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This Article Full Text Full Text (PDF) All Versions of this Article: EJE-07-0817v1 158/6/811    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Colombo-Benkmann, M. Articles by Frank-Raue, K. PubMed PubMed Citation Articles by Colombo-Benkmann, M. Articles by Frank-Raue, K.

Characterization of the RET protooncogene transmembrane domain mutation S649L associated with nonaggressive medullary thyroid carcinoma.

Department of General Surgery, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany¹ Department of Vectorology and Experimental Gene Therapy, Rostock University, 18057 Rostock, Germany² Department of Nuclear Medicine,, ³ Department of Internal Medicine,, ⁴ Gerhard-Domagk-Institute of Pathology,, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany⁵ Praxis für Innere Medizin,, Koblenz, Germany⁶ Endokrinologikum Hamburg,, 22767 Hamburg, Germany and ⁷ Endokrinologisch-Humangenetische Gemeinschaftspraxis,, Brückenstrasse 21, 69120 Heidelberg, Germany

(Correspondence should be addressed to K Frank-Raue; Email: karin.frankraue{at}raue-endokrinologie.de)

Context: For rare and novel RET mutations associated with hereditary medullary thyroid carcinoma (MTC), clinical and functional studies are needed to classify the RET mutation into one of the three clinical risk groups.

Objective: We analyzed proliferative properties and clinical implications associated with the RET protooncogene transmembrane domain mutation S649L.

Design: The transforming potential and mitogenic properties of S649L mutation were investigated clinically and by evaluating kinase activity, cell proliferation, and colony formation.

Patients: Fifteen individuals from five kindreds were identified as carriers of a RET protooncogene mutation in exon 11 codon 649 (TCG^SerTTG^Leu). In two out of five index patients, a second RET mutation (C634W or V804L) was detected.

Results: Eight gene carriers were operated on. Histology revealed MTC and C-cell hyperplasia in three index and three screening patients respectively. In all other gene carriers (aged 41–64 years), calcitonin levels were in the normal range, and pentagastrin-stimulated calcitonin levels were <100 pg/ml. Therefore, thyroidectomy had not yet been performed. In one index patient carrying the S649L mutation, hyperparathyroidism was confirmed histologically. RET S649L-expressing NIH3T3 cells exhibited a clear increase of phosphotyrosine and proliferation rate when compared with parental NIH3T3 cells but a significantly lower kinase activity and cell growth rate when compared with RET C634R-expressing cells. When compared with RET C634R, the S649L mutant showed moderate transforming potential with small-sized colonies.

Conclusions: Our clinical and in vitro findings indicate that the transmembrane RET S649L mutation is associated with late-onset non-aggressive disease. Recommendations for prophylactic thyroidectomy should be individualized depending on stimulated calcitonin levels.