Key Points
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The Pax-8–PPAR-γ fusion protein (PPFP) is a consequence of a chromosomal translocation found in approximately one-third of follicular carcinomas and some follicular-variant papillary carcinomas and benign follicular adenomas
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In vitro and in vivo evidence indicates that PPFP acts as an oncoprotein
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PPFP can act as a dominant-negative inhibitor of wild-type PPAR-γ and/or as a PPAR-γ-like transcription factor, and can activate or repress Pax-8-responsive genes
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The PPAR-γ agonist pioglitazone has beneficial effects in a mouse model of PPFP-positive thyroid carcinoma, and is currently being tested in a phase II clinical trial
Abstract
Thyroid carcinoma is the most common endocrine malignancy, and its incidence is continuing to increase. Most thyroid carcinomas contain one of several known driver mutations, such as the Val600Glu substitution in B-Raf, Ras mutations, RET gene fusions, or PAX8–PPARG gene fusions. The PAX8–PPARG gene fusion results in the production of a Pax-8–PPAR-γ fusion protein (PPFP), which is found in approximately one-third of follicular thyroid carcinomas, as well as some follicular-variant papillary thyroid carcinomas. In vitro and in vivo evidence indicates that PPFP is an oncoprotein. Although specific mechanisms of action remain to be defined, PPFP is considered to act as a dominant-negative inhibitor of wild-type PPAR-γ and/or as a unique transcriptional activator of subsets of PPAR-γ-responsive and Pax-8-responsive genes. Detection of the fusion transcript in thyroid nodule biopsy specimens can aid clinical decision-making when cytological findings are indeterminate. The PPAR-γ agonist pioglitazone is highly therapeutic in a transgenic mouse model of PPFP-positive thyroid carcinoma, suggesting that PPAR-γ agonists might be beneficial in patients with PPFP-positive thyroid carcinomas.
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R.J.K.'s research work was supported by NIH grants R01CA151842 and R01CA166033.
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Raman, P., Koenig, R. Pax-8–PPAR-γ fusion protein in thyroid carcinoma. Nat Rev Endocrinol 10, 616–623 (2014). https://doi.org/10.1038/nrendo.2014.115
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DOI: https://doi.org/10.1038/nrendo.2014.115
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