NEW MUTATIONS IN THE RET PROTOONCOGENE ASSOCIATED WITH MEDULLARY THYROID CARCINOMA

Rondot S.¹, Lorenz A.¹, Schulze E.¹, Dralle H.², Dohring J.³, Raue F.¹, Frank-Raue K.¹

¹ Endocrine Practice, Molecular Laboratory, Heidelberg, Germany, ²Martin-Luther-University of Halle-Wittenberg, Department of General, Visceral, and Vascular Surgery, Halle/ Saale, Germany, ³Practice for Radiology, Neuroradiology and Nuclear Medicine, Braunschweig, Germany

Context: Clinical studies are needed to classify rare and novel RET mutations associated with hereditary MTC into one of three clinical risk groups.

Objective: We analyzed genotype-phenotype correlations associated with the RET mutations R770Q, Y791 N and L881 V

Case 1: Calcitonin determination in a 44 year old female patient with multinodular goiter showed elevated levels (757 pg/ml; normal range <11 pg/ml). CEA was also elevated (27.6 ng/ml «2.5 ng/ml). RET analysis revealed a new mutation in exon 13 R770Q (CGA>CAA). Screening of the sister of the index patient revealed surprisingly another, previously not described amino-acid substitution Y791 N (TAT791 AAT) in the RET protooncogene.ln the parents the R770Q mutation was detected in the mother, the Y791 N mutation in the father. In the index case a thyroidectomy with central and lateral node dissection was done. Histology revealed MTC in a mixed variance with follicular cancer of 2 cm diameter, no lymph node involvement in 26 removed lymph nodes (T1 NOMO). Postoperatively there is no increase of calcitonin after pentagastrin stimulation, the patient is biochemically cured concerning MTC In all other gene carriers (aged 44-70 years), calcitonin levels were in the normal range, therefore, thyroidectomy had not yet been performed.

Case 2: A 46 year old female patient was operated on MTC by thyroidectomy, central and left lateral lymph node dissection. Histology revealed a microcarcinoma with one lymph node metastasis (T1 N1 (1/8)Mx). Postoperative calcitonin determination showed elevated levels (basal 39.5 pg/ml, stimulated 77.8 pg/ml), CEA was also elevated (5.7 ng/ml). There are no signs for primary hyperparathyroidism or pheochromocytoma. The patient is not cured concerning MTC, therefore a lymphadenectomy is planned. RET analysis revealed a new mutation in exon 15 L881V (CTG>GTG). One 20 year old son also carries the mutation, his calcitonin levels are normal. Calcitonin levels of the parents were normal, therefore RET mutation analysis was not performed.

Conclusions: Our clinical findings indicate that the RET R770Q and the L881 V mutations may be associated with late-onset nonaggressive disease. For the Y791 N mutation no association with MTC could be detected. The recommendations for prophylactic thyroidectomy should be individualized depending on stimulated calcitonin levels.