Dissecting molecular events in thyroid neoplasia provides evidence for distinct evolution of follicular thyroid adenoma and carcinoma.

Abstract

Benign hypofunctional cold thyroid nodules (CTNs) are a frequent scintiscan finding and need to be distinguished from thyroid carcinomas. The origin of CTNs with follicular morphologic features is unresolved. The DNA damage response might act as a physiologic barrier, inhibiting the progression of preneoplastic lesions to neoplasia. We investigated the following in hypofunctional follicular adenoma (FA) and follicular thyroid cancer (FTC): i) the mutation rate of frequently activated oncogenes, ii) the activation of DNA damage response checkpoints, and iii) the differential proteomic pattern between FA and FTC. Both FTC and FA, which did not harbor RAS, phosphoinositide-3-kinase, or PAX/peroxisome proliferator activated receptor-γ mutations, express various proteins in common and others that are more distinctly expressed in FTC rather than in FA or normal thyroid tissue. This finding is in line with the finding of constitutive DNA damage checkpoint activation (p-Chk2, γ-H2AX) and evidence for replicative stress causing genomic instability (increased cyclin E, retinoblastoma, or E2F1 mRNA expression) in FTC but not FA. We discuss the findings of the increased expression of translationally controlled tumor protein, phosphatase 2A inhibitor, and DJ-1 in FTC compared with FA identified by proteomics and their potential implication in follicular thyroid carcinogenesis. Our present findings argue for the definition of FA as a truly benign entity and against progressive development of FA to FTC.

• Authors: Kerstin Krause, Susanne Prawitt, Markus Eszlinger, Christian Ihling, Andrea Sinz, Katrin Schierle, Oliver Gimm, Henning Dralle, Frank Steinert, Sien-Yi Sheu, Kurt W Schmid, Dagmar Fuhrer
• Journal: The American journal of pathology (Am J Pathol) Vol. 179 Issue 6 Pg. 3066-74 (Dec 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21983636 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Neoplasm Proteins
• Nuclear Proteins
• PAX8 Transcription Factor
• PAX8 protein, human
• PI3KCA protein, human
• PPAR gamma
• Paired Box Transcription Factors
• Transcription Factors

Topics

• Adenocarcinoma, Follicular
• Adenoma (genetics)
• Biomarkers, Tumor (metabolism)
• DNA Damage (genetics)
• Gene Rearrangement
• Genes, ras (genetics)
• Genomic Instability (genetics)
• Humans
• Mutation Rate
• Neoplasm Proteins (metabolism)
• Nuclear Proteins (genetics)
• PAX8 Transcription Factor
• PPAR gamma (genetics)
• Paired Box Transcription Factors (genetics)
• Point Mutation (genetics)
• Proteomics
• Thyroid Neoplasms (genetics)
• Thyroid Nodule (genetics)
• Transcription Factors (genetics)