Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the genotype-phenotype for familial medullary thyroid carcinoma (FMTC) is well studied, only few low susceptibility risk loci were identified for familial non-medullary thyroid carcinoma (FNMTC). The aim of this study is to screen and identify high-penetrate genes for FNMTC. A total of 34 families with more than two first-degree relatives diagnosed as papillary thyroid cancer without other familial syndrome were recruited. Whole exome and target gene sequencing were performed for candidate variants. These variants were screened and analyzed with ESP6500, ExAC, 1000 genomes project, and the Cancer Genome Atlas (TCGA) with SIFT score and Polyphen2 prediction. Finally, we identified recurrent genetic mutation of MAP2K5 variants c.G961A and c.T1100C (p. A321T and p.M367 T) as susceptibility loci for FNMTC. The frequencies of MAP2K5 c.G961A and c.T1100C were found, 0.0385 and 0.0259 in FNMTC and 0 and 0.00022523 in healthy Chinese controls (n = 2200, P < 0.001), respectively. Both variants were located in the protein kinase domain. The functional study showed that MAP2K5 A321T or M367 T could consistently phosphorylate downstream protein ERK5 on site Ser731 + Thr733 or Ser496, promoting nuclear translocation and subsequently altering target gene expressions. Our data revealed that MAP2K5 variants A321T or M367 T can activate MAP2K5-ERK5 pathway, alter downstream gene expression, and subsequently induce thyroid epithelial cell malignant transformation. While classic MAP2K1/2(MEK1/2)-ERK1/2 signaling is well known for driving sporadic NMTC, our research indicated that MAP2K5 (MEK5) is a susceptibility gene for FNMTC. These findings highlight the potential application of MAP2K5 for molecular diagnosis as well as early prevention.
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PMID:Whole exome and target sequencing identifies MAP2K5 as novel susceptibility gene for familial non-medullary thyroid carcinoma. 3082 92

Although thyroid cancer generally has a good prognosis, there is a subset of patients for whom standard care (ie, treatment limited to surgery or surgery plus radioactive iodine) is either not appropriate because of the aggressive nature of their disease or not sufficient because of disease progression through standard treatment. Most of these tumors are in 3 groups: radioactive iodine-refractory differentiated thyroid carcinoma including poorly differentiated thyroid carcinoma anaplastic thyroid carcinoma, and progressive medullary thyroid carcinoma. Major classes of treatments in clinical development for these aggressive thyroid tumors include tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and mitogen-activated protein kinase kinase inhibitors.
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PMID:Treatment of Aggressive Thyroid Cancer. 3167

The diagnostic modalities, stratification tools, and treatment options for patients with thyroid cancer have rapidly evolved since the development of the American Thyroid Association (ATA) guidelines in 2015. This review compiles newer concepts in diagnosis, stratification tools and treatment options for patients with differentiated thyroid cancer (DTC), medullary thyroid carcinoma (MTC) and anaplastic thyroid cancer (ATC). Newer developments apply precision medicine in thyroid cancer patients to avoid over-treatment in low risk disease and under-treatment in high risk disease. Among novel patient-tailored therapies are selective RET inhibitors that have shown efficacy in the treatment of MTC with limited systemic toxicity compared with non-specific tyrosine kinase inhibitors. The combination of BRAF and MEK inhibitors have revolutionized management of BRAF V600E mutant ATC. Several immunotherapeutic agents are being actively investigated in the treatment of all forms of thyroid cancer. In this review, we describe the recent advances in the diagnosis and management of DTC, MTC, and ATC, with an emphasis on novel treatment modalities.
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PMID:Updates on the Management of Thyroid Cancer. 3204 Sep 62

The knowledge on thyroid cancer biology has grown over the past decade. Thus, diagnostic and therapeutic strategies to manage thyroid cancer are rapidly evolving. With new insights into tumor biology and cancer genetics, several novel therapies have been approved for the treatment of thyroid cancer. Tyrosine kinase inhibitors (TKIs), such as lenvatinib and sorafenib, have been successfully utilized for the treatment of radioactive iodine (RAI)-refractory metastatic differentiated thyroid cancer (DTC). In addition, pretreatment with mitogen-activated protein kinase (MAPK) inhibitors (trametinib and selumetinib) has been shown to restore RAI avidity in previously RAI-refractory DTCs. Local therapies, such as external beam radiation and radiofrequency/ethanol ablation, have also been employed for treatment of DTC. Vandetanib and cabozantinib are the two TKIs currently approved by the Food and Drug Administration (FDA) for the treatment of medullary thyroid cancer (MTC). Other novel therapies, such as peptide receptor radionuclide therapy and carcinoembryonic antigen (CEA) vaccine, have also been utilized in treating MTC. Ongoing trials on selective rearranged-during-transfection (RET) protooncogene inhibitors, such as LOXO-292 and BLU-667, have demonstrated promising results in the treatment of metastatic MTC resistant to non-selective TKIs. The FDA-approved BRAF/MEK inhibitor combination of dabrafenib and trametinib has revolutionized treatment of BRAFV600E mutation positive anaplastic thyroid cancer. Several other emerging classes of medications, such as gene fusion inhibitors and immune checkpoint inhibitors, are being actively investigated in several clinical trials. In this review, we describe the molecular landscape of thyroid cancer and novel targeted therapies and treatment combinations available for the treatment of metastatic thyroid cancer.
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PMID:Novel Targeted Therapies for Metastatic Thyroid Cancer-A Comprehensive Review. 3275 Nov 38


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