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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 5 2318-2326
Copyright © 2003 by The Endocrine Society

RAS Point Mutations and PAX8-PPAR{gamma} Rearrangement in Thyroid Tumors: Evidence for Distinct Molecular Pathways in Thyroid Follicular Carcinoma

Marina N. Nikiforova, Roy A. Lynch, Paul W. Biddinger, Erik K. Alexander, Gerald W. Dorn, II, Giovanni Tallini, Todd G. Kroll and Yuri E. Nikiforov

Department of Pathology and Laboratory Medicine (M.N.N., P.W.B., Y.E.N.) and Division of Cardiology (R.A.L., G.W.D.), University of Cincinnati, Cincinnati, Ohio 45267-0529; Department of Medicine (E.K.A.), Brigham and Women’s Hospital, Boston, Massachusetts 02115; Department of Pathology (G.T.), Yale University School of Medicine, New Haven, Connecticut 06510; and Department of Pathology and Laboratory Medicine (T.G.K.), Emory University School of Medicine, Winship Cancer Institute, Atlanta, Georgia 30322

Address all correspondence and requests for reprints to: Dr. Yuri Nikiforov, Department of Pathology, University of Cincinnati, 231 Albert Sabin Way, P.O. Box 670529, Cincinnati, Ohio 45267-0529. E-mail: yuri.nikiforov{at}uc.edu.

A series of 88 conventional follicular and Hürthle cell thyroid tumors were analyzed for RAS mutations and PAX8-PPAR{gamma} rearrangements using molecular methods and for galectin-3 and HBME-1 expression by immunohistochemistry. A novel LightCycler technology-based method was developed to detect point mutations in codons 12/13 and 61 of the H-RAS, K-RAS, and N-RAS genes. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPAR{gamma} rearrangement, and only one (3%) had both. In follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPAR{gamma} rearrangement, and 48% had neither. Follicular carcinomas with PAX8-PPAR{gamma} typically showed immunoreactivity for galectin-3 but not for HBME-1, tended to present at a younger patient age and be smaller size, and were almost always overtly invasive. In contrast, follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hürthle cell tumors infrequently had PAX8-PPAR{gamma} rearrangement or RAS mutations. These results suggest that conventional follicular thyroid carcinomas develop through at least two distinct and virtually nonoverlapping molecular pathways initiated by either RAS point mutation or PAX8-PPAR{gamma} rearrangement.

This work was supported by NIH Grants R01-CA88041 (to Y.N.) and CA75425 and a Georgia Cancer Coalition Distinguished Clinical Scientist Award (to T.G.K.). Tissue samples were collected in part using a support by a grant from the NIH (PHS M01 RR08084, the Children’s Hospital–University of Cincinnati General Clinical Research Center Tissue Procurement Facility) and through the Cooperative Human Tissue Network (CHTN), which is funded by the National Cancer Institute.

Abbreviations: FMCA, Fluorescence melting curve analysis; FNA, fine-needle aspiration; PPAR, peroxisome proliferator-activated receptor; Tm, melting temperature.




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