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-␥ 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, ␥-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.

The JAK-STAT Transcriptional Regulator, STAT-5, Activates the ATM DNA Damage Pathway to Induce HPV 31 Genome Amplification upon Epithelial Differentiation

“…A recent study suggested that the nuclear peroxisome proliferator-activated receptor γ (PPARγ) could activate CHK2 in the development of follicular thyroid cancer [24]. In addition, PPARγ transcription has been shown to be regulated by STAT-5 in adipogenesis [25].…”

Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice

“…Western Blot analysis was performed on samples of inguinal WAT (iWAT), gonadal WAT (gWAT) and BAT as described previously45. The following antibodies and dilutions were used: mouse polyclonal anti-Ucp1 antibody (1:500; Merck Millipore; Darmstadt, Germany), pHSL and HSL(1:1000; Cell Signaling Technology, Danvers, USA).…”

Differential Diagnostic Ultrasound Criteria of Papillary and Follicular Carcinomas: A Multivariate Analysis

“…Moleculargenetic analyses indicate that specific genetic changes are associated with both subtypes of differentiated thyroid cancer In cases of PTC, BRAF as well as modified RET/PTC and trc oncogenes could be verified, whereas in cases of FTC, PAX8/PPARγ rearrangements and RAS mutations could be found [14]. Whether FTC develops directly from follicular thyroid cells or from follicular adenomas is still a matter of scientific controversy [14,17]. In addition to the described mutations, epigenetic factors leading to gene activation or deactivation may play a role in the development of differentiated thyroid cancer and are co-determinants of the phenotypical appearance of PTC and FTC tumors [18].…”