RET codon 804 mutations in multiple endocrine neoplasia 2: genotype-phenotype correlations and implications in clinical management

Mukherjee, Shashwata; Zakalik, Dana

doi:10.1111/j.1399-0004.2010.01453.x

Cited by 24 publications

(11 citation statements)

References 116 publications

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“…The pattern of phenotypic variability (relatively broad age range of MTC diagnosis of 22-70 years) and the breadth of clinical presentation (seen in Table 1) is consistent with patterns observed with other uncommon RET germline mutations associated with MEN2, such as V804M and A883F (21)(22)(23). Further support for a hereditary role is that some of these eight cases exhibited MTC multifocality and/or CCH within their pathology specimen; such characteristics are often associated with hereditary MTC.…”

Section: Discussionsupporting

confidence: 70%

Medullary Thyroid Carcinoma Associated with Germline RET^K666N Mutation

Grubbs

Waguespack

et al. 2016

Thyroid

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Background: Multiple endocrine neoplasia type 2 is an autosomal dominant inherited syndrome caused by activating mutations in the RET proto-oncogene. The RET K666N DNA variant was previously reported in two isolated medullary thyroid carcinoma (MTC) cases, but no family studies are available, and its oncogenic significance remains unknown. Methods: The clinical features, genetic data, and family information of eight index MTC patients with a germline RET K666N variant were assessed. Results: Four probands presented with MTC and extensive nodal metastasis, one with biopsy-confirmed distant metastasis. Two additional probands presented with localized disease. However, nodal status was not available. Of the final two probands, one had an incidental 1.5 mm MTC and C-cell hyperplasia uncovered after surgery for papillary thyroid carcinoma, and one had two foci of MTC (largest dimension 2.3 cm) detected after surgery for dysphagia. Genetic screening identified 16 additional family members carrying the K666N variant (aged 5-90 years), 11 of whom have documented evaluation for MTC. Of these, only two were found to have elevated basal serum calcitonin upon screening, and the remaining patients had calcitonin levels within the reference range. One patient who elected to have a thyroidectomy at 70 years of age was confirmed to have MTC. The other subject, 57 years old, elected surveillance. Four prophylactic thyroidectomies were performed, with one case of C-cell hyperplasia at 20 years and three cases that revealed normal pathology at ages 21, 30, and 30 years. None of the K666N DNA variant carriers had evidence of primary hyperparathyroidism or pheochromocytoma. Conclusions: From this case series, the largest such experience to date, it is concluded that the RET K666N variant is likely pathogenic and associated with low penetrance of MTC. However, the findings are insufficient to define its pathogenicity clearly and make firm recommendations for screening and treatment. Given the potential benefit associated with early detection of aberrant C-cell growth, and the noninvasive nature of genetic testing, ''at risk'' individuals should be screened, and if the K666N variant is identified, they should be managed using a personalized screening approach for detection of MTC.

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Section: Discussionsupporting

confidence: 70%

Medullary Thyroid Carcinoma Associated with Germline RET^K666N Mutation

Grubbs

Waguespack

et al. 2016

Thyroid

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“…Indeed, data from the literature report that the phenotype associated to V804M mutation alone is mostly FMTC [8,9], though also MEN 2A cases have been described [9-11]. However, when this mutation is associated to another on the same allele (Y806C, S904C, E805K, V778I) the phenotype resembles that of MEN 2B [12-16]. …”

Section: European Comments To Ata-r 1-5 and 9-15mentioning

confidence: 99%

The optimal range of RET mutations to be tested: European comments to the guidelines of the American Thyroid Association

2013

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In the 9th ETA-CRN Meeting (September 2009, Lisbon) some recommendations from the American Thyroid Association (ATA) guidelines for the management of medullary thyroid cancer (MTC) were discussed by an European Panel of Experts (EPE). Among the 12 ATA recommendations related to hereditary MTC and to the optimal range of RET mutations to be tested (recommendations 1-5 and 9-15), 7 were shared and 5 were not shared by the EPE. In the present paper, the related comments and suggestions will be reported and discussed.

