Impact of CTNNB1 (beta-Catenin) Gene Mutation and the Wnt/beta-Catenin Pathway in Endometrial Cancer
Background: Endometrial cancer is the most common gynecologic malignancy, and the number of new cases each year continues to rise. New strategies are needed to identify early stage endometrial cancer patients at high risk of poor clinical outcomes. ^ Objectives: We sought to determine if endometrial cancer patients with CTNNB1 mutation in the tumor had shorter recurrence-free survival lengths than patients whose tumors were CTNNB1 wildtype (Aim 1). We also sought to determine if endometrial carcinomas with CTNNB1 mutation and/or activation of the Wnt/β-catenin pathway have immunosuppressive microenvironments characterized by higher levels of the cytokines TGF-β2 and IL-10 (Aim 2). ^ Methodology: A historical cohort study was performed that included women diagnosed with endometrial cancer whose tumors had undergone next generation sequencing at MD Anderson Cancer Center since the year 2000 (Aim 1). A second cohort of patients who had frozen tissue available in the Gynecologic Tumor Bank at MD Anderson Cancer Center was studied for Aim 2. Clinical information was extracted from the electronic medical record. DNA and RNA were isolated from the frozen tumor specimens. qRT-PCR was used on RNA samples to evaluate transcription levels of two cytokines associated with immune suppression (TGF-β2 and IL-10), as well as one of the downstream Wnt/β-catenin pathway components (Cyclin D1). Descriptive and comparative statistics were employed. Survival analyses were performed using Kaplan-Meier and Cox regressions. ^ Results: For both cohorts, baseline characteristics were similar to that expected from endometrial cancer patients in the United States. For the entire cohort used in Aim 1, 18% demonstrated a CTNNB1 tumor mutation. Patients with CTNNB1 tumor mutation were younger, and had tumors that were more often endometrioid histology, low grade, and less frequently had deep myometrial invasion or lymphovascular space invasion. Recurrence-free survival in patients with low grade, early stage tumors was shorter when a CTNNB1 mutation was present compared with wildtype tumors. TP53 was also associated with shorter recurrence-free survival. In the cohort of patients used for Aim 2, 20% had a CTNNB1 mutation. TGF-β2 levels were higher in tumors with CTNNB1 mutation (all histologies), but there were no differences in IL-10 levels. Tumors with high Cyclin D1 had higher levels of both TGF-β2 and IL-10. There was no association between CTNNB1 mutation status and levels of Cyclin D1. ^ Discussion: Patients with tumors harboring CTNNB1 mutation and/or TP53 mutation have worse recurrence-free survival. Tumors with high Cyclin D1, and therefore suspected Wnt/β-catenin pathway activation, have higher levels of cytokines suggestive of an immunosuppressed microenvironment. Although it appears that Wnt/β-catenin pathway activation may be associated with an immunosuppressed tumor microenvironment in endometrial cancer, the relationships with the CTNNB1 gene and clinical outcomes are complex and remain uncertain.^
Kurnit, Katherine C, "Impact of CTNNB1 (beta-Catenin) Gene Mutation and the Wnt/beta-Catenin Pathway in Endometrial Cancer" (2017). Texas Medical Center Dissertations (via ProQuest). AAI10275569.