RET Y791F: alone or accompanied?

Dear Editor,

We read with interest the article “Diagnosis, treatment, and follow-up of medullary thyroid carcinoma: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism” recently published in this Journal (¹).

The article was written by Brazilian endocrinologists and surgeons and consists of a consensus of the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism (SBEM). As a full version of it is also available in Portuguese language and free for download, it is definitely a valuable reference to Brazilian doctors in residency trainings and medical specialists in the fields of endocrinology, surgery, oncology and others.

Virtually all individuals carrying a germline mutation in the RETproto-oncogene will develop medullary thyroid carcinoma (MTC) and therefore total prophylactic thyroidectomy is indicated at early ages, based on the specificRET mutations (¹-³).

In this context, we would like to make a comment regarding to the Y791F variant located at the exon 13 of RET. Although initial data regarding this variant indicated that it could be a weak mutation associated with mild forms of the disease (⁴,⁵), recent studies have shown no association of this variant with an increased susceptibility to MTC. Erlic and cols. (⁶) and Toledo and cols. (⁷) have analyzed the frequencies of RET Y791F in large cohorts of tumor free individuals and showed that the variant behaves as a rare non-pathogenic polymorphism rather than a disease-causing mutation. In addition, a thorough review of the literature does not document a link of Y791F (alone) with familial MTC. On the contrary, the reported Y791F carriers who inadvertently underwent thyroidectomy presented no histopathological signs of disease (⁵,⁶).

These data indicate that thyroidectomy should not be recommended to cases with genetic testing results showing RET Y791F (alone). However, especial attention should be taken by Brazilian doctors, geneticists and surgeons, as theRET Y791F variant has been identified in combination with the strong RET C634Y (exon 11) mutation in more than 15 Brazilian families with MTC/MEN2 (⁷,⁸). Noteworthy, this combination changes completely the clinical scenario, and patients with RET C634Y/Y791F should be treated accordingly to the recommendations to cases carrying RET C634 mutations, in which early total thyroidectomy is needed to be performed (¹-³). Therefore, when receiving a genetic testing showing the presence of the RET Y791F variant, it is crucial to make sure that the remaining exons of the gene were completely sequenced as well, to fully certify whether is a Y791F-alone or a RET C634Y/Y791F patient (⁶).

In conclusion, we would like to congratulate the authors for the SBEM consensus and invite all the Brazilian medical doctors and geneticists to read our extended study and review of the literature about RET Y791F, a variant that need to be well understood by the health professionals of our country to the better management of Brazilian patients with MTC and their relatives (⁶).

Funding: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), grant number 401.990/2010-9 and the Fundação de Amparo à Pesquisa do Estado de São Paulo (Fapesp) grants number 2013/01476-9 (to Sergio P. A. Toledo) and 2006/60402-1 and 2010/51547-1 (to Rui M. B. Maciel). Rodrigo A. Toledo has received a Ciências Sem Fronteiras CNPq postdoctoral fellowship and is currently working at the Centro Nacional de Investigaciones Oncológicas (CNIO) in Madrid. Sergio P. A. Toledo is a Senior Professor in the Division of Endocrinology, Department of Medicine, Federal University of São Paulo, SP, Brazil, with a grant from the Programa de Visitante Nacional Sênior – Edital 028/2013 – from the Coordenadoria de Aperfeiçoamentos de Pessoal de Nível Superior (Capes), Brazil.

REFERENCES

• ¹
  Maia AL, Siqueira DR, Kulcsar MA, Tincani AJ, Mazeto GM, Maciel LM. Diagnosis, treatment, and follow-up of medullary thyroid carcinoma: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism. Arq Bras Endocrinol Metabol. 2014;58(7):667-700.
• ²
  Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86(12):5658-71.
• ³
  American Thyroid Association Guidelines Task Force; Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19(6):565-612.
• ⁴
  Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grussendorf M, et al. A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab. 1998;83(3):770-4.
• ⁵
  Gimm O, Niederle BE, Weber T, Bockhorn M, Ukkat J, Brauckhoff M, et al. RET proto-oncogene mutations affecting codon 790/791: A mild form of multiple endocrine neoplasia type 2A syndrome? Surgery. 2002;132(6):952-9.
• ⁶
  Erlic Z, Hoffmann MM, Sullivan M, Franke G, Peczkowska M, Harsch I, et al. Pathogenicity of DNA variants and double mutations in multiple endocrine neoplasia type 2 and von Hippel-Lindau syndrome. J Clin Endocrinol Metab. 2010;95(1):308-13.
• ⁷
  Toledo RA, Hatakana R, Lourenço DM Jr, Lindsey SC, Camacho CP, Almeida M, et al. Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility. Endocr Relat Cancer. 2015;22(1):65-76.
• ⁸
  Toledo RA, Wagner SM, Coutinho FL, Lourenço DM Jr, Azevedo JA, Longuini VC, et al. High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene. J Clin Endocrinol Metab. 2010;95(3):1318-27.
• ⁹
  Valente FO, Dias da Silva MR, Camacho CP, Kunii IS, Bastos AU, da Fonseca CC, et al. Comprehensive analysis of RET gene should be performed in patients with multiple endocrine neoplasia type 2 (MEN 2) syndrome and no apparent genotype-phenotype correlation: an appraisal of p.Y791F and p.C634Y RET mutations in five unrelated Brazilian families. J Endocrinol Invest. 2013;36(11):975-81.

Publication Dates

• Publication in this collection
  Oct 2015

History

• Received
  8 Apr 2015
• Accepted
  21 Apr 2015