Three novel mutations in the RET proto-oncogene

Калинин, В. Н.; Amosenko, F. A.; Shabanov, M; Lubchenko, L. N.; Hosch, Stefan B.; Gar'kavtseva, R F; Izbicki, J. R.

doi:10.1007/s001090100250

Cited by 23 publications

(11 citation statements)

References 14 publications

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“…3C). Consistent with this, mutations of serine 922, to either phenylalanine or proline, have been detected in sporadic medullary thyroid carcinoma (37,38), indicating that mutations of this residue may also be transforming in vivo. Conversely, whereas I913A and Y928A mutants retained some ability to autophosphorylate and bind substrate, they did not promote growth in soft agar assays, even on ligand stimulation (Fig.…”

Section: Discussionsupporting

confidence: 61%

Molecular Mechanisms of RET Receptor–Mediated Oncogenesis in Multiple Endocrine Neoplasia 2B

Gujral¹,

Singh

Jia

et al. 2006

Cancer Research

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Multiple endocrine neoplasia 2B (MEN 2B) is an inherited syndrome of early onset endocrine tumors and developmental anomalies. The disease is caused primarily by a methionine to threonine substitution of residue 918 in the kinase domain of the RET receptor (2B-RET); however, the molecular mechanisms that lead to the disease phenotype are unclear. In this study, we show that the M918T mutation causes a 10-fold increase in ATP binding affinity and leads to a more stable receptor-ATP complex, relative to the wild-type receptor. Further, the M918T mutation alters local protein conformation, correlating with a partial loss of RET kinase autoinhibition. Finally, we show that 2B-RET can dimerize and become autophosphorylated in the absence of ligand stimulation. Our data suggest that multiple distinct but complementary molecular mechanisms underlie the MEN 2B phenotype and provide potential targets for effective therapeutics for this disease.

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Section: Discussionsupporting

confidence: 61%

Molecular Mechanisms of RET Receptor–Mediated Oncogenesis in Multiple Endocrine Neoplasia 2B

Gujral¹,

Singh

Jia

et al. 2006

Cancer Research

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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%

“…A few patients with MEN 2B may also have a mutation in colon 883 (intracellular tyrosine kinase domain, exon 15) (10,95,(113)(114)(115). Several authors have previously described codon 922 in association with MEN 2B; however, these reports included patients with either somatic codon 922 mutations present only within tumor cells or a compound heterozygous genotype with germline codon 918 and 922 mutations (84,(116)(117)(118). Kitamura et al (118) found that the codon 922 mutation, which was maternally inherited (the codon 918 mutation occurred de novo in the patient), did not cause features of MEN 2B in the patient's mother and, therefore, concluded that the codon 922 mutation is unlikely to seriously affect the function of RET and seems not to confer a deleterious effect.…”

Section: Genotype-phenotype Correlationsmentioning

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

266

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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“…Somatic RET mutations are found in a fraction of sporadic MTCs and, rarely, in pheochromocytomas. Mutation at the codon 918 or at the cysteine codons 609, 611, 618, 620, 630, 634 appear in a significant amount of sporadic MTC cases and recently three new somatic missense mutations (at codons 639, 641, and 922) of the RET proto‐oncogene associated with sporadic MTC have been described (Kalimin et al, 2001).…”

Section: Sporadic Mtcmentioning

confidence: 99%

RET and NTRK1 proto‐oncogenes in human diseases

Alberti¹,

Carniti²,

Miranda³

et al. 2003

Journal Cellular Physiology

140

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RET and NTRK1 are receptor tyrosine kinase (RTK) proteins which play a role in the development and maturation of specific component of the nervous system. Their alterations have been associated to several human diseases, including some forms of cancer and developmental abnormalities. These features have contributed to the concept that one gene can be responsible for more than one disease. Moreover, both genes encoding for the two RTKs show genetic alterations that belong to either "gain of function" or "loss of function" class of mutations. In fact, receptor rearrangements or point mutations convert RET and NTRK1 in dominantly acting transforming genes leading to thyroid tumors, whereas inactivating mutations, associated with Hirschsprung's disease (HSCR) and congenital insensitivity to pain with anhidrosis (CIPA), impair RET and NTRK1 functions, respectively. In this review we have summarized the main features of the two receptors, their physiological and pathological roles. In addition, we attempted to identify the correlations between the different genetic alterations and the related pathogenetic mechanisms.

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Three novel mutations in the RET proto-oncogene

Cited by 23 publications

References 14 publications

Molecular Mechanisms of RET Receptor–Mediated Oncogenesis in Multiple Endocrine Neoplasia 2B

Molecular Mechanisms of RET Receptor–Mediated Oncogenesis in Multiple Endocrine Neoplasia 2B

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

RET and NTRK1 proto‐oncogenes in human diseases

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