scholarly journals Identification of mutation in the RET gene in a patient with medullary thyroid cancer

2016 ◽  
Vol 14 (3) ◽  
pp. 405-410
Author(s):  
Nguyễn Hải Hà ◽  
Trần Thị Hải Yến ◽  
Vũ Phương Nhung ◽  
Ma Thị Huyền Thương ◽  
Nguyễn Đăng Tôn ◽  
...  
Keyword(s):  
Medullary Thyroid Cancer ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Medullary Thyroid ◽  
Ret Gene ◽  
Activating Mutations ◽  
Thyroid Malignancies ◽  
Sanger Method ◽  
Normal Health

Medullary thyroid carcinoma (MTC) is a type of tumors drived from thyroid parafollicular cells (C-cells), comprises 5–10% of all thyroid malignancies. About 25% of MTC cases occur as an autosomal dominant heredited disorder which is mostly caused by activating mutations of RET pro-oncogen and they occur as components of the multiple endocrine neoplasia type 2 syndromes (MEN 2A and 2B) or familial MTC. The guidelines for genetic testing in MTC of the European Thyroid Association recommend that exons 5, 8, 10, 11, 13, 14, 15 and 16 should always be screened starting in patients. This study aims to identify the genetic causes of a male patient diagnosed with MEN2 and pheochromocytoma. Genomic DNA was extracted from peripheral blood of patient. Eight recommened exons (5, 8, 10, 11, 13, 14, 15 and 16) of the RET gene were amplified by PCR and sequenced by Sanger method on the ABI 3500 genetic annalyzer. The results showed a heterozygous C to T transition at nucleotide 2753 in exon 16 of the RET gene. The c.2753 C>T transition resulted in a missense mutation of methionine to threonine (p.M918T) in the RET protein. This mutation was located in the intracellular tyrosine kinase domain of protein and has been reported in 95% of MEN2B cases, therefore, it would be the causative mutant of our patient. Our patient harboring a pM918T germline mutation and there is a 50% probability that he will pass this mutation to a child. Thus, his six-year-old boy with normal health status was advised to have the genetic test for this mutation. The results showed that he had not inherited the mutation c.2753T> C from his father.

scholarly journals Two Sequences Variations of the E768D Mutation Found in Familial Medullary Thyroid Carcinomas

2021 ◽  
Vol 3 (2) ◽  
Keyword(s):  
Index Case ◽  
Hereditary Disease ◽  
Genetic Mutation ◽  
Dominant Mode ◽  
Medullary Thyroid ◽  
Ret Gene ◽  
Men 2 ◽  
Familial Form ◽  
Medullary Thyroid Carcinomas

Medullary thyroid cancer or MTC is present in sporadic form (75% of cases) and in familial form (25% of cases), in this latter situation, the MTC is a part of Multiple Endocrine Neoplasia type 2 (MEN 2). The MEN2 is divided into MEN2A, MEN2B and FMTC or isolated familial MTC. The MEN2 are rare hereditary disease, transmitted as an autosomal dominant mode, linked to mutations of the RET gene. The discovery of a mutation in the RET proto-oncogene by molecular biology techniques in a index case of MTC confirms the diagnosis of familial and allows the genetic testing of healthy clinically related index case: those who carry the genetic mutation, will be offered prophylactic thyroidectomy before any biological or clinical manifestation. The genetic analysis of the RET gene was performed by PCR / sequencing. The E768D mutation was found in the exon 13 of the RET gene in 2 differences sequences forms (GAG/GAC et GAG/GAT). This mutation, already described, found in the FMTC.

scholarly journals Geographical Variation in the profile of RET Variants in Patients with Medullary Thyroid Cancer: A Comprehensive Review

2021 ◽  
Author(s):  
Rui M. B. Maciel ◽  
Ana Luiza Maia
Keyword(s):  
Haplotype Analysis ◽  
Medullary Thyroid Cancer ◽  
Genetic Diagnosis ◽  
Epidemiological Data ◽  
Global Perspective ◽  
Causative Role ◽  
Medullary Thyroid ◽  
Pathogenic Variants

Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98%, 50% and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants have been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation.

SRC Is a Critical Signaling Mediator in FLT3-ITD Positive AML.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 477-477
Author(s):  
Hannes Leischner ◽  
Rebekka Grundler ◽  
Corinna Albers ◽  
Anna Lena Illert ◽  
Karsten Spiekermann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Point Mutations ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Control Group ◽  
Tyrosine Kinase Domain ◽  
Myeloproliferative Disease ◽  
Activating Mutations ◽  
Tandem Duplications

