffering \nfrom endometriosis that the risk of developing ovarian \ncancer is low and that early care for the patient’s  mental \nwell-being, for instance, psychological support groups, or \nresources for managing anxiety and fear, should be \nrecommended by clinicians. Counseling programs for the \npatients should also be provided to test for ARID1a \nmutations. Another important pr actical consideration in \nregard to the clinical implications of endometriosis -\nassociated ovarian cancer should focus on fertility \npreservation, especially nowadays since couples tend to \ndelay the age of the first pregnancy. The earlier -\nmentioned counseling  programs for affected women \nshould also contain the advantages and disadvantages of \nassisted reproductive technologies, such as the \ncryopreservation of oocytes as a potential clinical \nintervention to preserve fertility [10]. \n \nFigure 1. Schematic representation of ARID1a mutation as potential early marker for malignant transformation of \nendometriosis and endometroid ovarian cancer initiation in women.  \nAcknowledgments \n \nFigure 1 was created with biorender.com. The funding of \nthe Debiuty IV IDUB grant is gratefully acknowledged.  \n \nConflict of interest \n \nThe Authors declare no Competing Financial or Non -\nFinancial Interests. \n \n\n\n Kordowitzki P., et al.                                                              ARID1a gene and endometriosis-associated ovarian cancer\n   \nAging and Disease • Volume 15, Number 6, December 2024                                                                        2333 \n \nAuthor Contribution \n \nP.K.: conceptualization and writing, figure preparation, \nfunding acquisition; S.M. and L.A.: writing and revising \nthe final manuscript, J.S.: revising the final manuscript. \n \nReferences \n \n[1] Anglesio MS, Papadopoulos N, Ayhan A, Nazeran TM, \nNoë M, Horlings HM et al. (2017). Cancer -Associated \nMutations in Endometriosis without Cancer. N Engl J \nMed. 376(19):1835-1848.  \n[2] Fonseca MAS, Haro M, Wright KN, Lin X, Abbasi F, \nSun J et al. (2023). Single-cell transcriptomic analysis of \nendometriosis. Nat Genet 55, 255–267 (2023).  \n[3] Kvaskoff M, Horne AW, Missmer SA (2017). Informing \nwomen with endometriosis about ovarian cancer risk. \nLancet. 390(10111):2433-2434.  \n[4] Laganà AS, La Rosa VL, Rapisarda AMC, Valenti G, \nSapia F, Chiofalo B, et al. (2017). Anxiety and \ndepression in patients with endometriosis: impact and \nmanagement challenges. Int J Womens Health. 9:323 -\n330.  \n[5] Kinose Y, Xu H, Kim H, Kumar S, Shan X, George E, et \nal.(2023). Dual blockade of BRD4 and ATR/WEE1 \npathways exploits ARID1A loss in clear cell ovarian \ncancer. Res Sq, 27:rs.3.rs-3314138.  \n[6] Borrelli GM, Abrão MS, Taube ET, Darb -Esfahani S, \nKöhler C, Kaufmann AM, et al. (2015). \nImmunohistochemical Investigation of Metastasis -\nRelated Chemokines in Deep -Infiltrating Endometriosis \nand Compromised Pelvic Sentinel Lymph Nodes. \nReprod Sci. 22(12):1632-42.  \n[7] Wu JN, Roberts CW (2023). ARID1A mutations in \ncancer: another epigenetic tumor suppressor? Cancer \nDiscov. 3(1):35-43. \n[8] Gourley C (2012). Link between endometriosis and \novarian-cancer subtypes. Lancet Oncol. 13(4):326-8.  \n[9] Wiegand KC, Shah SP, Al -Agha OM, Zhao Y, Tse K, \nZeng T et al. (2010). ARID1A mutations in \nendometriosis-associated ovarian carcinomas. N Engl J \nMed; 363: 1532–43. \n[10] Younis JS (2022). Endometriosis -Associated Ovarian \nCancer: What Are the Implications for Women with \nIntact Endometrioma Planning for a Future Pregnancy? \nA Reproductive Clinical Outlook. Biomolecules. \n21;12(11):1721.","source_license":"CC0","license_restricted":false}