Expression profiling reveals a distinct transcription signature in follicular thyroid carcinomas with a PAX8-PPARc fusion oncogene Weng-Onn Lui* ,1,7 , Theodoros Foukakis 1,2,3 , Johan Lide´n 4 , Srinivasan R Thoppe 1 , Trisha Dwight 1,2 ,AndersHo¨o¨g 5 ,JanZedenius 2 ,Go¨ranWallin 3 ,MarkReimers 6 andCatharinaLarsson 1 1 Department of Molecular Medicine, Karolinska University Hospital, Solna, CMM L8:01, SE-171 76 Stockholm, Sweden; 2 Center for Surgical Sciences, Karolinska University Hospital, Huddinge, K54, SE-141 86 Huddinge, Sweden; 3 Department of Surgical Sciences, Karolinska University Hospital, Solna, P9:03, SE-171 76 Stockholm, Sweden; 4 Department of Biosciences, NOVUM, SE-141 57 Huddinge, Sweden; 5 Department of Oncology-Pathology, Karolinska University Hospital, Solna, P1:02, SE-171 76, Stockholm, Sweden; 6 Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, MD 20892, USA The demonstration of the PAX8-PPARc fusion oncogene in a subset of follicular thyroid tumors provides a new and promising starting point to dissect the molecular genetic events involved in the development of this tumor form. In the present study, we compared the gene expression profiles of follicular thyroid carcinomas (FTCs) bearing a PAX8-PPARc fusion against FTCs that lack this fusion. Using unsupervised clustering and multidimensional scal- ing analyses, we show that FTCs possessing a PAX8- PPARc fusion have a highly uniform and distinct gene expression signature that clearly distinguishes them from FTCs without the fusion. The PAX8-PPARc( þ ) FTCs grouped in a defined cluster, where highly ranked genes were mostly associated with signal transduction, cell growth and translation control. Notably, a large number of ribosomal protein and translation-associated genes were concurrently underexpressed in the FTCs with the fusion. Taken together, our findings further support that follicular carcinomas with a PAX8-PPARc rearrange- ment constitute a distinct biological entity. The current data represent one step to elucidate the molecular pathways in the development of FTCs with the specific PAX8-PPARc fusion. Oncogene (2005) 24, 1467–1476.doi:10.1038/sj.onc.1208135 Published online 20 December 2004 Keywords: follicular thyroid carcinomas; fusion onco- gene; PAX8-PPARg; expression array Introduction Human thyroid tumors constitute several different histopathologicalandbiologicalsubtypes,amongwhich the majority of clinically important cancers are of the follicularandpapillarytypes(Gimm,2001).Despitethe presumed common cellular origin of follicular and papillary carcinomas, accumulating evidence indicates that follicular thyroid carcinomas (FTCs) arise through an oncogenic pathway distinct from that of papillary thyroid carcinomas (PTCs). In PTC, oncogenic activa- tion of RET or NTRK1 resulting from chromosomal rearrangements leads to abnormal tyrosine kinase activity (A ˚ man, 1999; Pierotti, 2001; Lui and Dwight, 2003). This functional aberration has been shown to play a pivotal role in PTC oncogenesis. In addition, activatingmutationsof BRAF werereportedrecentlyin a large proportion of PTCs, which may represent an alternative pathway to oncogenic MAPK activation in PTCs without RET- or NTRK1- activation (Cohen et al., 2003; Kimura et al., 2003; Soares et al., 2003; Frattini etal., 2004). The identification of a follicular specific fusion oncogene highlights the importance of chromosomal translocations also in these tumors (Kroll et al., 2000). ThefirstfusiononcogeneidentifiedinFTCinvolvesthe PAX8 (paired box 8) and PPARg (peroxisome prolif- erator-activated receptor gamma) genes, and results from a specific translocation between chromosomes 2 and 3, t(2;3)(q13;p25) (Kroll etal., 2000). Through this translocation, a fusion transcript is expressed in which the 5 0 region of PAX8 is fused in-frame to exon 1 of PPARg. PAX8 encodes a paired domain transcription factor that is essential for normal thyroid development (Poleev etal.,1992). PPARg isamemberofthenuclear hormone receptor subfamily of transcription factors, which is involved in pathways related to cell prolifera- tion and differentiation in various malignancies, in addition to its important role in adipocyte differentia- tionandinsulinsensitization(Manse´n etal.,1996;Fajas et al., 1997, 2001; Lefebvre et al., 1998; Mueller et al., 1998, 2000). PAX8-PPARg rearrangements have been demon- strated in FTCs and follicular adenomas, but not in other types of thyroid tumors or hyperplastic nodules (Kroll et al., 2000; Marques et al., 2002; Nikiforova et al., 2002, 2003; Cheung et al., 2003; Dwight et al, 2003). Screening of large tumor series has identified Received 24 June 2004; revised 3 August 2004; accepted 16 September 2004; published online 20 December 2004 *Correspondence: W-O, Lui; E-mail: weng-onn.lui@cmm.ki.se; wolui@stanford.edu 7 Current address: Department of Pathology, Stanford University SchoolofMedicine,300PasteurDrive,LaneBuilding,L313Stanford CA 94305-5324, USA Oncogene (2005) 24, 1467–1476 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc ONCOGENOMICS