自身免疫性甲状腺疾病的遗传学发病机制进展

自身免疫疾病是遗传和环境相互影响的结果.免疫调节基因和甲状腺特异基因在自身免疫性甲状腺疾病的发病过程中起重要作用.     

自身免疫性甲状腺疾病的遗传学发病机制进展

自身免疫疾病是遗传和环境相互影响的结果.免疫调节基因和甲状腺特异基因在自身免疫性甲状腺疾病的发病过程中起重要作用.     

自身免疫性甲状腺疾病的遗传学发病机制进展

自身免疫疾病是遗传和环境相互影响的结果.免疫调节基因和甲状腺特异基因在自身免疫性甲状腺疾病的发病过程中起重要作用.     

自身免疫性甲状腺疾病的遗传学发病机制进展

自身免疫疾病是遗传和环境相互影响的结果.免疫调节基因和甲状腺特异基因在自身免疫性甲状腺疾病的发病过程中起重要作用.     

自身免疫性甲状腺疾病的遗传学发病机制进展

自身免疫疾病是遗传和环境相互影响的结果.免疫调节基因和甲状腺特异基因在自身免疫性甲状腺疾病的发病过程中起重要作用.     

自身免疫性甲状腺疾病的遗传学发病机制进展

自身免疫疾病是遗传和环境相互影响的结果.免疫调节基因和甲状腺特异基因在自身免疫性甲状腺疾病的发病过程中起重要作用.     

自身免疫性甲状腺疾病的遗传学发病机制进展

自身免疫疾病是遗传和环境相互影响的结果.免疫调节基因和甲状腺特异基因在自身免疫性甲状腺疾病的发病过程中起重要作用.     

自身免疫性甲状腺疾病的遗传学发病机制进展

自身免疫疾病是遗传和环境相互影响的结果.免疫调节基因和甲状腺特异基因在自身免疫性甲状腺疾病的发病过程中起重要作用.     

自身免疫性甲状腺疾病的遗传学发病机制进展

自身免疫疾病是遗传和环境相互影响的结果.免疫调节基因和甲状腺特异基因在自身免疫性甲状腺疾病的发病过程中起重要作用.     

自身免疫性甲状腺疾病的遗传学发病机制进展

自身免疫疾病是遗传和环境相互影响的结果.免疫调节基因和甲状腺特异基因在自身免疫性甲状腺疾病的发病过程中起重要作用.     

Epigenetic dysregulation in thyroid neoplasia.

Gain-of-function mutations in oncogenes have aided our understanding of the molecular mechanisms of thyroid carcinogenesis. Mutations or deletions cause inactivation of tumor suppressor genes in thyroid carcinomas. However, recent advances have disclosed the significance of epigenetic events in the development and progression of human tumorigenesis. Indeed, various tumor-suppressor genes and thyroid hormone-related genes are epigenetically silenced in thyroid tumors. This article reviews the evidence for epigenetic gene dysregulation in follicular cell-derived thyroid carcinomas including papillary thyroid carcinoma, follicular thyroid carcinoma, and undifferentiated thyroid carcinoma. The authors also discuss future applications of epigenetics as ancillary diagnostic tools and in the design of targeted therapies for thyroid cancer.     

Identifying differentially expressed genes associated with metastasis of follicular thyroid cancer by cDNA expression array.

Patients with follicular thyroid carcinoma have a higher incidence of metastasis than papillary thyroid carcinoma when thyroid cancer is diagnosed. The cDNA expression array technology is utilized herein to profile differentially expressed genes from metastatic human follicular thyroid carcinoma and reveal new tumor markers as well as target genes for therapeutic intervention. Tissue samples were obtained during surgical resection of the thyroid follicular carcinoma and metastatic tissue in the brain of the same patient. Two identical Atlas human cDNA expression arrays were hybridized with 32P-labeled cDNA probes derived from RNA of either primary thyroid cancer or metastatic tissue. Parallel analysis of the hybridized signals allowed us to identify the alteration of gene expression in the metastasis process. Eighteen genes significantly overexpressed and 40 genes significantly underexpressed were identified in the metastatic thyroid cancer. Genes that displayed an altered expression were associated with the processes of cell cycle regulation, apoptosis, DNA damage response, angiogenesis, cell adhesion and mobility, invasion, and immune response. An expression profile of genes that are associated with metastasis process of follicular thyroid cancer was also discussed. Further investigation is required to understand the precise relationship between the altered expression of these genes and the metastasis process of follicular thyroid cancer.     

