scholarly journals A Novel Point Mutation of theRETProtooncogene Involving the Second Intracellular Tyrosine Kinase Domain in a Family with Medullary Thyroid Carcinoma

2004 ◽  
Vol 89 (7) ◽  
pp. 3521-3526 ◽  
Author(s):  
Camilo Jimenez ◽  
Gerald T. Dang ◽  
Pamela N. Schultz ◽  
Adel El-Naggar ◽  
Suzanne Shapiro ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Tyrosine Kinase ◽  
Medullary Thyroid Carcinoma ◽  
Point Mutation ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Medullary Thyroid ◽  
Intracellular Tyrosine Kinase Domain

scholarly journals RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors

2006 ◽  
Vol 27 (5) ◽  
pp. 535-560 ◽  
Author(s):  
Jan Willem B. de Groot ◽  
Thera P. Links ◽  
John T. M. Plukker ◽  
Cornelis J. M. Lips ◽  
Robert M. W. Hofstra
Keyword(s):  
Thyroid Carcinoma ◽  
Tyrosine Kinase ◽  
Medullary Thyroid Carcinoma ◽  
Therapeutic Option ◽  
Dominant Negative ◽  
Tyrosine Kinase Domain ◽  
Endocrine Tumors ◽  
Medullary Thyroid ◽  
Familial Medullary Thyroid Carcinoma ◽  
Men 2

The RET gene encodes a receptor tyrosine kinase that is expressed in neural crest-derived cell lineages. The RET receptor plays a crucial role in regulating cell proliferation, migration, differentiation, and survival through embryogenesis. Activating mutations in RET lead to the development of several inherited and noninherited diseases. Germline point mutations are found in the cancer syndromes multiple endocrine neoplasia (MEN) type 2, including MEN 2A and 2B, and familial medullary thyroid carcinoma. These syndromes are autosomal dominantly inherited. The identification of mutations associated with these syndromes has led to genetic testing to identify patients at risk for MEN 2 and familial medullary thyroid carcinoma and subsequent implementation of prophylactic thyroidectomy in mutation carriers. In addition, more than 10 somatic rearrangements of RET have been identified from papillary thyroid carcinomas. These mutations, as those found in MEN 2, induce oncogenic activation of the RET tyrosine kinase domain via different mechanisms, making RET an excellent candidate for the design of molecular targeted therapy. Recently, various kinds of therapeutic approaches, such as tyrosine kinase inhibition, gene therapy with dominant negative RET mutants, monoclonal antibodies against oncogene products, and nuclease-resistant aptamers that recognize and inhibit RET have been developed. The use of these strategies in preclinical models has provided evidence that RET is indeed a potential target for selective cancer therapy. However, a clinically useful therapeutic option for treating patients with RET-associated cancer is still not available.

Molecular mechanism(s) of resistance to vandetanib in medullary thyroid carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15628-e15628
Author(s):  
Brittany Glassberg ◽  
Sophia Khan ◽  
Alex Pemov ◽  
Robert Hawley ◽  
Brigitte C. Widemann ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Tyrosine Kinase ◽  
Cell Line ◽  
Rna Sequencing ◽  
Medullary Thyroid Carcinoma ◽  
Cell Lines ◽  
Resistant Cell ◽  
Knock Out ◽  
Medullary Thyroid ◽  
Genome Wide

e15628 Background: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor arising from parafollicular C cells of the thyroid. Pediatric cases of this cancer are associated with the diagnosis of multiple endocrine neoplasia, which is caused by a mutation in the rearranged during transfection ( RET) gene. Vandetanib, an oral receptor tyrosine kinase inhibitor, is approved for the treatment of patients with progressive MTC. While there is a response rate of 50%, the majority of patients eventually develop resistant disease. The goal of this work is to understand genetic and epigenetic underpinnings of sensitivity and resistance to vandetanib, and develop novel synergistic combination therapies in medullary thyroid carcinoma. Methods: The TT cell line (RET mutation p.C634W) was cultured in increasing concentrations of vandetanib in order to generate a vandetanib resistant cell line. Both vandetanib-sensitive and vandetanib-resistant lines were evaluated. Each line underwent exome sequencing, RNA sequencing, and methylation array analysis. In parallel we performed Genome-wide CRISPR knock-out and CRISPR activation of both cell lines using the TKO Version 3 Library, consisting of 71,090 gRNAs targeting 18,000 genes, and the Calabrese P65-HSF activation Library, using 56,762 guides for 18,000 genes. Results: Both whole exome and RNA sequencing demonstrate increased expression of RET C634W in both cell lines, to a significantly greater extent in the drug-resistant line than in the sensitive line. RNA sequencing demonstrates differential expression of transcripts between the vandetanib-sensitive and vandetanib-resistant cell lines, including multidrug-resistance 1 (which confers drug resistance in other cancers) and autotaxin (promotes cell survival). Genome-wide CRISPR knock-out showed enrichment of genes necessary for growth suppression by vandetanib, including MACROD2, GORASP2, and MAP3K genes. Gene set enrichment analysis of the CRISPR knock-out data showed enrichment of the proteasome pathway as a potential candidate of growth suppression by vandetanib, which was validated via exposure of the cell lines to bortezomib (IC50 = 3.62nM), a molecularly targeted proteasome-inhibitor. Conclusions: DNA mutations and epigenetic modification confer resistance of medullary thyroid carcinoma to tyrosine kinase inhibition. Adding further therapeutic agents to target these genetic alterations is a potential strategy for overcoming resistance.

