Mutations of the ret protooncogene in German multiple endocrine neoplasia families: relation between genotype and phenotype. German Medullary Thyroid Carcinoma Study Group.

Frank‐Raue, Karin; Höppner, Wolfgang; Frilling, A.; Kotzerke, Jörg; Dralle, Henning; Haase, Richard F.; Mann, Klaus; Seif, F. J.; Kirchner, R.; Rendl, J.; Deckart, H; Ritter, Michael M.; Hampel, Harald; Klempa, J; Scholz, Gerhard H.; Raue, F.

doi:10.1210/jcem.81.5.8626834

Cited by 71 publications

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“…There is controversy regarding whether the C634R mutation confers a greater risk of developing parathyroid disease (4,7,9,24,25). Our investigation showed a significantly higher HPT prevalence in C634R carriers than in those with the C634Y mutation, despite the fact that more patients above the age of 40 years harboured the C634Y mutation and that the risk of developing HPT increases beyond this age.…”

Section: Discussionmentioning

confidence: 50%

RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation

Valdés

Navarro

Mesa

et al. 2015

European Journal of Endocrinology

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Objective: Specific germline mutations in the RET proto-oncogene are correlated with clinical features in multiple endocrine neoplasia type 2A (MEN2A); however, data are scarce regarding differences in clinical profiles dependent on the type of nucleotide and amino acid substitution at the same codon. We aimed to analyse differences in clinical risk profiles and outcomes among different amino acids encoded by codon 634. Design: The study was retrospective and multicentric. Methods: We collected data included in the Spanish Online National Database from patients with MEN2A carrying a RET proto-oncogene mutation on codon 634. The mean follow-up time was 7.6G6.9 years (1-32). Results: Patients (nZ173) from 49 unrelated families were C634Y carriers, and 26 patients from eight different families had C634R mutation. We found higher penetrance of medullary thyroid carcinoma, phaeochromocytoma and hyperparathyroidism (P!0.001, PZ0.007 and P!0.001 respectively) in C634R carriers than in C634Y carriers. The Kaplan-Meier estimate of cumulative lymph node and distant metastases rates showed that these events occurred earlier in patients harbouring the C634R mutation (P!0.001). A multivariate adjusted Cox regression analysis indicated that the C634R mutation was an independent factor for persistent/recurrent disease (hazard ratio, 3.17; 95% CI: 1.66-6.03; P!0.001). Conclusions: Our results suggest that there could be clinical differences caused by different amino acid substitutions at codon 634; specifically, the C634R mutation was associated with a more aggressive MEN2A phenotype than the C634Y mutation.

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Section: Discussionmentioning

confidence: 50%

RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation

Valdés

Navarro

Mesa

et al. 2015

European Journal of Endocrinology

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“…The most common mutation of codon 634 is TGC-CGC (Cys-Arg), it has been associated with pheochromocytoma and parathyroid gland involvement with MEN 2A families [17][18][19]. Therefore, individuals with this mutation should be annually screened for these endocrinopathies.…”

Section: Genotype Phenotype Correlationmentioning

confidence: 99%

Update multiple endocrine neoplasia type 2

2010

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Multiple endocrine neoplasia type 2 (MEN2) is a autosomal dominat inherited tumour-syndrome caused by germline activating mutations of the RET proto-oncogene on chromosome 10. It is clinically characterized by the presence of medullary thyroid carcinoma (MTC), bilateral pheochromocytoma and primary hyperparathyroidism (MEN2A) within a single patient. Three distinct clinical forms have been described depending on the phenotype: the classical MEN 2A, MEN 2B, an association of MTC, pheochromocytoma and mucosal neuroma, (FMTC) familial MTC with a low incidence of other endocrinopathies. Each variant of MEN2 results from different RET gene mutation, with a good genotype phenotype correlation. Genetic testing detects nearly 100% of mutation carriers and is considered the standard of care for all first degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on a classification into four risk levels utilizing the genotype-phenotype correlations. MEN 2 gives a unique model for early prevention and cure of cancer and for stratified roles of mutation-based diagnosis of carriers.

