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.