Pax-8–PPAR-γ fusion protein in thyroid carcinoma

Abstract

Thyroid carcinoma is the most common endocrine malignancy, and the incidence of thyroid carcinoma has been progressively increasing. Most thyroid carcinomas contain one of a small number of mutually exclusive driver mutations, such as BRAFV600E, RAS mutations, RET gene fusions, or PAX8/PPARG gene fusions. The PAX8/PPARG gene fusion results in production of a PAX8-PPARγ fusion protein, denoted PPFP, and is found in ~30 – 35% of follicular thyroid carcinomas as well as a subset of follicular variant of papillary thyroid carcinomas. In vitro and in vivo evidence indicate that PPFP can act as an oncoprotein. Although the specific mechanism of PPFP action is yet to be defined, PPFP is considered to act as a dominant negative inhibitor of wild type PPARγ and/or as a unique transcriptional activator of subsets of PPARγ and PAX8 responsive genes. Detection of the fusion transcript in thyroid nodule biopsy specimens can aid clinical decision-making when cytological analyses are indeterminate. The PPARγ agonist pioglitazone is highly therapeutic in a transgenic mouse model of PPFP thyroid carcinoma, suggesting that PPARγ agonists may be therapeutic in patients with PPFP thyroid carcinomas.

Development of the thyroid gland

“…Follicular thyroid cancer (FTC), which retains a follicular phenotype and functional differentiation even in metastatic disease, accounts for less than 10% of thyroid malignancies. Interestingly, PAX8, the master gene of thyroid differentiation, is involved in tumor development in one-third of FTCs; its rearrangement with PPARG, which encodes a peroxisome proliferator-activated receptor, generates an oncogenic PAX8-PPARγ fusion protein (Raman and Koenig, 2014). A putative role of mutant PAX8 in FTC tumor development is, however, unknown.…”

DIAGNOSIS OF ENDOCRINE DISEASE: High-yield thyroid fine-needle aspiration cytology: an update focused on ancillary techniques improving its accuracy

“…RET/PTC translocations have also been described in follicular adenoma (FA) and follicular oncocytic carcinoma, and are no more exclusively restricted to PC (22). The PAX8/PPARg translocation is found in FC with frequencies up to 30%, to a lesser extent in some FV of PC and rarely in FA (23,24). For some authors, the presence of the PAX8/PPARg translocation in an FA in which capsular and/or vascular invasion could not be demonstrated histologically warrants the use of the term 'in situ' FC, corresponding to a probable FC.…”

Loss of PAX8 in high-grade serous ovarian cancer reduces cell survival despite unique modes of action in the fallopian tube and ovarian surface epithelium

“…In thyroid carcinomas, PAX8 undergoes translocation with the PPARγ to create a fusion protein [15]. This fusion protein can act as an oncogene, and is found in approximately 35% of follicular thyroid carcinomas [15].…”

“…In thyroid carcinomas, PAX8 undergoes translocation with the PPARγ to create a fusion protein [15]. This fusion protein can act as an oncogene, and is found in approximately 35% of follicular thyroid carcinomas [15]. In rat thyroid epithelial cells, PAX8 increased cell survival and proliferation through transcriptional inhibition of the p53 positive regulator protein, p53inp1 [16].…”