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The Ras Effector NORE1A Is Suppressed in Follicular Thyroid Carcinomas with a PAX8-PPAR Fusion

Department of Molecular Medicine and Surgery, Karolinska University Hospital (T.F., G.W., J.G., L.F., W.-O.L., J.Z., C.L.), SE-171 76 Stockholm, Sweden; and Cancer Genetics Unit, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital (A.Y.M.A., R.C.-B., B.G.R.), Sydney, New South Wales 2065, Australia

Address all correspondence and requests for reprints to: Dr. Theodoros Foukakis, Department of Molecular Medicine and Surgery, Karolinska University Hospital, CMM L8:01, SE-171 76 Stockholm, Sweden. E-mail: theodoros.foukakis{at}ki.se.

Context: The Ras effector NORE1A (RASSF5A) is a putative tumor suppressor and is inactivated in several human cancers. NORE1A has not been studied in thyroid cancer.

Objective: The objective of this study was to investigate whether NORE1A is involved in follicular thyroid cancer (FTC) development.

Design: We analyzed NORE1A expression in 25 FTCs, eight follicular thyroid adenomas, and seven normal thyroid tissues by TaqMan quantitative RT-PCR. The results were evaluated in relation to RASSF1A expression, RAS mutations, and PAX8-PPAR fusions assessed in the same material. NORE1A promoter methylation was assessed by the combined bisulfite restriction endonuclease assay.

Results: Although the NORE1A mRNA levels of the majority of the tumors were similar to those in the normal controls, the cases harboring a PAX8-PPAR translocation (n = 6) exhibited dramatically reduced NORE1A expression (P < 0.001). In contrast, RAS mutations (n = 5) and NORE1A down-regulation were mutually exclusive. A significant reduction in the expression of the NORE1A homolog and the bona fide tumor suppressor gene RASSF1A was observed, but with weak correlation to the respective NORE1A values. No NORE1A promoter methylation was detected in the 32 thyroid tumors analyzed.

Conclusions: Our experiments demonstrate the suppression of NORE1A, a known Ras effector, in PAX8-PPAR carrying FTCs.

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