PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]
ABSTRACT 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.
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ABSTRACT: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.Cell 10/2014; 159(3):676-90. DOI:10.1016/j.cell.2014.09.050. · 33.12 Impact Factor
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ABSTRACT: Fat distribution is associated with metabolic risk; differences in cellular characteristics and metabolic functions of these depots have been described, but the molecular mechanisms involved are not understood. The pathogenesis and pathophysiology of metabolic disease can well be understood by studying the molecular mechanisms that control the development and function of adipose tissue (adipogenesis). Homeobox genes are transcription factors that act during normal development and contain the homeobox, a 183bp DNA sequence coding for a 61 amino acid domain defined as homeodomain (HD). Class 1 homeobox genes (Hox genes) have a critical role in controlling positional information and tissue patterning during development. The expression of the whole HOX gene network in different deposits of normal adult human white adipose tissue (intraperitoneal, extra-peritoneal, and dermis) indicate a marked expression in adipose tissue. Furthermore this expression seems to vary in different bodily deposits of white adipose tissue and between white and brown adipose tissue. The purpose of this mini-review is to discuss the role of HOX genes in metabolic diseases.Cell Biology International 07/2013; DOI:10.1002/cbin.10145 · 1.64 Impact Factor
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ABSTRACT: Neoplasms frequently present structural chromosomal aberrations that can alter the level of expression of a protein or to the expression of an aberrant chimeric protein. In the thyroid, the PAX8-PPARG fusion is present in the neoplastic lesions that have a follicular architecture-follicular thyroid carcinoma (FTC) and follicular variant of papillary thyroid carcinoma (FVPTC), and less frequently in follicular thyroid adenoma (FTA), while the presence of RET/PTC fusions are largely restricted to papillary thyroid carcinoma (PTC). The ability to detect fusion genes is relevant for a correct diagnosis and for therapy. We have developed a new fusion gene microarray-based approach for simultaneous analysis of all known and predicted fusion gene variants. We did a comprehensive screen for 548 known and putative fusion genes in 27 samples of thyroid tumors and three positive controls-one thyroid cancer cell line (TPC-1) and two PTCs with known CCDC6-RET (alias RET/PTC1) fusion gene, using this microarray. Within the thyroid tumors tested, only well known, previously reported fusion genes in thyroid oncology were identified. Our results reinforce the pathogenic role played by RET/PTC1, RET/PTC3, and PAX8-PPARG fusion genes in thyroid tumorigenesis. © 2012 Wiley Periodicals, Inc.Genes Chromosomes and Cancer 12/2012; 51(12):1154-64. DOI:10.1002/gcc.22003 · 3.84 Impact Factor