Analysis of RET proto-oncogene abnormalities in patients with MEN 2A, MEN 2B, familial or sporadic medullary thyroid carcinoma

Chiefari, Eusebio; Russo, Diego; Giuffrida, Dario; Zampa, G. A.; Meringolo, Domenico; Arturi, Franco; Chiodini, Iacopo; Bianchi, Davide Gianluca; Attard, Marco; Trischitta, Vincenzo; Bruno, Rocco; Giannasio, P.; Pontecorvi, Alfredo

doi:10.1007/bf03350771

Cited by 40 publications

(24 citation statements)

References 19 publications

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“…Somatic RET mutations at codons 608, 611, 618, 629, 630, 634, 639, 641, 918, or 922 are found in approximately 25% of patients with sporadic MTC, with mutations at codon 918 occurring most frequently (81)(82)(83)(84)(85)(86)(87)(88)(89). As with germline 918 mutations, the somatic 918 mutations are associated with aggressive MTC behavior (9,90).…”

Section: Germline and Somatic Mutationsmentioning

confidence: 99%

RETProto-Oncogene: A Review and Update of Genotype–Phenotype Correlations in Hereditary Medullary Thyroid Cancer and Associated Endocrine Tumors

Kouvaraki

Shapiro

Perrier

et al. 2005

Thyroid

267

193

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Hereditary medullary thyroid carcinoma (MTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. Associations between specific RET mutations (genotype) and the aggressiveness of MTC and presence or absence of other endocrine neoplasms (phenotype) are well documented. Mutations in six exons (10, 11, 13, 14, 15, and 16) located in either cysteine-rich or tyrosine kinase domains cause one of three distinctive clinical subtypes: familial MTC, multiple endocrine neoplasia (MEN) type 2A (including variants with Hirschsprung's disease and cutaneous lichen amyloidosis), and MEN 2B. Hallmarks of MEN 2A include MTC, pheochromocytoma, and hyperparathyroidism. MEN 2B is associated with an earlier onset of MTC and pheochromocytoma, the absence of hyperparathyroidism, and the presence of striking physical stigmata (e.g., coarse facies, ganglioneuromatosis, and marfanoid habitus). Familial MTC is not associated with other endocrine neoplasms; however, the accurate distinction between familial MTC and MEN 2A may be difficult in kindreds with small size, incomplete histories, or a predominance of young individuals who may not have yet fully manifested the syndrome. Genetic testing detects greater than 95% 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 the extent of surgery are based upon a model that utilizes genotype-phenotype correlations to stratify mutations into three risk levels. 531

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Section: Germline and Somatic Mutationsmentioning

confidence: 99%

RETProto-Oncogene: A Review and Update of Genotype–Phenotype Correlations in Hereditary Medullary Thyroid Cancer and Associated Endocrine Tumors

Kouvaraki

Shapiro

Perrier

et al. 2005

Thyroid

267

193

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“…MEN2 patients most commonly develop MTC and pheochromocytoma (adrenal tumors). The importance of Ret in these tumors became evident with the discovery that sporadic MTC and pheochromocytomas frequently harbor Ret mutations (Chiefari et al 1998;Scurini et al 1998). Both tumor types show secondary somatic chromosomal deletions, suggesting a role for tumor suppressors in tumor initiation or progression, but the identities of such genes are unknown (Khosla et al 1991;Mulligan et al 1993a;Marsh et al 2003).…”

Section: Genementioning

confidence: 99%

“…MEN2B patients possess mutations that cluster within the tyrosine kinase domain, most commonly a methionine-to-threonine substitution (M918T) and, less frequently, mutations such as A883F or V804M and Y806C/S904C (Carlson et al 1994b;Eng et al 1994;Hofstra et al 1994;Smith et al 1997;Miyauchi et al 1999;Menko et al 2002). Sporadic MTC and papillary thyroid carcinoma also display dominant activating Ret mutations (Grieco et al 1990;Bongarzone et al 1994;Chiefari et al 1998;Scurini et al 1998).…”

