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RET/Papillary Thyroid Cancer Rearrangement in Nonneoplastic Thyrocytes: Follicular Cells of Hashimoto’s Thyroiditis Share Low-Level Recombination Events with a Subset of Papillary Carcinoma

J. B. Pierce Laboratory (K.J.R.), School of Medicine Departments of Genetics (Y.Y., M.B.Q.) and Pathology (G.T.), Yale University, New Haven, Connecticut 06520; Institute of Molecular Radiobiology (K.U., V.V., H.Z.), Forschungszentrum für Umwelt und Gesundheit-National Research Center for Environment and Health, D-85764 Neuherberg, Germany; Department of Cellular and Molecular Pathology/Istituto di Endocrinologia ed Oncologia Sperimentale (G.S., A.F., M.S.), Consiglio Nazionale delle Ricerche, Universita di Napoli Federico II, 80131 Naples, Italy; Istituto Nazionale dei Tumori (G.C.), Fondazione Pascale, 80131 Naples, Italy; Kimmel Cancer Center, Department of Microbiology/Immunology and Otolaryngology-Head and Neck Surgery (J.L.R.), Thomas Jefferson University, Philadelphia, Pennsylvania 19107; and Naples Oncogenomic Center-CEINGE (A.F.), Biotecnologie Avanzate, 80145 Naples, Italy

Address all correspondence and requests for reprints to: Giovanni Tallini, M.D., Ospedale Bellaria, Via Altura 3, 40139 Bologna, Italy. E-mail: Giovanni.Tallini{at}ausl.bo.it.

Context: RET/papillary thyroid cancer (PTC) is a marker for papillary thyroid carcinoma, but its specificity has been questioned because of the disputed identification of RET/PTC in Hashimoto’s thyroiditis (HT), oncocytic tumors, and other thyroid lesions.

Objective: The objective of this study was to determine 1) whether RET/PTC occurs in nonneoplastic follicular cells of HT, and 2) its recombination rate in thyroid tumors.

Design/Patients: Forty-three samples from 31 cases of HT were examined using interphase fluorescence in situ hybridization (FISH) with RET probes spanning the breakpoint region; real-time RT-PCR to quantify RET/PTC1, RET/PTC3, and c-RET transcripts; and RT-PCR after laser capture microdissection to enrich samples for follicular cells. The results were compared with those similarly obtained in 34 papillary carcinomas, eight thyroid oncocytic tumors, and 21 normal thyroids.

Results: Normal samples showed no RET rearrangement. Sixty-eight percent (15 of 22) of HT were positive by FISH; in all thyroiditis, signals were localized to rare nonneoplastic follicular cells; low-level RET/PTC was identified in 17% (five of 29) of thyroiditis cases by real-time RT-PCR and in an additional six of 11 real-time negative cases after increasing sensitivity with laser capture microdissection. Low RET/PTC1 levels were detected in 26% (nine of 34) of papillary carcinomas with an expression pattern and proportion of FISH-positive cells similar to those of the thyroiditis. Forty-seven percent (16 of 34) of papillary carcinomas and one oncocytic carcinoma expressed high RET/PTC1 mRNA levels.

Conclusions: Low-level RET/PTC recombination occurs in nonneoplastic follicular cells in HT and in a subset of papillary thyroid carcinomas. RET/PTC expression variability should be taken into account for the molecular diagnosis of thyroid lesions. Overlapping molecular mechanisms may govern early stages of tumor development and inflammation in the thyroid.

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