New Mutations in the RET Protooncogene-L881V – Associated with Medullary Thyroid Carcinoma and -R770Q – in a Patient with Mixed Medullar/Follicular Thyroid Tumour

Abstract

Clinical studies are needed to classify rare and novel RET mutations associated with hereditary medullary thyroid carcinoma (MTC) into one of the clinical risk groups. Here we describe two new RET mutations/variants, R770Q and L881V, in patients with MTC and analyzed genotype-phenotype correlations associated with these RET mutations in the gene carriers.

Family 1: Calcitonin screening in a 42-year-old female patient with multinodular goiter showed elevated levels. RET mutation analysis revealed a new variant in exon 13 R770Q (CGA>CAA) in the patient. A thyroidectomy with central and lateral node dissection was done. Histology showed MTC in a mixed variance with follicular cancer of 2 cm diameter (T2N0M0). Postoperatively there was no increase of calcitonin after pentagastrin stimulation. The patient is biochemically cured concerning MTC and FTC after radioiodine therapy. In the sister of the index patient surprisingly another, previously not described amino-acid substitution Y791N (TAT><) in the RET protooncogene was found. In the parents the R770Q variant was detected in the mother, the Y791N mutation in the father. Another sister carries the R770Q variant. In all other gene carriers (aged 44–70 years), calcitonin levels were in the normal range, therefore, thyroidectomy had not yet been performed.

Family 2: In a 46-year-old female patient with nodular goiter thyroidectomy, central and left lateral lymph node dissection was done because of elevated calcitonin levels. Histology revealed a microcarcinoma with one lymph node metastasis (T1N1(1/8)Mx). RET analysis revealed a new mutation in exon 15 L881V (CTG>GTG). The L881V mutation was detected in five other family members. In the first generation stimulated calcitonin levels were in the normal range, therefore thyroidectomy had not yet been performed. In the sons of the index case thyroidectomy revealed CCH in the older one, no MTC in both. In a cousin thyroidectomy is intended because of elevated basal and stimulated calcitonin.

Conclusion: Our clinical findings indicate that the L881V mutation may be associated with late-onset nonaggressive disease. If the germline RET R770Q variant has a causative role in the pathogenesis of the mixed medullar/follicular derived histology of the thyroid tumour in the index patient of family 1 has to be proven. The recommendations for prophylactic thyroidectomy in these mutations should be individualized depending on basal and stimulated calcitonin levels until more data are available.

Key words

medullary thyroid carcinoma - RET mutation - multiple endocrine - neoplasia type 2

References

• 1 Mulligan LM, Kwok JBJ, Healey CS. et al . Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2a (MEN 2A).  Nature. 1993;  363 458-469
• 2 Donis-Keller H, Dou S, Chi D. et al . Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.  Hum Mol Gen. 1993;  2 851-856
• 3 Wells SA, Chi DD, Toshima K. et al . Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2a.  Ann Surg. 1994;  220 237-250
• 4 Skinner MA, Moley JA, Dilley WG. et al . Prophylactic thyroidectomy in multiple endocrine neoplasia type 2.  N Engl J Med. 2005;  353 1105-1113
• 5 Machens A, Niccoli-Sire P, Hoegel J. et al. . For the European Multiple Endocrine neoplasia (EUROMEN) Study Group   Early malignant progression of hereditary medullary thyroid cancer.  N Engl J Med. 2003;  349 1517-1525
• 6 Brandi ML, Gagel RF, Angeli A. et al . Guidelines for diagnosis and therapy of MEN Type 1 and Type 2.  J Clin Endocrinol Metab. 2001;  86 5658-5671
• 7 Kloos RT, Eng C, Evans DB. et al . Medullary thyroid Cancer: Management guidelines of the American Thyroid Association.  Thyroid. 2009;  19 565-612
• 8 Frank-Raue K, Rondot S, Höppner W. et al . Coincidence of multiple endocrine neoplasia type 1 and 2: mutations in the RET proto-oncogene and MEN 1 tumor suppessor gene in a family presenting with recurrent primary hyperparathyroidism.  J Clin Endocrinol Metab. 2005;  90 4063-4067
• 9 Luboshitzky R, Dharan M. Mixed follicular-medullary thyroid carcinoma: a case report.  Diagn Cytopathol. 2004;  30 122-124
• 10 Kostoglou-Athanassiou I, Athanassiou P, Vecchini G. et al . Mixed medullary-follicular thyroid carcinoma. Report of a case and review of the literature.  Horm Res. 2004;  61 300-304
• 11 Trincado P, Lopez JM, Mosso L. et al . Thyroid neoplasm of mid follicular-medullary type; an uncommon, particular and aggressive form: report of 3 cases.  Rev Med Chil. 1997;  125 1371-1376
• 12 Elisei R, Pinchera A, Romei C. et al . Expression of thyrotropin receptor (TSH-R), thyroglobulin, thyroperoxidase, and calcitonin messenger ribonucleic acids in thyroid carcinomas: evidence of TSH-R gene transcript in medullary histotype.  J Clin Endocrinol Metab. 1994;  78 867-871
• 13 Frank-Raue K, Machens A, Scheuba C. et al. . Raue F and the MEN2study Group   Difference in development of medullary thyroid carcinoma among carriers of RET mutations in codons 790 and 79.  Clin Endocrinol. 2008;  69 259-263
• 14 Colombo-Benkmann M, Li Z, Riemann B. et al . Characterization of the RET Protooncogene Transmembrane Domain Mutation S649L Associated with Nonaggressive Medullary Thyroid Carcinoma.  Eur J Endocrinol. 2008;  158 811-816
• 15 Smith DP, Houghton C, Ponder JB. Germline mutation of RET codon 883 in two cases of de novo MEN 2B.  Oncogene. 1997;  15 1213-1217
• 16 Elisei R, Cosci B, Romei C. et al . Identification of a novel point mutation in the RET gene (Ala883Thr), which is associated with medullary thyroid carcinoma phenotype only in homozygous condition.  J Clin Endocrinol Metab. 2004;  89 5823-5827
• 17 Bugalho MJ, Coelho I, Sobrinho LG. Somatic trinucleotide change encompassing codons 882 and 883 of the RET proto-oncogene in a patient with sporadic medullary thyroid carcinoma.  Eur J Endocrinol. 2000;  142 573-575
• 18 Frank-Raue K, Buhr H, Dralle H. et al . Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype.  Eur J Endocrinol. 2006;  155 229-236

Correspondence