Update on the Treatment of Medullary Thyroid Carcinoma in Patients with Multiple Endocrine Neoplasia Type 2

2020 ◽  
Vol 52 (08) ◽  
pp. 588-597 ◽  
Author(s):  
Maran Ilanchezhian ◽  
Sophia Khan ◽  
Christian Okafor ◽  
John Glod ◽  
Jaydira Del Rivero
Keyword(s):  
Thyroid Carcinoma ◽  
Tyrosine Kinase ◽  
Medullary Thyroid Carcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Multiple Endocrine Neoplasia ◽  
Kinase Inhibitors ◽  
Multiple Endocrine Neoplasia Type ◽  
Medullary Thyroid ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type

AbstractMedullary Thyroid Carcinoma (MTC) is a rare neuroendocrine cancer that accounts for 1–2% of thyroid cancers in the United States (U.S.). While most cases are sporadic, 25% of MTC cases are hereditary. These hereditary cases occur in the setting of Multiple Endocrine Neoplasia Type 2A (MEN2A) or 2B (MEN2B) driven by mutations in the Rearranged during Transfection RET proto-oncogene. This article discusses hereditary MTC in the setting of MEN2 and the treatment options available for it. The first line treatment for this disease is typically a total thyroidectomy and tyrosine kinase inhibitors. Two tyrosine kinase inhibitors, vandetanib and cabozantinib, have been approved for treatment of advanced MTC, but options beyond those are limited. However, several promising treatments are being studied, which are discussed in this review.

Molecular analysis of the RET proto-oncogene in patients with sporadic medullary thyroid carcinoma: a novel point mutation in the extracellular cysteine-rich domain

1997 ◽  
Vol 136 (4) ◽  
pp. 423-426 ◽  
Author(s):  
Maria João Bugalho ◽  
João Pedro Frade ◽  
Jorge Rosa Santos ◽  
Edward Limbert ◽  
Luis Sobrinho
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Point Mutation ◽  
De Novo ◽  
Point Mutations ◽  
The Other ◽  
Missense Mutations ◽  
Sporadic Medullary Thyroid Carcinoma ◽  
Medullary Thyroid ◽  
Rich Domain

Abstract Germline point mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia type 2 (2A and 2B) and familial medullary thyroid carcinoma. On the other hand, somatic point mutations of RET have been described in a subset of sporadic medullary thyroid carcinomas (MTCs). We examined tumor and blood DNA of thirteen apparently sporadic MTC patients for mutations in RET exons 10, 11, 13, 15 and 16 to determine whether they had true sporadic tumors or either de novo or occult germline mutations. Three different somatic missense mutations were documented in seven patients. In five patients a mutation in exon 16, codon 918, (ATG→ACG) causing a Met→Thr substitution was found. In the remaining two patients the mutation affected exon 11: codon 630 in one case and codon 634 in the other. In both cases a T→C transversion was identified causing a Cys→Arg substitution. In conclusion, absence of a germline mutation in RETexons 10, 11, 13 or 16 is evidence against an inherited form in all cases. In seven patients, identification of a somatic mutation supported the previous clinical diagnosis of sporadic medullary thyroid carcinoma; in one of them we identified a hitherto undescribed somatic point mutation at codon 630. European Journal of Endocrinology 136 42 3–426

C-Cell Neoplasia in Asymptomatic Carriers of RET Mutation in Extracellular Cysteine-Rich and Intracellular Tyrosine Kinase Domain

2015 ◽  
Vol 46 (8) ◽  
pp. 1121-1128 ◽  
Author(s):  
Rita Abi-Raad ◽  
Renu K. Virk ◽  
Catherine A. Dinauer ◽  
A. Prasad ◽  
Raffaella A. Morotti ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Asymptomatic Carriers ◽  
Ret Mutation ◽  
C Cell ◽  
Intracellular Tyrosine Kinase Domain

A GTG to ATG novel point mutation at codon 804 in exon 14 of the RET proto-oncogene in two families affected by familial medullary thyroid carcinoma

1998 ◽  
Vol 11 (S1) ◽  
pp. S167-S171 ◽  
Author(s):  
Olimpia Fattoruso ◽  
Loredana Quadro ◽  
Alfonso Libroia ◽  
Uberta Verga ◽  
Giovanni Lupoli ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Point Mutation ◽  
Medullary Thyroid ◽  
Familial Medullary Thyroid Carcinoma
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