Oncogene database

5468

PPARG

peroxisome proliferator-activated receptor gamma;PPARG;peroxisome proliferator-activated receptor gamma

PPAR-gamma|nuclear receptor subfamily 1 group C member 3|peroxisome proliferator-activated nuclear receptor gamma variant 1

3p25

protein-coding

Chromosomal translocations that encode fusion oncoproteins have been observed consistently in leukemias/lymphomas and sarcomas but not in carcinomas, the most common human cancers. Here, we report that t(2;3)(q13;p25), a translocation identified in a subset of human thyroid follicular carcinomas, results in fusion of the DNA binding domains of the thyroid transcription factor PAX8 to domains A to F of the peroxisome proliferator-activated receptor (PPAR) gamma1. PAX8-PPARgamma1 mRNA and protein were detected in 5 of 8 thyroid follicular carcinomas but not in 20 follicular adenomas, 10 papillary carcinomas, or 10 multinodular hyperplasias. PAX8-PPARgamma1 inhibited thiazolidinedione-induced transactivation by PPARgamma1 in a dominant negative manner. The experiments demonstrate an oncogenic role for PPARgamma and suggest that PAX8-PPARgamma1 may be useful in the diagnosis and treatment of thyroid carcinoma.

Chromosomal translocations encoding fusion oncoproteins are common in hematological malignancies, sarcomas, and papillary thyroid carcinomas. A recent study of follicular thyroid carcinomas reported a novel chromosomal translocation, t(2;3)(q13;p25), that fused the thyroid-specific transcription factor PAX8 with a nuclear receptor, peroxisome proliferator-activated receptor gamma (PPAR gamma). Herein we report the detection of this putative oncoprotein in 6 of 17 (35%) follicular thyroid carcinomas as well as in 6 of 11 (55%) follicular thyroid adenomas. Concordant expression of protein was found in 91% of those tumors in which PAX8-PPAR gamma mRNA was detected by RT-PCR, whereas a further 20% of follicular tumors were positive for PPAR gamma immunohistochemistry alone. Our findings suggest that the PAX8-PPAR gamma fusion protein promotes differentiated follicular thyroid neoplasia, although it is not sufficient per se for carcinogenesis.

The American cancer Society estimates 30,180 new cases of thyroid cancer in the United States in 2006. Of ALL thyroid cancers, 15-20% are follicular thyroid carcinoma (FTC), making this the second most common thyroid malignancy (after papillary carcinoma). A proportion of FTC has been found to be associated with a chromosomal translocation, t (2, 3)(q13;p25), which fuses the thyroid-specific transcription factor paired box-8 with the peroxisome proliferator-activated receptor-gamma nuclear receptor, a ubiquitously expressed transcription factor. This fusion event causes expression of a paired box-8/peroxisome proliferator-activated receptor-gamma fusion protein (PPFP). PPFP is detected in approximately 30% of FTC. In this report we review data on the role of PPFP in FTC, its mechanism of oncogenesis, and PPFP targeting as a strategy in thyroid cancer treatment.

US-guided fine needle aspiration cytology is currently the best diagnostic tool for thyroid nodules. However, it is not sensitive and specific enough for differentiating between benign and malignant follicular tumors. A potentially useful marker for this differentiation is the PAX8-PPARgamma rearrangement, identified in follicular thyroid carcinomas, but not in follicular adenomas or other types of thyroid tumors. The aim of this research was to determine the clinical significance of the PAX8-PPARgamma oncogene in diagnostics follicular thyroid tumors. The study included 62 patients with follicular or Hurthle cell tumors. Gene expression was determined by reverse transcription-polymerase chain reaction (RT-PCR) from paraffin embedded tissues, and PCR products were checked using the agarose gel electrophoresis. The immunohistochemical analysis was performed on archive paraffin embedded tissues with the monoclonal PPARgamma antibody. The statistical analysis has indicated that neither the expression of PAX8-PPARgamma mRNA, nor the immunohystochemical analysis with the PPARgamma antibody correlate with the patohystological diagnosis. The oncogene, PAX8-PPARgamma has not met the expectations as a reliable tumor marker for differentiation between benign and malignant thyroid tumors, which makes the only reliable histological criteria--capsular and vascular invasion.