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

Background Activating mutations affecting exon 3 of the β-catenin ( CTNNB1 ) gene result in constitutive activation of WNT signaling and are a diagnostic hallmark of several tumor entities including desmoid-type fibromatosis. They also define clinically relevant tumor subtypes within certain entities such as endometrioid carcinoma. In diagnostics, β-catenin immunohistochemistry is widely used as a surrogate for CTNNB1 mutations, but is often difficult to assess in practice, given that the characteristic nuclear translocation may be focal or hard to distinguish from spillover of the normal membranous staining. Study design and methods We therefore examined Lymphoid Enhancer-Binding Factor 1 (LEF1) immunostaining, a nuclear marker of WNT activation that serves as a potential surrogate of CTNNB1 mutations. Results In a cohort of endometrial carcinomas (n=255) LEF1 predicted CTNNB1 mutations correctly in 85%, while β-catenin was 76% accurate. Across a variety of entities characterized 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 β-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 favorably complements β-catenin immunohistochemistry and outperforms the latter as a single marker.