MOLECULAR CHARACTERISTICS AND GENETIC APPROACHES OF ENDOMETRIOSIS-RELATED OVARIAN CANCER: A SYSTEMATIC REVIEW

Introduction: Endometriosis is a benign gynecological condition that affects approximately 5-10% of reproductive aged women all over the world. The oncogenic role ofendometriosis has first been described first in 1952 by Sampson, that proposed a theory of malignant progression. Endometriosis-related ovarian cancer (ERONs) represent agroup of tumors including clear cell carcinoma, endometrioid carcinoma and seromucinous borderline tumors that supports the hypothesis that endometriosis is a cancerprecursor. The aim of this study was to review the mechanisms whereby genetic and molecular factors can be involved in the neoplastic progression of this pathology.Methods: A comprehensive research of the literature was performed using PubMed, Scopus, Google scholar and Science Direct databases, up to 31 March 2018. The researchhad the purpose to identify the original and review papers that mentioned the genetic and molecular factors that are potentially involved in the oncogenic role of endometriosis.Results: A total of 35 articles met the inclusion criteria and were included in our review. ERONs have different prevalence: 30%-60% are endometrioid carcinomas, 20%-35% cleacell carcinomas, 5%-10% serous carcinomas and 4%-10% mucinous carcinomas. Molecular analyses of the ERONs have identified a series of alterations that involves: theaberrant activation or inactivation of pathways such as PTEN, KRAS, TP53, PIK3 CA, β-catenin and rarely, P53. The loss of heterozygosity (LOH) at the PTEN locus is proved tobe present in 10%-20% of endometriosis cases and the patterns of LOH in ERONs are similar. LOH in the Xq region is about 38% of ERONs but it is infrequent in endometriosis.In atypical endometriosis, which is a high risk factor for ovarian cancer, LOH of 10q23 is found in 40% of cases, while in ERONs, LOH of 10q23 is higher than 45%. K-Rasmutation is frequently found in endometriosis-associated carcinoma (10-20% of cases) and in more than 50% of cases of mucinous ovarian carcinoma. u0392-catenin is encoded byCTNNB1 and the Wnt/β-catenin signaling pathway dysregulation is occurring in 16-38% of ovarian endometrioid carcinoma, for which this mutation seems to be characteristic.PTEN-PIK3CA-mTOR pathway has also been implicated in the tumor progression process, identifying PIK3CA mutation in approximately 46% of clear cell ovarian cancers. Theloss of ARID1A, a tumor suppressor gene that encodes BAF250a protein, is the most common molecular change in ERONs and seems also to be an early mechanism. In ovariancancers, it have been proved that ARID1A mutations are found in 50% of endometrioid cancers and in 73% of clear-cell cancers, compared to approximately 10% of non-ERONs. Conclusion: Endometriosis is a multi-factorial disease with a strong oncogenic potential. The molecular and genetic mechanisms remain still unclear and there are required futurestudies that will be the key-point for the early detection and for improved treatment strategies for ERONs.