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“…A single activating mutation on one allele of the RET proto-oncogene is sufficient to induce neoplastic transformation [30]. …”

Section: Genetic Analysis Of Ret Proto-oncogene In Men Typementioning

confidence: 99%

“…FMTC is also associated with non-cysteine mutations in the intracellular tyrosine kinase domain; this includes exon 13 (codons 768, 790, 791), 14 (codon 804) and 15 (codon 891). Recently it has been suggested that FMTC is part of MEN 2A spectrum, indicating variable allelic penetrance [30]. …”

Section: Genetic Analysis Of Ret Proto-oncogene In Men Typementioning

confidence: 99%

“…These mutations alter either adenosine triphosphate binding (codons 768, 790, 791, 804 and 891) or the substrate recognition pocket of the catalytic core (codon 918) resulting in altered substrate specificity of the RET protein. These altered RET isoforms cause aberrant phosphorylation of the substrate and activation of RET signaling pathways that induce cellular transformation [30]. …”

Section: Genetic Analysis Of Ret Proto-oncogene In Men Typementioning

confidence: 99%

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Multiple endocrine neoplasias type 2B and RET proto-oncogene

et al. 2012

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Multiple Endocrine Neoplasia type 2B (MEN 2B) is an autosomal dominant complex oncologic neurocristopathy including medullary thyroid carcinoma, pheochromocytoma, gastrointestinal disorders, marphanoid face, and mucosal multiple ganglioneuromas. Medullary thyroid carcinoma is the major cause of mortality in MEN 2B syndrome, and it often appears during the first years of life. RET proto-oncogene germline activating mutations are causative for MEN 2B. The 95% of MEN 2B patients are associated with a point mutation in exon 16 (M918/T). A second point mutation at codon 883 has been found in 2%-3% of MEN 2B cases. RET proto-oncogene is also involved in different neoplastic and not neoplastic neurocristopathies. Other RET mutations cause MEN 2A syndrome, familial medullary thyroid carcinoma, or Hirschsprung's disease. RET gene expression is also involved in Neuroblastoma. The main diagnosis standards are the acetylcholinesterase study of rectal mucosa and the molecular analysis of RET. In our protocol the rectal biopsy is, therefore, the first approach. RET mutation detection offers the possibility to diagnose MEN 2B predisposition at a pre-clinical stage in familial cases, and to perform an early total prophylactic thyroidectomy. The surgical treatment of MEN 2B is total thyroidectomy with cervical limphadenectomy of the central compartment of the neck. When possible, this intervention should be performed with prophylactic aim before 1 year of age in patients with molecular genetic diagnosis. Recent advances into the mechanisms of RET proto-oncogene signaling and pathways of RET signal transduction in the development of MEN 2 and MTC will allow new treatment possibilities.

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RET codon 804 mutations in multiple endocrine neoplasia 2: genotype-phenotype correlations and implications in clinical management

Cited by 24 publications

References 116 publications

Medullary Thyroid Carcinoma Associated with Germline RET^K666N Mutation

Medullary Thyroid Carcinoma Associated with Germline RET^K666N Mutation

The optimal range of RET mutations to be tested: European comments to the guidelines of the American Thyroid Association

Multiple endocrine neoplasias type 2B and RET proto-oncogene

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RET codon 804 mutations in multiple endocrine neoplasia 2: genotype-phenotype correlations and implications in clinical management

Cited by 24 publications

References 116 publications

Medullary Thyroid Carcinoma Associated with Germline RETK666N Mutation

Medullary Thyroid Carcinoma Associated with Germline RETK666N Mutation

The optimal range of RET mutations to be tested: European comments to the guidelines of the American Thyroid Association

Multiple endocrine neoplasias type 2B and RET proto-oncogene

Contact Info

Product

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Medullary Thyroid Carcinoma Associated with Germline RET^K666N Mutation

Medullary Thyroid Carcinoma Associated with Germline RET^K666N Mutation