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1.
Artigo em Chinês | MEDLINE | ID: mdl-31623036

RESUMO

Objective:To explore the relationships between trefoil factor 3(TFF3) gene polymorphisms and susceptibility to papillary thyroid carcinoma(PTC) in Han population of northern China. Method:A case-control study was performed in 123 PTC patients and 108 healthy controls. Four SNPs in the TFF3 gene, including rs225361, rs533093, rs9981660 and rs225439, were detected by gene sequencing. Result:Compared with healthy people, there was no significant difference in the genotype frequencies of rs225361, rs9981660, rs533093 and rs225439 alleles in the PTC group(P>0.05). The CGTC and CGTT haploids of TFF3 gene were positively correlated with the occurrence of PTC, and CGCC and TGTC haploids were negatively correlated with the occurrence of PTC. TT genotype of rs9981660 had significant differences in the distribution of PTC with and without lymph node metastasis(P<0.05). Conclusion:Polymorphisms in 4 SNP loci in the TFF3 gene may be unrelated to the occurrence of PTC. The CGTC, CGTT, CGCC and TGTC haploids in the TFF3 gene might be related to the development of PTC. The TT genotype at rs9981660 may be associated with lymph node metastasis of PTC.


Assuntos
Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Fator Trefoil-3/metabolismo , Carcinoma Papilar , Estudos de Casos e Controles , China , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único
2.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(4): 517-523, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31484615

RESUMO

To analyze the potential associations of ultrasound-guided fine-needle aspiration(FNA),BRAF V600E gene mutation detection,and the combination of these two techniques with the clinicopathological features of papillary thyroid cancer(PTC). Methods Patients with PTC confirmed by surgery from April 2016 to July 2017 were included in this study.The relationship between clinicopathological features and BRAF V600E mutation,FNA results,and the combination of them were explored. Results The sensitivity of FNA was 86.3%(227/263)and the mutation rate of BRAF V600E was 85.9%(226/263)in 263 patients with PTC.The mutation rate of papillary thyroid microcarcinoma(PTMC)was 91.1%(153/168)and that of non-PTMC was 76.8%(73/95).A total of 225 patients underwent lymph node dissection.The lymph node metastasis rate was 35.6%(80/225),and it was 23.8%(34/143)in PTMC,56.1%(46/82)in non-PTMC;in addition,9.9%(26/263)of PTC patients had extracapsular invasion.BRAF V600E mutation rate was higher in patients with the following features:aged over 45 years(P=0.043);the tumor was FNA diagnosed as malignant or suspected malignant(P=0.011);the tumor had a maximum diameter of ≤1 cm(P=0.001);and the primary tumor was in stage T1(P=0.039);however,there was no significant difference in BRAF V600E mutation rate among patients with different sex,capsule invasion,or lymph node metastasis.The diagnostic sensitivity of FNA was not statistically different under different clinical and pathological characteristics.The clinicopathologic features of FNA and BRAF V600E double-positive patients were not significantly different from those of other patients. Conclusion FNA-confirmed malignancy,BRAF V600E gene mutation,and their double-positive results are not correlated with the invasive pathological features of PTC,and thus their roles in guiding an extended operation(or not)are limited.


Assuntos
Biópsia por Agulha Fina , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Humanos , Metástase Linfática , Mutação , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética
3.
Orv Hetil ; 160(36): 1417-1425, 2019 Sep.
Artigo em Húngaro | MEDLINE | ID: mdl-31492087

RESUMO

Introduction: Twenty-five percent of fine-needle aspiration biopsy samples of thyroid nodules produce indeterminate cytological results. Genetic testing of nodules can contribute to accurate diagnosis. Aim: Developing the first gene panel in Europe utilizing the 23 most relevant thyroid oncogenes with 568 mutations. Method: Examination of the isolated DNA from biopsy samples by Ion Torrent new generation sequencing. Results: The validation of our method was performed on tumor tissue samples, in which 127 genetic variations were identified, yet unknown in thyroid tumors. AXIN1 was the most polymorphic gene, while BRAF c.1799T>A (V600E) was the most frequently identified mutation. We detected 36 clinically relevant variants, 75% of which have not been described in the literature. Six of our 8 cytologically malignant and 8 of our 14 indeterminate as well as 20 of our 28 cytologically benign samples were identified as containing pathologic variants in a driver gene (BRAF c.1799T>A, NRAS c.181C>A). Conclusion: We have developed a validated, reliable new generation sequencing-based method with high positive predictive value (89%) and sensitivity (79%), suitable for the early detection of malignant lesions in the thyroid. Orv Hetil. 2019; 160(36): 1417-1425.


