β-Catenin dysregulation in thyroid neoplasms -: Down-regulation, aberrant nuclear expression, and CTNNB1 exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis

beta -catenin has a role in cell adhesion and Wnt signaling. It is mutated or otherwise dysregulated in a variety of human cancers. In this study we assess beta -catenin alteration in 145 thyroid tumors samples from 127 patients. beta -catenin was localized using immunofluorescence and mutational analysis was performed by single-strand conformational polymorphism. Membrane beta -catenin expression was decreased in eight of 12 (66%) adenomas and in all 115 carcinomas (P < 0.0001). Among carcinomas, reduced membrane <beta>-catenin was associated with progressive loss of tumor differentiation (P < 0.0001). CTNNB1 exon 5 mutations and nuclear <beta>-catenin localization were restricted to poorly differentiated [7 of 28 (25%) and 6 of 28 cases (21.4%), respectively] or undifferentiated carcinomas [19 of 29 (65.5%) and 14 of 29 (48.3%) cases, respectively]. Poorly differentiated tumors always featured mutations involving Ser and Thr residues and were characterized by Thr to Ile amino acid substitutions (P = 0.0283). The association between CTNNB1 exon 3 mutations and aberrant nuclear immunoreactivity (P = 0.0020) is consistent with Wnt activation because of stabilizing beta -catenin mutations. Low membrane beta -catenin expression as well as its nuclear localization or CTNNB1 exon 5 mutations are significantly associated with poor prognosis, independent of conventional prognostic indicators for thyroid cancer but not of tumor differentiation. Analysis of beta -catenin dysregulation may be useful to objectively subtype thyroid neoplasms and more accurately predict outcomes.