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confidence: 99%

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

Read¹,

et al. 2005

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Dominant mutations in the Ret receptor tyrosine kinase lead to the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that Ret MEN2 mutations significantly alter Ret-signaling properties, but the precise mechanisms by which Ret MEN2 promotes tumorigenesis remain poorly understood. To determine the signal transduction pathways required for Ret MEN2 activity, we analyzed analogous mutations in the Drosophila Ret ortholog dRet. Overexpressed dRet MEN2 isoforms targeted to the developing retina led to aberrant cell proliferation, inappropriate cell fate specification, and excessive Ras pathway activation. Genetic analysis indicated that dRet MEN2 acts through the Ras-ERK, Src, and Jun kinase pathways. A genetic screen for mutations that dominantly suppress or enhance dRet MEN2 phenotypes identified new genes that are required for the phenotypic outcomes of dRet MEN2 activity. Finally, we identified human orthologs for many of these genes and examined their status in human tumors. Two of these loci showed loss of heterozygosity (LOH) within both sporadic and MEN2-associated pheochromocytomas, suggesting that they may contribute to Ret-dependent oncogenesis. D URING development, receptor tyrosine kinases (RTKs) integrate extracellular signals to influence cellular processes such as growth and differentiation. Signaling through RTKs requires ligand-induced oligomerization to direct tyrosine autophosphorylation; autophosphorylation both stimulates catalytic activity and creates phospho-tyrosine docking sites for cytoplasmic proteins that activate intracellular signaling pathways. To date, mutations in more than half of all RTKs have been implicated in human cancer (reviewed in Blume-Jensen and Hunter 2001). These mutations commonly function by relieving RTK regulatory constraints, leading to inappropriate kinase activity and hyperactivation of downstream pathways. These events promote oncogenic transformation by driving aberrant cellular growth, proliferation, and survival. Still, tumorigenesis requires mutations in multiple loci: along with dominant mutations in oncogenes such as RTKs, tumorigenesis also requires loss-of-function mutations in tumor suppressors. The relationship between oncogenic tyrosine kinases and tumor suppressors, and the extent to which mutations in each cooperate to direct oncogenic growth, is not well understood.The Ret RTK plays an essential role in both development and oncogenesis. During embryogenesis, Ret is required for development of the sympathetic and enteric nervous systems, the neural crest, and the excretory system (Schuchardt et al. 1994;Durbec et al. 1996;Enomoto et al. 2001). The extracellular portion of Ret contains cysteine repeats and a cadherinlike domain. The intracellular portion of Ret contains a tyrosine kinase catalytic domain and multiple tyrosine autophosphorylation sites. Four activating ligands have been identified: GDNF, Neurturin, Persephin, and Artemin all activate Ret through the GPI-linked co-

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“…For amplification of the exons 13 and 14 DNA segments the following primers were used: primers 13F (5 -CTCTCTGTCTGAACTTGGGC), 13R (5 -TCACCC TGCAGCAGGCCTTA), 14F (5 -TGGCTCCTGGAA GACCCA) and 14R (5 -AGAGCCATATGCACG CAC) (Chiefari et al 1998).…”

Section: Pcr Amplificationmentioning

confidence: 99%

Molecular genetic diagnostic program of multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma syndromes in Hungary

Klein

Ésik²,

Homolya

et al. 2001

Journal of Endocrinology

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Medullary thyroid carcinoma (MTC) occurs usually in sporadic form, but about a quarter of the cases are hereditary and appear as part of one of the multiple endocrine neoplasia type 2 (MEN2) syndromes. Mutations in the RET protooncogene are known to be the cause of the MEN2A and familial medullary thyroid carcinoma (FMTC) syndromes in the majority of the families. Direct DNA testing allows prophylactic thyroidectomy to be offered to individuals carrying a mutation in the above codons, and in mutation-negative cases it reduces the yearly screening-related burden on family members at risk of the disease. By DNA sequencing and PCR-restriction fragment length polymorphisms, 65 MTC probands were examined for mutations in residues 609, 611, 618, 620 of exon 10, and in residues 634, 768, 804 of exons 11, 13, and 14 respectively of the RET protooncogene. In our study, mutations in the above codons were detected in all of the 14 clinically MEN2A and FMTC families. One of these mutations, TGC609 TCC has not been reported previously. Of the 14 probands with the mutation, 25 relatives also had the identified mutation and 18 relatives proved to be non-carriers. Among the 51 probands with clinically sporadic MTC, none was found to carry a mutation in the above positions even if indirect signs of MTC, pheochromocytoma or hyperparathyroidism could be detected in some families. The frequency of the TGC634AGC mutation is unexpectedly high in our samples, which can probably be attributed to a founder effect. We conclude that screening for mutations in these codons is effective in families fulfilling the strict clinical criteria of MEN2A or FMTC.

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Analysis of RET proto-oncogene abnormalities in patients with MEN 2A, MEN 2B, familial or sporadic medullary thyroid carcinoma

Cited by 40 publications

References 19 publications

RETProto-Oncogene: A Review and Update of Genotype–Phenotype Correlations in Hereditary Medullary Thyroid Cancer and Associated Endocrine Tumors

RETProto-Oncogene: A Review and Update of Genotype–Phenotype Correlations in Hereditary Medullary Thyroid Cancer and Associated Endocrine Tumors

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

Molecular genetic diagnostic program of multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma syndromes in Hungary

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