RET Codon 634 Mutations in Multiple Endocrine Neoplasia Type 2: Variable Clinical Features and Clinical Outcome

Abstract

Since the establishment of a protocol for molecular analysis of hereditary medullary thyroid carcinoma (MTC) in southern Brazil, in 1997, 17 independent families with RET germline mutation have been identified. Because neither molecular diagnosis nor the pentagastrin test were available before the establishment of this protocol, we had the opportunity to observe a large number of patients in whom the disease has evolved naturally without medical intervention, namely prophylactic thyroidectomy. We observed a wide spectrum in terms of clinical presentation and natural course of the disease even among genetically related individuals. Sixty-nine individuals from 12 different families presented a codon 634 mutation, the most prevailing missense mutation in our series. The specific mutations identified were C634Y (n = 49), C634R (n = 13), and C634W (n = 7). Individuals with the C634R mutation presented significantly more distant metastases at diagnosis than subjects with the C634Y or C634W mutations (54.5% vs. 19.4% vs. 14.3%, respectively, P = 0.03). Further analysis of the estimated cumulative frequency of lymph node and/or distant metastases by Kaplan-Meier curves showed that the appearance of lymph nodes and metastases occurred later in patients with C634Y than in those with C634R (P = 0.001). Our results suggest that specific nucleotide and amino acid exchanges at codon 634 might have a direct impact on tumor aggressiveness in MEN 2A syndrome.

A Rare Case of De novo C634G Germline Mutation of the RET Proto-Oncogene in a Patient With MEN 2A Syndrome With Aggressive Pheochromocytoma

“…The most penetrant mutation, which also confers the most aggressive phenotype, was found to be Cys634 Arg [8,10,11]. This feature was further supported by another study, which showed that the patients with Cys634Arg mutation had more distant MTC metastases at the time of diagnosis than those with the Cys634Tyr or Cys634Trp mutations and that the metastases developed earlier in patients with Cys634Arg mutations than in those affected by Cys634Tyr mutation [12]. The very low number of identified cases of families with the Cys634Gly mutation makes it improbable to predict the phenotypic and clinical behavior determined by this mutation, despite the fact that one study has suggested that this unique mutation might be associated with early MTC development and high consecutive risk of lymph nodes dissemination [13].…”

Characterization of Wild-Type and Mutated RET Proto-Oncogene Associated with Familial Medullary Thyroid Cancer

“…Specific nucleotide and amino acid exchanges at codon634leads in ligand-independent receptor dimerization and auto-phosphorylation, converting the mutated allele to a dominant transforming gene (Asai et al, 1995), and might have a direct impact on tumor aggressiveness in MEN 2A syndrome (Punales et al, 2003). Previously, it has been clearly suggested that C.G2251A (P.G691S) mutation of the RET is related to the early appearance of symptoms in MEN 2A patients; therefore, it is not oncogenic per se (Borrello et al, 2011), and may consider as a low penetrance gene or genetic modifier that associates with a small to moderate increased risk for developing a MTC (Robledo et al, 2003).…”

Screening of RET gene mutations in multiple endocrine neoplasia type-2 using Conformation Sensitive Gel Electrophoresis (CSGE)

“…Several Brazilian studies on MEN2 have been recently published, in which clinical and genetic aspects of MEN2 were extensively reviewed (2)(3)(4)(5)(7)(8)(9)(10)(11)(12)(13)(14). All clinical variants of MEN2 have a high penetrance rate for MTC and most (90%) RET mutation carriers will exhibit evidence for MTC during their lifetime (15).…”

“…Briefly, MEN2A comprises 75% of MEN2 cases and most cases (98%) harbor a RET mutation in exons 10 or 11 (codons 609, 611, 618, 620, 630, and 634). RET variants in codon 634 cause 85% of MEN2A cases, mostly with the Cys634Arg and Cys634Tyr mutations (1,7). Furthermore, FMTC cases comprise 20% of MEN2 patients and most of them (85%) have RET mutations in codons 10 or 11 (1,8,15).…”

“…Furthermore, FMTC cases comprise 20% of MEN2 patients and most of them (85%) have RET mutations in codons 10 or 11 (1,8,15). Less frequent mutations in codons 609, 611, 768, and 804 are usually associated with FMTC, but rarely to MEN2A (1,7). Met918Thr (exon 16) mutation has been reported in 95% of MEN2B cases, which comprise 5% of MEN2 cases (1,15).…”