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“…Allelic germline mutations of the RET proto-oncogene are responsible for the three MEN 2 variants (Donis-Keller et al, 1993;Mulligan et al, 1993;Carlson et al, 1994;Eng et al, 1994;Hofstra et al, 1994) and a recent survey of a large panel of MEN 2 families supports the existence of a correlation between the position and nature of the RET mutations and the clinical phenotype (Eng et al, 1996). The vast majority of MEN2A and FMTC mutations aects one of six juxtamembrane cysteines (Cys 609, 611, 618, 620, 630 and 634) and these mutations result in the substitution of a cysteine for a Correspondence: M Billaud The ®rst two authors contributed equally to this paper Received 24 July 1997; revised 9 June 1998; accepted 12 June 1998 Oncogene (1998) et al, 1994a; Schuffenecker et al, 1994;Eng et al, 1996;Frank-Raue et al, 1996). However, mutations at codon specifying cysteine 634 occur in 85% of MEN 2A cases, whereas mutations causing FMTC are more evenly distributed among codons 618, 620 and 634 (Eng et al, 1996).…”

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Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines

Chappuis-Flament

Pasini

et al. 1998

Oncogene

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The RET gene encodes a receptor tyrosine kinase whose function is essential during the development of kidney and the intestinal nervous system. Germline mutations aecting one of ®ve cysteines (Cys609, 611, 618, 620 and 634) located in the juxtamembrane domain of the RET receptor are responsible for the vast majority of two cancer-prone disorders, multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC). These mutations lead to the replacement of a cysteine by an alternate amino acid. Mutations of the RET gene are also the underlying genetic cause of Hirschsprung disease (HSCR), a congenital aganglionosis of the hindgut. In a fraction of kindreds, MEN 2A cosegregate with HSCR and aected individuals carry a single mutation at codons 609, 618 or 620. To examine the consequences of cysteine substitution on RET function, we have introduced a Cys to Arg mutation into the wild-type RET at either codons 609, 618, 620, 630 or 634. We now report that each mutation induces a constitutive catalytic activity due to the aberrant disul®de homodimerization of RET. However, mutations 630 and 634 activate RET more strongly than mutations 609, 618 or 620 as demonstrated by quantitative assays in rodent ®broblasts and pheochromocytoma PC12 cells. Biochemical analysis revealed that mutations 618 and 620, and to a lesser extent mutation 609, result in a marked reduction of the level of RET at the cell surface and as a consequence decrease the amount of RET covalent dimer. These ®ndings provide a molecular basis explaining the range of phenotype engendered by alterations of RET cysteines and suggest a novel mechanism whereby mutations of cysteines 609, 618 and 620 exert both activating and inactivating eects.Keywords: MEN 2; Hirschsprung disease; RET receptor; tyrosine kinase IntroductionMutations in the RET proto-oncogene, which encodes a transmembrane protein tyrosine kinase, cause two inherited neural crest disorders: multiple endocrine neoplasia type 2 (MEN 2) and Hirschsprung disease (HSCR). Recent studies have provided evidence that RET is a component of a multi-subunit complex which acts as a receptor for the Glial cell-line Derived Neurotrophic Factor (GDNF) and for neurturin, two homologous members of the transforming growth factor b (TGF-b) family (reviewed in Lindsay and Yancopoulos, 1996. For references see Milbrandt et al., 1998). GDNF and neurturin-binding require accessory receptors called GFRa-1 and GFRa-2 that associate with RET and are anchored to the plasma membrane via a glycosyl ± phosphatidylinositol linkage (reviewed in Lindsay and Yancopoulos, 1996. For references see Milbrandt et al., 1998). Mice homozygous for a disruptive mutation either in the RET or the GDNF gene show renal agenesis or dysgenesis of the kidneys and lack the intestinal nervous system (reviewed in Lindsay and Yancopoulos, 1996). These results indicate that RET and GDNF play a critical role during renal organogenesis and are required for the development of a subset of vagal neural crest cells.MEN 2 is a f...

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Mutations of the ret protooncogene in German multiple endocrine neoplasia families: relation between genotype and phenotype. German Medullary Thyroid Carcinoma Study Group.

Cited by 71 publications

References 0 publications

RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation

RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation

Update multiple endocrine neoplasia type 2

Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines

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