Alterations in β-catenin, microsatellite instability, and HNF-1β levels are independently associated with ovarian endometriosis–associated tumorigenesis

Abstract

We focused on specific molecular events during the development of endometriosis-associated ovarian endometrioid carcinoma (OEmCa) and ovarian clear cell carcinoma (OCCCa). Alterations in β-catenin (encoded by CTNNB1) and microsatellite instability (MSI), as well as changes in the expression levels of HNF-1β and DNA mismatch repair (MMR) proteins were investigated in 50 OEmCas and 21 OCCCas with endometriotic lesions. Mutations of CTNNB1 were identified in 28 (56%) of the 50 OEmCa cases and 26 (41.9%) of the 62 coexisting endometriosis lesions. MSI-high (H) was observed in 7 (14.6%) of the 48 OEmCa and 14 (23.3%) of the 60 coexisting endometriosis, and was significantly associated with loss of MMR protein expression, but not CTNNB1 mutations. Nonidentical CTNNB1 status between 2 different epithelial lesions within endometriosis was observed in 8 of 10 informative endometriosis cases that had adjacent OEmCa. Similar findings for MSI features were also found in 2 of 3 informative cases, suggesting that endometriotic lesions may predominantly consist of polyclonal cells. In contrast, high HNF-1β expression was significantly associated with SLC3A1 expression, which plays a major role in HNF-1β-triggered induction of reactive oxygen species in OCCCas, independent of abnormalities in both β-catenin and MSI/MMR status. Finally, 4 inflammatory parameters associated with repeated hemorrhaging in endometriosis were significantly higher in endometriosis with MSI-high when compared with that with MSS, independent of both β-catenin and HNF-1β status. In conclusion, different molecular pathways including alterations in β-catenin, MSI, and HNF-1β levels may contribute to tumorigenesis in endometriosis-associated carcinoma.