Tumorigenesis and Neoplastic Progression Follicular Thyroid Tumors with the PAX8-PPAR 1 Rearrangement Display Characteristic Genetic Alterations

Follicular thyroid carcinomas (FTC) arise through oncogenic pathways distinct from those involved in the papillary histotype. Recently, a t(2;3)(q13;p25) rearrangement, which juxtaposes the thyroid transcription factor PAX8 to the peroxisome proliferator-activated receptor (PPAR) 1, was described in FTCs. In this report, we describe gene expression in 11 normal tissues, 4 adenomas, and 8 FTCs, with or without the PAX8-PPAR 1 translocation, using custom 60-mer oligonucleotide microarrays. Results were confirmed by quantitative real-time polymerase chain reaction of 65 thyroid tissues and by immunohistochemistry. Statistical analysis revealed a pattern of 93 genes discriminating FTCs, with or without the translocation, that were morphologically undistinguishable. Although the expression of thyroid-specific genes was detectable, none appeared to be differentially regulated between tumors with or without the translocation. Differentially expressed genes included genes related to lipid/glucose/amino acid metabolism, tumorigenesis, and angiogenesis. Surprisingly, several PPAR target genes were up-regulated in PAX8PPAR -positive FTCs such as angiopoietin-like 4 and aquaporin 7. Moreover many genes involved in PAX8PPAR expression profile presented a putative PPAR -promoter site, compatible with a direct activity of the fusion product. These data identify several differentially expressed genes, such as FGD3, that may serve as potential targets of PPAR and as members of novel molecular pathways involved in the development of thyroid carcinomas. (Am J Pathol 2005, 167:223–231)