Lymphoid enhancer-binding factor 1 (LEF1) immunostaining as a surrogate for β-catenin (CTNNB1) mutations

Aims Mutations affecting exon 3 of the beta-catenin (CTNNB1) gene result in constitutive activation of WNT signalling and are a diagnostic hallmark of several tumour entities including desmoid-type fibromatosis. They also define clinically relevant tumour subtypes within certain entities, such as endometrioid carcinoma. In diagnostics, beta-catenin immunohistochemistry is widely used as a surrogate for CTNNB1 mutations. Yet, it is often difficult to assess in practice, given that the characteristic nuclear translocation may be focal or hard to distinguish from the spillover of the normal membranous staining.Methods We therefore examined lymphoid enhancer-binding factor 1 (LEF1) immunostaining, a nuclear marker of WNT activation that serves as a potential surrogate for CTNNB1 mutations.Results In a cohort of endometrial carcinomas with known mutation status (n=130) LEF1 was 85% accurate in predicting CTNNB1 mutation status (64% sensitivity, 90% specificity) while beta-catenin was 76% accurate (72% sensitivity; 77% specificity). Across a variety of entities characterised by CTNNB1 mutations as putative drivers, we found diffuse and strong expression of LEF1 in 77% of cases. LEF1 immunostaining proved easier to interpret than beta-catenin immunostaining in 54% of cases, more difficult in 1% of cases and comparable in the remaining cases.Conclusion We conclude that LEF1 immunostaining is a useful surrogate marker for CTNNB1 mutations. It favourably complements beta-catenin immunohistochemistry and outperforms the latter as a single marker.