Abstract Abstract 477 Activating mutations of FLT3 are frequent in patients with AML. Two types of mutations are most common: Internal tandem duplications (ITD) of the juxtamembrane domain in approximately 30% of patients and point mutations within the second tyrosine kinase domain (TKD) in about 7% of AML patients. Patients carrying the FLT3-ITD mutation have a significantly worse prognosis whereas FLT3-TKD mutations do not appear to influence the clinical outcome. Studies have shown that mice receiving a transplant of bone marrow expressing FLT3 ITD develop a myeloproliferative disease. In contrast, mice which were transplanted with FLT3 TKD infected bone marrow, suffer from a lymphoid disease. Thus, both FLT3 mutations seem to exert different biological functions. Interestingly, FLT3-ITD but not FLT3-TKD or FLT3-WT leads to a strong activation of the STAT5 signaling pathway. Therefore, STAT5 activation may be responsible for the observed differences in biology. Here we investigated the signalling pathways leading to STAT5 activation downstream of FLT3-ITD. FLT3-ITD does not bind STAT5 directly nor does it activate the classical JAK2 pathway. Instead FLT3-ITD utilizes c-Src to activate STAT5. Co-immunoprecipitations and GST pull downs revealed a strong and exclusive interaction between Src and FLT3 ITD, which is mediated by the Src-SH2 domain. This interaction is absent in FLT3-TKD or FLT3-WT after ligand stimulation. The sequence duplication in FLT3-ITD leads to additional potential Src-SH2 binding sites. We identified tyrosines 589 and 591 of FLT3-ITD to be essential for Src binding and subsequent STAT5 activation. Specific Src inhibitors or Src-siRNA blocked STAT5 activation and growth induced by FLT3-ITD but not FLT3-TKD. FLT3-ITD positive cells with a stable Src knockdown injected into syngenic mice led to a leukemic disease with a significant delayed onset and prolonged survival in comparison to the control group. Finally, a combination of FLT3 and Src inhibitors was tested. This combination was highly efficient in FLT3-ITD positive cells but not in FLT-TKD positive cells. Together these findings show that Src plays an important role in the signalling of FLT3-ITD but not FLT3-TKD. Thus, Src might be an interesting therapeutic target for FLT3-ITD positive AML. Disclosures: No relevant conflicts of interest to declare.

Combination of c-SRC and FLT3 Inhibitors Has An Additive Inhibitory Effect on FLT3 ITD but Not on FLT3 TKD Positive Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2892-2892 ◽  
Author(s):  
Hannes Leischner ◽  
Rebekka Grundler ◽  
Corinna Albers ◽  
Anna Lena Illert ◽  
Katharina Götze ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Inhibition ◽  
Conflicts Of Interest ◽  
Point Mutations ◽  
Inhibitory Effect ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Myeloproliferative Disease ◽  
Activating Mutations ◽  
Flt3 Inhibitors

Abstract Abstract 2892 Activating mutations of FLT3 are frequent in patients with AML. Two types of mutations are most common: Internal tandem duplications (ITD) of the juxtamembrane domain in approximately 30% of patients and point mutations within the second tyrosine kinase domain (TKD) in about 7% of AML patients. Patients carrying the FLT3-ITD mutation have a significantly worse prognosis whereas FLT3-TKD mutations do not appear to influence the clinical outcome. Studies have shown that mice receiving a transplant of bone marrow expressing FLT3 ITD develop a myeloproliferative disease. In contrast, mice which were transplanted with FLT3 TKD infected bone marrow, suffer from a lymphoid disease. Thus, both FLT3 mutations seem to exert different biological functions. Interestingly, FLT3-ITD but not FLT3-TKD or FLT3-WT leads to a strong activation of the STAT5 signaling pathway. Recently we have shown that c-SRC is the crucial signaling mediator of FLT3 ITD to activate STAT5. Based on these findings we investigated the effect of FLT3 inhibitors (Midostaurin, Sorafenib and Sunitinib) in combination with c-SRC inhibitors (Dasatinib and PD166-326) on FLT3 ITD and FLT3 TKD murine and human cell lines as well as on primary patient material. In FLT3 ITD expressing murine myeloid 32D cells c-SRC inhibitors in combination with FLT3 inhibitors showed clear additive effects on growth inhibition, apoptosis and activation of STAT5. In contrast, c-SRC inhibitors had no additional effects in FLT3 TKD expressing cells. Accordingly, a strong additive effect of c-SRC and FLT3 inhibitors could also be demonstrated in the FLT3 ITD positive human AML cell line MV4-11. Finally FLT3 ITD and FLT3 TKD positive primary human AML cells were investigated. We were able to detect a significant additional growth inhibition of FLT3 ITD positive human cells by combining c-SRC and FLT3 inhibitors. In contrast, no further growth inhibition was observed by c-SRC inhibition in primary AML cells expressing the FLT3 TKD mutation. Together our results confirm c-SRC as a crucial signaling mediator in FLT3-ITD but not FLT3-TKD positive AML. The combination of FLT3 and c-SRC inhibitors warrants further investigation in FLT3 ITD positive AML. Disclosures: No relevant conflicts of interest to declare.

