Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study

Abstract

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.

Primary hyperparathyroidism as first manifestation in multiple endocrine neoplasia type 2A: an international multicenter study

“…In our overall cohort, the most frequently mutated codon was 634, followed by codons 804, 618, 620, 790, 611, 891, 609, 768 and other rarely mutated codons. With only minor differences, likely accounted for by founder effects, the distribution of mutations in our cohort is, by and large, comparable to that of series in the literature (7,17,19,20,21,38,39,40,41,42,43,44,45).…”

“…Data were drawn from the registry of each center. Some of the patients have been reported on previous occasions and updated data were obtained (17,18,19,20,21,22,23,24,25,26).…”

Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives

“…The clinical course of MTC in patients with MEN 2A is variable, and the disease progression is associated with codon-specific mutations in the RET proto-oncogene (Eng et al 1996a, Machens et al 2003. Approximately 98% of MEN 2A is associated with RET mutations in the cysteinerich extracellular domain, particularly in exons 10 and 11, codons 609, 611, 618, 620, and 634, which is responsible for at least 85% of MEN 2A cases and correlated with the presence of PHEO, HPT, and CLA (Eng et al 1996b, Raue & Frank-Raue 2009, Scapineli et al 2016, Maciel et al 2019. Amino acid change in the intracellular domain of RET in exon 13 (codons 768,790 and 791), exon 14 (codons 804 and 844) and exon 15 (codon 891) are less frequent.…”

“…Amino acid change in the intracellular domain of RET in exon 13 (codons 768,790 and 791), exon 14 (codons 804 and 844) and exon 15 (codon 891) are less frequent. Mutations in exon 8 (codon 533) is rare, but they have been described in a large Brazilian family (Da Silva et al 2003) and are most prevalent in familial cases in the Greek population (Sarika et al 2015, Maciel et al 2019. In 2-5% of cases of apparently hereditary MTC, no RET mutations are found (Leboulleux et al 2004).…”

Using genetics to inform the pharmacological targeting of neuroendocrine neoplasms

“…Hereditary MTC (20-25% of tumours) appears as part of multiple endocrine neoplasia syndrome type 2 (MEN2), which can be sub-classified into MEN2A or MEN2B (Ceolin et al 2019). The disease progression of MTC in MEN2A is associated with the RET codon in which the causal mutation exists -the vast majority affect the cysteine-rich extracellular domain, although amino acid changes in codons 768, 790, 791, 804, 844 and 891 have been seen and mutations in non-cysteine codons appear to lower aggressiveness (Machens et al 2003, Maciel et al 2019.…”