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From the Department of Pathology,*
Yale University
School of Medicine, New Haven, Connecticut; and the Department of
Pathology,
Oviedo University School of
Medicine, Asturias, Spain
ß-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 ß-catenin alteration in 145 thyroid tumors samples from 127 patients. ß-catenin was localized using immunofluorescence and mutational analysis was performed by single-strand conformational polymorphism. Membrane ß-catenin expression was decreased in eight of 12 (66%) adenomas and in all 115 carcinomas (P < 0.0001). Among carcinomas, reduced membrane ß-catenin was associated with progressive loss of tumor differentiation (P < 0.0001). CTNNB1 exon 3 mutations and nuclear ß-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 ß-catenin mutations. Low membrane ß-catenin expression as well as its nuclear localization or CTNNB1 exon 3 mutations are significantly associated with poor prognosis, independent of conventional prognostic indicators for thyroid cancer but not of tumor differentiation. Analysis of ß-catenin dysregulation may be useful to objectively subtype thyroid neoplasms and more accurately predict outcomes.
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