Gene methylation in thyroid tumorigenesis

Aberrant gene methylation plays an important role in human tumorigenesis, including thyroid tumorigenesis. Many tumor suppressor genes are aberrantly methylated in thyroid cancer, and some even in benign thyroid tumors, suggesting a role of this epigenetic event in early thyroid tumorigenesis. Methylation of some of these genes tends to occur in certain types of thyroid cancer and is related to specific signaling pathways. For example, methylation of PTEN and RASSF1A genes occurs mostly in follicular thyroid cancer, and its tumorigenic role may be related to the phosphatidylinositol 3-kinase/Akt signaling pathway, whereas methylation of genes for tissue inhibitor of metalloproteinase-3, SLC5A8, and death-associated protein kinase occurs in papillary thyroid cancer and is related to the BRAF/MAPK kinase/MAPK pathway. Methylation of thyroid-specific genes, such as those for sodium/iodide symporter and thyroid-stimulating hormone receptor, is also common in thyroid cancer. Although its tumorigenic role is not clear, methylation, and hence silencing, of these thyroid-specific genes is a cause for the failure of clinical radioiodine treatment of thyroid cancer. Unlike gene methylation, histone modifications have been relatively poorly investigated in thyroid tumors. Future studies need to emphasize the mechanistic aspects of these two types of epigenetic alterations to uncover new molecular mechanisms in thyroid tumorigenesis and to provide novel therapeutic targets for thyroid cancer.     

Identification of TNIK as a novel potential drug target in thyroid cancer based on protein druggability prediction

Thyroid cancer is a common endocrine malignancy; however, surgery remains its primary treatment option. A novel targeted drug for the development and application of targeted therapy in thyroid cancer treatment remain underexplored.We obtained RNA sequence data of thyroid cancer from The Cancer Genome Atlas database and identified differentially expressed genes (DEGs). Then, we constructed co-expression network with DEGs and combined it with differentially methylation analysis to screen the key genes in thyroid cancer. PockDrug-Server, an online tool, was applied to predict the druggability of the key genes. Finally, we constructed protein-protein interaction (PPI) network to observe potential targeted drugs for thyroid cancer.We identified 3 genes correlated with altered DNA methylation level and oncogenesis of thyroid cancer. According to the druggable analysis and PPI network, we predicted TRAF2 and NCK-interacting protein kinase (TNIK) sever as the drug targeted for thyroid cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that genes in protein-protein interaction network of TNIK enriched in mitogen-activated protein kinase signaling pathway. For drug repositioning, we identified a targeted drug of genes in PPI network.Our study provides a bioinformatics method for screening drug targets and provides a theoretical basis for thyroid cancer targeted therapy.     

A comprehensive analysis of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA in familial nonmedullary thyroid cancer: confirmation of linkage to TCO1

About 5% of nonmedullary thyroid cancer is familial. These familial nonmedullary thyroid cancer cases are characterized by an earlier age of onset, more aggressive phenotype, and in some families a high propensity to benign thyroid disease. Little is known about the genes conferring predisposition to nonmedullary thyroid cancer. Three loci have been identified through genetic linkage: MNG1 on 14q32, TCO1 on 19p13.2, and fPTC on 1p21. In addition to these putative genes, a number of loci represent candidate familial nonmedullary thyroid cancer predisposition genes by virtue of their involvement in sporadic disease (TRKA), their role in benign disease (TSHR), and because they underlie syndromes with a risk of nonmedullary thyroid cancer (PTEN). To evaluate the roles of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA in familial nonmedullary thyroid cancer, we have carried out a comprehensive mutation and linkage analysis of these genes in 22 families. One family was linked to chromosome 19q13.2, confirming that TCO1 underlies a subset of familial nonmedullary thyroid cancer. None of the families was linked to MNG1 or fPTC, and there was no evidence to support the roles of PTEN, TSHR, or TRKA. Familial nonmedullary thyroid cancer is an emerging clinical phenotype that is genetically heterogeneous, and none of the currently identified genes accounts for the majority of families.     

