Beta-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 3 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 3 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.
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA. ggarcia@cnio.es
G
G
Garcia-Rostan
R L
RL
Camp
A
A
Herrero
M L
ML
Carcangiu
D L
DL
Rimm
G
G
Tallini
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D015689:Oncogene Protein p21(ras) / Q000235:genetics; D010641:Phenotype; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D015996:Survival Rate; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015534:Trans-Activators; D051176:beta Catenin
D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D015689:Oncogene Protein p21(ras)