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

Abstract

Activating mutations affecting exon 3 of the β-Catenin (CTNNB1) gene result in constitutive activation of WNT signalling and are a diagnostic hallmark of several tumour entities including desmoid-type fibromatosis or define clinically relevant subtypes such as in endometrioid carcinoma. In a diagnostic setting, β-Catenin immunohistochemistry is widely used as a surrogate of 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. We therefore assessed Lymphoid Enhancer-Binding Factor 1 (LEF1) immunohistochemistry, a nuclear marker of WNT activation as a potential surrogate of CTNNB1 mutations. Across a variety of entities characterised by CTNNB1 mutations as a putative driver we found diffuse and strong expression of LEF1 in 77% of cases. In a cohort of endometrial carcinomas (n=255) LEF1 was accurate to predict CTNNB1 mutations in 85% (p<0.001), while β-Catenin was accurate in 76% (p<0.001). Irrespective of tumour type, we found LEF1 immunostaining to be easier to interpret than β-Catenin immunostaining in 54% of cases, more difficult in 1% and equally easy to interpret in the remainder. We conclude that LEF1 immunostaining is a highly useful surrogate marker of CTNNB1 mutations in lesions which are driven by WNT signalling, favourably complementing β-Catenin immunohistochemistry and outperforming the latter as a single marker.