Lack of mutations in the thyroid hormone receptor (TR) alpha and beta genes but frequent hypermethylation of the TRbeta gene in differentiated thyroid tumors

CONTEXT: It remains inconclusive whether mutations in thyroid hormone receptor (TR) genes naturally occur in thyroid cancer and whether these genes could be suppressors of this cancer. OBJECTIVES: Our objectives were to examine further mutations of TRalpha and TRbeta genes in thyroid cancer and also to examine their methylation as an epigenetic silencing mechanism in thyroid cancer. EXPERIMENTAL DESIGN: Instead of using a cDNA sequencing approach used in previous studies, we used genomic DNA to sequence directly the coding regions of the TRalpha and TRbeta genes to search mutations in various differentiated thyroid tumors and used methylation-specific PCR to analyze promoter methylation of these genes. Allelic zygosity status at TRbeta was also analyzed. RESULTS: We found no TRalpha gene mutation in 17 papillary thyroid cancers (PTCs) and 11 follicular thyroid cancers (FTCs), and no TRbeta gene mutation in 16 PTCs and 12 FTCs. We also found no methylation of the TRalpha gene in 33 PTCs, 31 FTCs, 20 follicular thyroid adenomas (FTAs), and 10 thyroid tumor cell lines. In contrast, we found hypermethylation of the TRbeta gene in 10 of 29 (34%) PTCs, 22 of 27 (81%) FTCs, five of 20 (25%) follicular thyroid adenomas, and three of 10 (30%) thyroid tumor cell lines, with the highest prevalence in FTC. We additionally examined loss of heterozygosity at TRbeta and found it in three of nine (33%) PTCs and three of nine (33%) FTCs. CONCLUSIONS: Mutation is not common in TR genes, whereas hypermethylation of the TRbeta gene as an alternative gene silencing mechanism is highly prevalent in thyroid cancer, particularly FTC, consistent with a possible tumor suppressor role of this gene for FTC.     

Transcriptional profiling reveals coordinated up-regulation of oxidative metabolism genes in thyroid oncocytic tumors

Oncocytomas are large cell tumors characterized by an abnormal proliferation of mitochondria. To investigate this phenomenon in thyroid oncocytomas, we determined gene expression profiles of 87 samples using microarrays of 6720 PCR products from cDNA clones. Samples included 29 thyroid oncocytomas and six papillary carcinomas, the remainder representing other thyroid pathologies or mitochondria-rich tumor samples, normal thyroid samples, and two thyroid cell lines. Hierarchical clustering and supervised analysis identified two specific oncocytic clusters and 163 distinctly regulated genes between oncocytoma and normal thyroid. Differential expression of five selected genes (APOD, BCL-2, COX, CTSB, and MAP2) was confirmed by immunohistochemistry. The two specific oncocytic clusters were rich in mitochondrial genes and revealed coordinated expression of nuclear and mitochondrial respiratory chain genes. We also observed the up-regulation of genes involved in mitochondrial biogenesis, such as nuclear respiratory factor 1 and the endothelial nitric oxide synthase. Several oxidative metabolism genes were overexpressed in oncocytomas, including those from the tricarboxylic acid cycle (MDH1) and cytosolic glycolysis (GAPD, ENO1, and GPI). On the contrary, the lactate dehydrogenase A gene, involved in anaerobic metabolism, was down-regulated. Our results suggest that, unlike a large number of solid tumors, thyroid oncocytomas produce energy through an aerobic pathway.     

先天性甲状腺功能减退症的基因研究

先天性甲状腺功能减退症(先天性甲减)是最常见的小儿代谢性疾病,如果不及时治疗可引起严重的智力及体格发育障碍。其病因系先天性甲状腺发育不良或甲状腺激素合成途径中的酶缺陷所造成,大多数为散发,少数有家族史。影响甲状腺发育的基因有:促甲状腺激素受体、转录因子s、hh基因的缺陷,影响甲状腺激素合成的基因有:甲状腺过氧化物酶、甲状腺球蛋白、PDS基因、钠碘同向转运体、甲状腺氧化酶基因缺陷。这些基因缺陷在先天性甲减患者中起着重要的作用。