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Diverse Mechanisms of ß-Catenin Deregulation in Ovarian Endometrioid Adenocarcinomas

Departments of Pathology [R. W., Y. Z., E. R. F., K. R. C.], Internal Medicine [E. R. F., K. R. C.], and Human Genetics [E. R. F.], The University of Michigan Medical School, Ann Arbor, Michigan 48109

Clinical and molecular findings suggest that the four major histological subtypes of ovarian carcinoma (serous, clear cell, mucinous, and endometrioid) likely represent distinct disease entities. Prior studies have shown that ovarian endometrioid adenocarcinomas (OEAs) often carry mutations in the CTNNB1 gene, which encodes ß-catenin, a critical component of the Wnt signaling pathway. However, the nature of other defects in the Wnt signaling pathway in ovarian carcinomas remains largely unknown. Thus, in 45 primary OEAs and two OEA-derived cell lines, we sought to comprehensively address the prevalence of and mechanisms underlying ß-catenin and Wnt pathway deregulation. CTNNB1 missense mutations were detected in 14 primary tumors. All mutations affected the NH₂-terminal regulatory domain of ß-catenin, presumably rendering the mutant proteins resistant to degradation. Immunohistochemical studies revealed nuclear accumulation of ß-catenin in all but two tumors with CTNNB1 mutations. Two primary tumors lacking CTNNBI mutations showed strong nuclear immunoreactivity for ß-catenin. In one of the two tumors, biallelic inactivation of the APC gene was found. In the remaining 29 primary OEAs, unequivocal nuclear ß-catenin immunoreactivity was not observed, though a nonsense mutation in AXIN1 was observed in one tumor and a truncating frameshift mutation in AXIN2 was seen in another case. Both OEA-derived cell lines studied (TOV-112D and MDAH-2774) had elevated constitutive T-cell factor/lymphoid enhancer factor transcriptional activity. TOV-112D cells were shown to harbor mutant ß-catenin, whereas a missense AXIN1 sequence alteration was identified in MDAH-2774 cells. Collectively, our findings demonstrate frequent defects of the Wnt signaling pathway in a particular subtype of ovarian carcinomas, i.e., OEAs. Although mutations in the CTNNB1 gene are the most common mechanism of ß-catenin deregulation in OEAs, ß-catenin deregulation may also result from mutations in the APC, AXIN1, and AXIN2 genes.

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