Activating FLT3 Mutations in CD4+/CD8− Pediatric T-Cell Acute Lymphoblastic Leukemias.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1465-1465
Author(s):  
Pieter Van Vlierberghe ◽  
Jules P.P. Meijerink ◽  
Ronald W. Stam ◽  
Wendy van der Smissen ◽  
Elisabeth R. van Wering ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Point Mutations ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Activating Mutations ◽  
Activated State ◽  
Flt3 Mutations ◽  
Genetic Aberration ◽  
High Level

Abstract Activating mutations in the FMS-like tyrosine kinase 3 gene (FLT3) are the most common genetic aberration in acute myeloid leukemia (AML). Internal tandem duplications (ITD) in the juxtamembrane (JM) domain, or point mutations (PM) in the activation loop of the tyrosine kinase domain lead to a constitutive activated state of the FLT3 tyrosine kinase. Recently, FLT3 mutations were identified in a cohort of 69 adult T-ALL patients, showing that this genetic abnormality is not only restricted to myeloid leukemias. To validate the incidence of FLT3 mutations in pediatric T-ALL and investigate its relation to outcome and other clinical and immunophenotypical parameters, we screened 72 diagnostic pediatric T-ALL samples. FLT3/ITD mutations were identified in 2/72 pediatric T-ALLs (2.7%), whereas 0/72 showed point mutations in the kinase domain. Immunophenotypic analysis revealed a similar profile for both FLT3 mutated patient samples, i.e. TdT+, CD2+, CD5+, CD7+, CD4+/CD8−, cytoplasmic CD3+, surface CD3− and CD10−. Although representing early T-cell differentiation stages for both patient samples, these cases seem to have a more advanced immunophenotype compared to the FLT3 mutated adult T-ALL cases, previously described (CD34+, CD4−/CD8−). Both FLT3 mutated patients showed high level LYL1 and LMO2 expression. In addition, both pediatric samples contained a HOX11L2 translocation, which was not present in the FLT3 mutated adult T-ALL cases. The first FLT3 mutated patient suffered a relapse 13 months after initial diagnosis, whereas the other is still in continued complete remission for 61+ months. Interestingly, the relapse material showed no FLT3/ITD mutation, indicating that the FLT3 mutated T-ALL subclone seems to be effectively eradicated by current chemotherapy. These data suggest that the application of FLT3 inhibitors for FLT3-mutated T-ALLs, as recently suggested in literature, may not further improve treatment outcome in pediatric T-ALL.

scholarly journals A Case of Lenvatinib-Induced Focal Segmental Glomerulosclerosis (FSGS) in Metastatic Medullary Thyroid Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Kathryn Fleming ◽  
James McGuinness ◽  
David Kipgen ◽  
Hilary Glen ◽  
Pavlina Spiliopoulou
Keyword(s):  
Thyroid Cancer ◽  
Focal Segmental Glomerulosclerosis ◽  
Medullary Thyroid Cancer ◽  
Common Side Effect ◽  
Medullary Thyroid ◽  
Segmental Glomerulosclerosis ◽  
Targeted Treatments ◽  
Discontinuation Of Treatment ◽  
Thyroid Malignancies ◽  
The Uk

We describe a case of lenvatinib (E7080) associated focal segmental glomerulosclerosis (FSGS) encountered during the treatment of metastatic medullary thyroid cancer. Proteinuria is a relatively common side effect of VEGF-targeted treatments and can occasionally result in treatment discontinuation. Here, we describe a patient who developed secondary FSGS necessitating discontinuation of treatment at first but who was subsequently rechallenged with anti-VEGF-targeted treatment without recurrence of proteinuria. Lenvatinib was a novel experimental agent at the time the treatment took place; however, its recent licensing for the treatment of thyroid malignancies in the UK makes reporting of these adverse effects all the more important now.

AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 265-273 ◽  
Author(s):  
Chunaram Choudhary ◽  
Joachim Schwäble ◽  
Christian Brandts ◽  
Lara Tickenbrock ◽  
Bülent Sargin ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Target Genes ◽  
Kinase Inhibitor ◽  
Point Mutations ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Activating Mutations ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Kinase Domain Mutations

Activating mutations of Flt3 are found in approximately one third of patients with acute myeloid leukemia (AML) and are an attractive drug target. Two classes of Flt3 mutations occur: internal tandem duplications (ITDs) in the juxtamembrane and point mutations in the tyrosine kinase domain (TKD). We and others have shown that Flt3-ITD induced aberrant signaling including strong activation of signal transducer and activator of transcription 5 (STAT5) and repression of CCAAT/estradiol-binding protein α (c/EBPα) and Pu.1. Here, we compared the signaling properties of Flt3-ITD versus Flt3-TKD in myeloid progenitor cells. We demonstrate that Flt3-TKD mutations induced autonomous growth of 32D cells in suspension cultures. However, in contrast to Flt3-ITD and similar to wild-type Flt3 (Flt3-WT), Flt3-TKD cannot support colony formation in semisolid media. Also, in contrast to Flt3-ITD, neither Flt3-WT nor Flt3-TKD induced activation or induction of STAT5 target genes. Flt3-TKD also failed to repress c/EBPα and Pu.1. No significant differences were observed in receptor autophosphorylation and the phosphorylation of Erk-1 and -2, Akt, and Shc. Importantly, TKD but not ITD mutations were a log power more sensitive toward the tyrosine kinase inhibitor protein kinase C 412 (PKC412) than Flt3-WT. In conclusion, Flt3-ITD and Flt3-TKD mutations display differences in their signaling properties that could have important implications for their transforming capacity and for the design of mutation-specific therapeutic approaches.

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