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

• Published in: Virchows Archiv : an international journal of pathology 2021-12, Vol.479 (6), p.1167-1176
• Main Authors: Ruz-Caracuel, Ignacio, López-Janeiro, Álvaro, Heredia-Soto, Victoria, Ramón-Patino, Jorge L., Yébenes, Laura, Berjón, Alberto, Hernández, Alicia, Gallego, Alejandro, Ruiz, Patricia, Redondo, Andrés, Peláez-García, Alberto, Mendiola, Marta, Hardisson, David
• Format: Article
• Language: English
• Subjects: Aged; beta Catenin - analysis; beta Catenin - genetics; Biomarkers; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Carcinoma; Carcinoma, Endometrioid - chemistry; Carcinoma, Endometrioid - genetics; Carcinoma, Endometrioid - pathology; Carcinoma, Endometrioid - surgery; Disease-Free Survival; DNA Mutational Analysis; Endometrial cancer; Endometrial Neoplasms - chemistry; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; Endometrial Neoplasms - surgery; Endometrium; Exons; Female; Humans; Immunohistochemistry; Lymphoid Enhancer-Binding Factor 1 - analysis; Medical prognosis; Medicine; Medicine & Public Health; Middle Aged; Mismatch repair; MLH1 protein; MSH2 protein; MSH6 protein; Mutation; Mutation hot spots; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Original; Original Article; p53 Protein; Pathology; Proteins; Repair; Retrospective Studies; Risk analysis; Risk Assessment; Risk Factors; Survival; Tumors; Uterine cancer; β-Catenin
• ISSN: 0945-6317; 1432-2307
• DOI: 10.1007/s00428-021-03176-5

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