Assuntos
Testes Genéticos/métodos , Patologia Molecular/métodos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/genética , Biópsia por Agulha Fina/métodos , Análise Mutacional de DNA , Europa (Continente) , Humanos , Mutação , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/patologia
4.
Zhonghua Yi Xue Za Zhi ; 99(36): 2831-2835, 2019 Sep 24.
Artigo em Chinês | MEDLINE | ID: mdl-31550811

RESUMO

Objective: To investigate the expression of Golgi phosphoprotein 3 (GOLPH3) in papillary thyroid carcinoma (PTC) and its relationship with clinicopathological characteristics of PTC and American Thyroid Association (ATA) risk of recurrence stratification. Methods: The mRNA expression level of GOLPH3 in PTC tissues and the matched adjacent noncancerous tissues from 30 cases of PTC undergoing surgical operation in Fujian Provincial Hospital between March 2017 and April 2018 was detected by reverse transcription-quantitative PCR (RT-qPCR). The protein expression of GOLPH3 in PTC tissues and the matched adjacent noncancerous tissues of 135 cases of PTC between January 2013 and April 2018 was measured by immunohistochemistry. The correlation between the expression of GOLPH3 in PTC and clinicopathologic characteristics and ATA risk of recurrence stratification was analyzed. Results: The mRNA level of GOLPH3 in PTC tissues was significantly higher than that in adjacent noncancerous tissues (7.53±1.32 vs 3.64±1.44, P<0.001). The protein expression level of GOLPH3 in PTC tissues was significantly higher than that in adjacent noncancerous tissues [66(30, 95) vs 34(20, 72), P<0.001]. The expression of GOLPH3 was significantly correlated to the tumor size (P=0.026), extrathyroid invasion (P=0.016), lymph node metastasis (P=0.001) and TNM stage (P=0.027) in PTC. Multivariate logistic regression analysis showed that GOLPH3 expression was independently correlated to tumor size (OR=3.58, 95%CI: 1.19-15.46, P=0.017) and lymph node metastasis (OR=7.28, 95%CI: 2.43-10.08, P=0.002). The expression of GOLPH3 was positively correlated to ATA risk of recurrence stratification (P=0.041). Conclusions: Overexpression of GOLPH3 is associated with the development of PTC and poor prognosis in patients with PTC. Detection of GOLPH3 expression can help evaluate proliferative and metastatic potential of PTC, as well as the risk of postoperative recurrence in patients with PTC.


Assuntos
Proteínas de Membrana/genética , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Metástase Linfática , Recidiva Local de Neoplasia , Fosfoproteínas , Prognóstico , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética
5.
Anticancer Res ; 39(8): 4095-4100, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366493

RESUMO

BACKGROUND/AIM: Ethacridine is used as a topical antiseptic as well as for second-trimester abortion. Recent studies showed that ethacridine is an inhibitor of poly(ADP-ribose) glycohydrolase (PARG) and an activator of the transcriptional coactivator with PDZ-binding motif (TAZ). This study examined the effects of ethacridine on thyroid cancer cells. MATERIALS AND METHODS: Thyroid cancer cell lines (FTC133 and SW1736) and thyroid follicular epithelial cells (Nthy-ori 3-1) were treated with ethacridine. Viability, clonogenicity, cell-cycle distribution, and apoptosis were evaluated. The expression of thyroid differentiation markers (TTF-1, PAX8, and NIS) was determined by real-time PCR. RESULTS: Ethacridine suppressed cell growth and clonogenic ability of thyroid cancer cells in a time- and dose-dependent manner (p<0.001). No cell-cycle arrest was found, but ethacridine dose-dependently induced apoptosis of thyroid cancer cells (p<0.001). The PAX8 and NIS expressions were significantly increased in SW1736 (3.41-fold and 1.53-fold, respectively) and Nthy-ori 3-1 cells (2.73-fold and 4.12-fold, respectively). CONCLUSION: Ethacridine elicits apoptotic cell death in thyroid cancer cells and promotes differentiation in a subset of thyroid follicular cells.


