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Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas
R Wu1, Y Zhai, E R Fearon
1Department of Pathology, The University of Michigan Medical School, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA.
Abstract:
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 beta-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 beta-catenin and Wnt pathway deregulation. CTNNB1 missense mutations were detected in 14 primary tumors. All mutations affected the NH(2)-terminal regulatory domain of beta-catenin, presumably rendering the mutant proteins resistant to degradation. Immunohistochemical studies revealed nuclear accumulation of beta-catenin in all but two tumors with CTNNB1 mutations. Two primary tumors lacking CTNNBI mutations showed strong nuclear immunoreactivity for beta-catenin. In one of the two tumors, biallelic inactivation of the APC gene was found. In the remaining 29 primary OEAs, unequivocal nuclear beta-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 beta-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 beta-catenin deregulation in OEAs, beta-catenin deregulation may also result from mutations in the APC, AXIN1, and AXIN2 genes.
Insights
Wnt signaling pathway defects are common in ovarian endometrioid adenocarcinomas (OEAs). Mutations in CTNNB1 are frequent, but APC, AXIN1, and AXIN2 gene alterations also contribute to beta-catenin deregulation in OEAs.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ovarian endometrioid adenocarcinomas (OEAs) are a distinct subtype of ovarian cancer.
- Prior research indicates frequent CTNNB1 gene mutations in OEAs, affecting beta-catenin within the Wnt signaling pathway.
- The full spectrum of Wnt pathway alterations in OEAs remains largely uncharacterized.
Purpose of the Study:
- To comprehensively investigate the prevalence and mechanisms of beta-catenin and Wnt pathway deregulation in 45 primary OEAs and two derived cell lines.
- To identify specific genetic alterations responsible for aberrant Wnt signaling in this ovarian cancer subtype.
Main Methods:
- Analysis of CTNNB1 gene mutations in primary tumors and cell lines.
- Immunohistochemical assessment of beta-catenin nuclear accumulation.
- Investigation of mutations in APC, AXIN1, and AXIN2 genes.
- Evaluation of T-cell factor/lymphoid enhancer factor transcriptional activity in cell lines.
Main Results:
- CTNNB1 missense mutations were found in 14% of primary OEAs, impacting the beta-catenin degradation domain.
- Nuclear beta-catenin accumulation was observed in tumors with CTNNB1 mutations and in some without.
- Mutations in APC, AXIN1, and AXIN2 were identified in a subset of OEAs lacking CTNNB1 mutations.
- OEA cell lines exhibited elevated Wnt pathway activity due to mutant beta-catenin or AXIN1 alterations.
Conclusions:
- Frequent defects in the Wnt signaling pathway are characteristic of ovarian endometrioid adenocarcinomas.
- While CTNNB1 mutations are the primary driver, alterations in APC, AXIN1, and AXIN2 also contribute to beta-catenin deregulation in OEAs.
- These findings highlight the complex genetic landscape of Wnt pathway involvement in OEA pathogenesis.
