Clinicopathological features and prognostic significance of CTNNB1 mutation in low-grade, early-stage endometrial endometrioid carcinoma

Abstract

Low-grade and early-stage endometrioid endometrial carcinomas (EECs) have an overall good prognosis but biomarkers identifying patients at risk of relapse are still lacking. Recently, CTNNB1 exon 3 mutation has been identified as a potential risk factor of recurrence in these patients. We evaluate the prognostic value of CTNNB1 mutation in a single-centre cohort of 218 low-grade, early-stage EECs, and the correlation with beta-catenin and LEF1 immunohistochemistry as candidate surrogate markers. CTNNB1 exon 3 hotspot mutations were evaluated by Sanger sequencing. Immunohistochemical staining of mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), p53, beta-catenin, and LEF1 was performed in representative tissue microarrays. Tumours were also reviewed for mucinous and squamous differentiation, and MELF pattern. Nineteen (8.7%) tumours harboured a mutation in CTNNB1 exon 3. Nuclear beta-catenin and LEF1 were significantly associated with CTNNB1 mutation, showing nuclear beta-catenin a better specificity and positive predictive value for CTNNB1 mutation. Tumours with CTNNB1 exon 3 mutation were associated with reduced disease-free survival (p = 0.010), but no impact on overall survival was found (p = 0.807). The risk of relapse in tumours with CTNNB1 exon 3 mutation was independent of FIGO stage, tumour grade, mismatch repair protein expression, or the presence of lymphovascular space invasion. CTNNB1 exon 3 mutation has a negative impact on disease-free survival in low-grade, early-stage EECs. Nuclear beta-catenin shows a higher positive predictive value than LEF1 for CTNNB1 exon 3 mutation in these tumours. Graphical abstract

Prognosis Stratification Tools in Early-Stage Endometrial Cancer: Could We Improve Their Accuracy?

“…Our results are similar regarding positivity rates to those published for the PORTEC-1 trial samples, but do not reach significance, probably because of the lower positivity of the marker and the smaller size of our cohort [ 40 ]. The other biomarker frequently associated with prognosis is CTNNB1 [ 13 , 41 ]. In our cohort, it showed significance only when intermediate risk groups were merged, and for this reason it was subsequently considered for their inclusion in the risk classifier.…”

“…Amplification and increased expression of human epidermal growth factor receptor 2 (HER2) has been correlated with poor prognosis and more aggressive tumour behaviour [ 11 ]. Those with EC harbouring catenin beta 1 ( CTNNB1) mutation encompass a more aggressive subset within low-grade early-stage endometrioid EC [ 12 , 13 ]. Other biomarkers such as phosphatase and tensin homolog (PTEN), AT-rich interactive domain-containing protein 1A (ARID1A) or E-cadherin (ECAD) have also had a possible impact on prognosis in some studies [ 14 ].…”

The Role of CTNNB1 in Endometrial Cancer

“…They usually occur in women with EC at younger age, which clinically indicates a low risk of recurrence [ 11 , 18 , 20 , 48 ]. However, mutations of CTNNB1 gene are related to worse outcomes with significantly increased rate of disease recurrence and lower overall survival, compared to other tumours with low-grade histology, specifically in relation to mutations in exon 3 [ 20 , 52 ]. This shows the necessity of integrating molecular markers to adequately assess the prognosis of tumours with low-grade histopathological characteristics to adjust therapeutical solutions and offer possibility of targeted therapy.…”

Lymphoid Enhancer-Binding Factor 1 (LEF1) immunostaining as a surrogate of β-catenin (CTNNB1) mutations

“…Ruz-Caracuel et al compared the prediction of CTNNB1 exon 3 mutations by immunohistochemistry for β-Catenin and LEF-1 in low-grade, early-stage endometrial endometrioid carcinoma and found β-Catenin to be both more specific for the presence of mutations [21]. An adverse effect of the presence of a CTNNB1 mutation in these tumours has been reported as well [4,21].…”

“…Ruz-Caracuel et al compared the prediction of CTNNB1 exon 3 mutations by immunohistochemistry for β-Catenin and LEF-1 in low-grade, early-stage endometrial endometrioid carcinoma and found β-Catenin to be both more specific for the presence of mutations [21]. An adverse effect of the presence of a CTNNB1 mutation in these tumours has been reported as well [4,21]. A subgroup analysis of early endometrioid carcinomas of our cohort revealed a nonsignificant trend towards an adverse outcome in the presence of a CTNNB1 mutation, confirming these results.…”