Abstract IA16: Endometriosis-related ovarian cancer.

Abstract Endometriosis-related ovarian neoplasms (ERONs) include clear cell carcinoma, endometrioid carcinoma, and, least frequently, seromucinous carcinomas. They belong to a unique group of ovarian tumors in that unlike other histotypes of ovarian cancer, these tumors are frequently associated with endometriosis, especially the lesions presenting as ovarian endometriotic cysts or endometriomas. ERONs usually present as large, unilateral, cystic neoplasms. In general, ERONs tend to behave in an indolent fashion because many of the diseases present at early clinical stages. When confined to the ovary, they have an excellent prognosis, but advanced stage tumors have a poor outcome. It has been demonstrated that ERONs can develop from endometriotic cyst epithelium through sequential stages of tumor progression. The microenvironment of an endometriotic cyst is highly inflammatory, and the cyst contains abundant iron-induced reactive oxygen species that are thought to be genotoxic and mutagenic. Chronic exposure of cystic epithelium to this microenvironment likely facilitates the accumulation of somatic molecular genetic changes that ultimately transform the cells and lead to tumor development. Molecular analyses of ERONs, including genome-wide analysis, have identified several alterations associated with aberrant activation or inactivation of pathways involving ARID1A, PI3K, Wnt, PP2A and mismatch repair. Specifically, canonical Wnt signaling pathway defects and microsatellite instability are more frequently detected in endometrioid carcinomas than in clear cell carcinomas. Among all of the molecular genetic changes identified to date, inactivating mutations of the ARID1A tumor suppressor gene are most common in ERON. Interestingly, ARID1A mutations are rarely observed in other types of ovarian cancer. ARID1A participates in the SWI/SNF chromatin remodeling complex, which plays a fundamental role in a variety of cellular processes, including DNA damage repair, telomere maintenance, transcription and DNA synthesis and methylation. The molecular events that dictate the development of different ERONs remain elusive, but studies using genetically engineered mouse models demonstrate that co-deletion of ARID1A and PTEN results in ovarian endometrioid carcinoma, while co-deletion of ARID1A and PIK3CA leads to formation of clear cell-like ovarian neoplasms in mice. However, deletion of ARID1A by itself is insufficient to drive ovarian tumor formation. Understanding the molecular changes and pathogenesis involved in the development of ERON is fundamental for future translational studies aimed at designing new diagnostic tests for outcome prediction and at identifying critical molecular features for target-based therapy. Citation Format: Ie-Ming Shih. Endometriosis-related ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA16.