Clinicopathologic Evaluation of CTNNB1 Mutations in High-Intermediate Risk Endometrial Endometrioid Carcinoma

Abstract

CTNNB1 mutations convey increased risk of recurrence in low-risk endometrial endometrioid carcinoma (EEC). Results from previous high-intermediate risk (HIR) cohorts are mixed. The aims of this study were to correlate CTNNB1 mutational status with clinical outcomes and to evaluate the relationship between CTNNB1 mutations and the 4 prognostic subgroups defined by The Cancer Genome Atlas in HIR EEC. CTNNB1 mutational status was determined by Sanger sequencing of exon 3 of the CTNNB1 gene. Mismatch repair, POLE, p53, and L1 cell-adhesion molecule (L1CAM) status were also evaluated. Descriptive statistics and survival analyses were performed. Eighty-eight cases of HIR EEC were identified, of which 22 (25%) were CTNNB1 mutant (CTNNB1-mut) and 66 (75%) were wild-type (CTNNB1-WT). Median follow-up was 60 mo. Recurrence occurred in 13/88 (15%) patients. Recurrence rates were not significantly different between patients with CTNNB1-mut and CTNNB1-WT tumors (14% vs. 15%, P=0.86). Recurrence-free survival and overall survival were not significantly different (recurrence-free survival hazard ratio: 0.97, 95% confidence interval: 0.27–3.52, P=0.96; overall survival hazard ratio: 0.23, 95% confidence interval: 0.03–1.71, P=0.15). Mismatch repair deficiency was more prevalent in CTNNB1-WT compared with CTNNB1-mut tumors (46% vs. 14%, P=0.01); prevalence of POLE mutations and aberrant p53 were not significantly different. In contrast to patients with low-risk EEC, no differences in recurrence or survival were found in patients with HIR EEC with CTNNB1-mut compared with CTNNB1-WT tumors.

Prospective Clinical Prognostication of Endometrial Carcinomas Based on Next-Generation Sequencing and Immunohistochemistry—Real-World Implementation and Results at a Tertiary Care Center

“…Table 4 displays the rates of mutations per subgroup (displayed as percentage of cases with a mutation in the gene) in a subset of the genes analyzed by the NGS panel. As expected based on previous reports, CTNNB1 mutations were most prevalent in the NSMP subgroup (P < 0.0005 vs MMRd, P < 0.001 vs p53abn, P = 0.7183 vs POLE [likely due to low n in POLE subgroup] by Fisher's exact test) (6,32,33). All detected CTNNB1 mutations were at known oncogenic or likely oncogenic hotspots (as determined by OncoKB [oncokb.org]) with the exception of 2 in-frame deletions of unknown significance (I35_H36del and Y30_S33del) that are in the same region as known activating point mutations.…”

The Evolving Spectrum of Endometrial Glandular Proliferations With Corded and Hyalinized Features

“…Interestingly, despite otherwise favorable clinicopathologic features, CTNNB1 mutations in predominantly early-stage and low-grade NSMP endometrial carcinomas have been reported as a poor prognostic marker associated with decreased recurrence-free survival 8,11–15 . Although these data include a subset of cases of CHEC, 1,2 it should be noted that some studies have not confirmed the prognostic significance of aberrant beta-catenin 10,16,17 . Abnormal nuclear beta-catenin expression has been described in almost all reported cases of CHEC 2–4 .…”

“…Beta-catenin immunohistochemistry is generally considered to be a reliable surrogate for CTNNB1 exon 3 activating mutation, with sensitivity ranging from 85% to 91% and specificity ranging from 82% to 100%, depending on the study parameters, specific mutation, and beta-catenin antibody clone. [8][9][10] Interestingly, despite otherwise favorable clinicopathologic features, CTNNB1 mutations in predominantly early-stage and low-grade NSMP endometrial carcinomas have been reported as a poor prognostic marker associated with decreased recurrence-free survival. 8,[11][12][13][14][15] Although these data include a subset of cases of CHEC, 1,2 it should be noted that some studies have not confirmed the prognostic significance of aberrant beta-catenin.…”

“…8,[11][12][13][14][15] Although these data include a subset of cases of CHEC, 1,2 it should be noted that some studies have not confirmed the prognostic significance of aberrant beta-catenin. 10,16,17 Abnormal nuclear beta-catenin expression has been described in almost all reported cases of CHEC. [2][3][4] In keeping with this, we found ubiquitous nuclear beta-catenin staining in the glandular and corded and hyalinized components of all cases in our study, including all cases of CHEH, suggesting that CTNNB1 mutations are an early and defining feature of tumorigenesis in endometrial glandular lesions with corded and hyalinized features.…”

“…Recurrent point mutations in exon 3 of the CTNNB1 gene result in oncogenic activation of the Wnt-beta-catenin signaling pathway, and aberrant translocation of beta-catenin from the cell membrane to the nucleus can be detected as abnormal nuclear staining by immunohistochemistry. Beta-catenin immunohistochemistry is generally considered to be a reliable surrogate for CTNNB1 exon 3 activating mutation, with sensitivity ranging from 85% to 91% and specificity ranging from 82% to 100%, depending on the study parameters, specific mutation, and beta-catenin antibody clone 8–10 …”