Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome

ContextFor rare and novelRETmutations associated with hereditary medullary thyroid carcinoma (MTC), clinical and functional studies are needed to classify theRETmutation into one of the three clinical risk groups.ObjectiveWe analyzed proliferative properties and clinical implications associated with theRETprotooncogene transmembrane domain mutation S649L.DesignThe transforming potential and mitogenic properties of S649L mutation were investigated clinically and by evaluating kinase activity, cell proliferation, and colony formation.PatientsFifteen individuals from five kindreds were identified as carriers of aRETprotooncogene mutation in exon 11 codon 649 (TCGSer→TTGLeu). In two out of five index patients, a secondRETmutation (C634W or V804L) was detected.ResultsEight 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.RETS649L-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 withRETC634R-expressing cells. When compared withRETC634R, the S649L mutant showed moderate transforming potential with small-sized colonies.ConclusionsOur clinical and in vitro findings indicate that the transmembraneRETS649L mutation is associated with late-onset non-aggressive disease. Recommendations for prophylactic thyroidectomy should be individualized depending on stimulated calcitonin levels.

Download Full-text

Clinical case of familial medullary thyroid carcinoma

Clinical endocrinology and endocrine surgery ◽

10.30978/cees-2021-1-76 ◽

2021 ◽

pp. 76-81

Author(s):

V. Palamarchuk ◽

V. V. Voitenko ◽

N. Shapoval ◽

T. Ogryzko

Keyword(s):

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Clinical Case ◽

Molecular Genetic ◽

Heterozygous State ◽

Prophylactic Thyroidectomy ◽

Medullary Thyroid ◽

Familial Medullary Thyroid Carcinoma ◽

Timely Diagnosis

Medullary thyroid cancer (MTC) accounts for 5—10 % of all thyroid cancers. Most cases are sporadic (75 %), but the proportion of patients with MTC and familial medullary thyroid carcinoma (FMTC) is the highest among any hereditary cancer syndromes (approximately 25 %), and this risk should be considered when evaluating a patient with MTC. In this clinical case study, case of FMTC has been elucidated. Diagnostic criteria of the disease, molecular-genetic aspects, treatment tactics and post-operative observation findings have been presented. The case study illustrates, the efficacy of genomic profiling for the identification of molecular genetic drivers of the disease and its role in ensuring proper and timely diagnosis and treatment of familial form of MTC. When planning prophylactic thyroidectomy, it is recommended to focus on the stratification of the level of RET gene mutation and the timing of prophylactic thyroidectomy as proposed by the American Thyroid Association. The use of molecular genetic investigations in clinical practice for diagnosing MTC makes it possible to objectify the genetic line of the disease in a particular biological family. The patient was found to have a pathogenic germline missense mutation c.2304 G> T (p.E768D, CM020961) in a heterozygous state, which refers to moderate risk of aggressiveness of MTC. In addition, molecular genetic test was performed for the patient's biological child, a 4-year-old girl. Pathogenic mutation was found in the CHEK2 gene, c.47OT> C (p.Ile 157 Thr) in a heterozygous state. These mutations increase the risk of developing breast cancer by 2-3 times, and by 4-5 times in the presence of family history of cancer. The presence of this mutation increases the risk of developing other types of cancers such as stomach, breast, intestinal, prostate and thyroid cancers. Timely diagnosis of FMTC allows to formulate adequate treatment strategy at the preclinical stage of the disease and can significantly improve the quality and duration of life.

Download Full-text