Assuntos
Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Etacridina/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Transcrição PAX8/genética , Simportadores/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Fator Nuclear 1 de Tireoide/genética
6.
Zhonghua Zhong Liu Za Zhi ; 41(8): 594-598, 2019 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-31434450

RESUMO

Objective: To explore the molecular characteristics of follicular variant papillary thyroid carcinoma (FVPTC), follicular thyroid adenoma (FTA) and follicular thyroid carcinoma (FTC), and investigate their role in tumorigenesis, differential diagnosis and prognosis evaluation in patients with follicular thyroid neoplasm. Methods: We retrospectively analyzed 50 surgical resection samples of follicular thyroid neoplasm. DNA was obtained from formalin-fixed, paraffin-embedded tissue, and subjected to next-generation sequencing (NGS) to analyze 50 hotspots for mutation in genes. Results: 47 samples passed quality control, including 29 FVPTCs, 8 FTAs and 10 FTCs. 75.9% of FVPTCs harbored mutated genes: BRAF V600E (31.0%, 9/29) was the most frequent, followed by TP53 (27.6%, 8/29), and N/KRAS (20.7%, 6/29). In contrast, 37.5% (3/8) FTAs carried NRAS Q61R mutation with 12.5% (1/8) FTA carrying mutated BRAF G466E. 20% (2/10) FTCs harbored NRAS Q61R mutation, and 20% (2/10) FTCs with TP53 mutations. BRAF V600E gene mutation only appeared in FVPTC, and was associated with age of onset and lymph node metastasis. There was no significant correlation between N/KRAS mutations and clinical pathologic features. Patients with lymph node metastasis group seems to have more TP53 mutation. Conclusions: BRAF V600E gene mutation can be used to identity FVPTC from FTA/FTC. N/KRAS mutations cannot be used as the exclusive indicator of benign and malignant in thyroid follicular tumor. TP53 mutations play an important role in the process of follicular thyroid neoplasm, indicating more aggressive behavior and poor prognosis.


Assuntos
Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Humanos , Metástase Linfática/genética , Mutação , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genética
7.
J Surg Oncol ; 120(6): 1023-1030, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31407354

RESUMO

BACKGROUND: Papillary thyroid microcarcinoma exhibits an indolent clinical course and could be a candidate for active surveillance in the appropriate setting. It remains unknown whether papillary microcarcinoma is biologically different from larger papillary carcinoma >1 cm. METHODS: We analyzed clinicopathological information and transcriptome data of papillary thyroid cancer samples from The Cancer Genome Atlas. Propensity-score matching was used to construct a matched cohort consisting of 29 microcarcinomas and 58 carcinomas. Principal component analysis and unsupervised hierarchical cluster analysis were carried out to investigate the similarity of gene expression profiles. RESULTS: After adjustment for differences in baseline clinicopathological and genetic factors, transcriptome could be grouped mainly on the basis of tumor class (BRAF-like vs RAS-like) and tumor size (microcarcinoma vs carcinoma). The gene set enrichment analysis showed that extracellular matrix-associated pathways were enriched in the MSigDB database. CONCLUSION: Papillary thyroid microcarcinomas display a distinct gene expression pattern different from the corresponding carcinomas. We hypothesize that tumor microenvironment may play a role in the microcarcinoma/carcinoma phenotypic divergence.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Papilar/patologia , Pontuação de Propensão , Neoplasias da Glândula Tireoide/patologia , Transcriptoma , Adulto , Carcinoma Papilar/classificação , Carcinoma Papilar/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/classificação , Neoplasias da Glândula Tireoide/genética
8.
Bioengineered ; 10(1): 306-315, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299871

RESUMO

Long non-coding RNA H19 (H19) is highly expressed in cancers and is considered to highly correlate with the extent of malignant degree. The present study was performed to determine the expression levels of H19 in anaplastic thyroid carcinoma (ATC) tissues and the role of H19 in ATC 8505C cells in vitro and in vivo. Expression of H19 was detected in 19 ATC and 19 normal thyroid tissues by real-time quantitative polymerase chain reaction. Utilizing the siRNA or short hairpin RNA (shRNA) directed against human H19 (H19 siRNA or shRNA H19) depleted H19 in ATC 8505C cells and characterized the outcomes. The results showed that H19 was overexpressed in ATC tissues. Targeting H19 inhibited proliferation, migration, and invasion and induced apoptosis in 8505C cells in vitro and inhibited tumorigenesis and metastasis in vivo. Therefore, the H19 might be an effective target for ATC molecular therapy.


Assuntos
Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Terapia de Alvo Molecular/métodos , RNA Longo não Codificante/genética , Carcinoma Anaplásico da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Animais , Apoptose/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Metástase Linfática , Camundongos , Camundongos Nus , Invasividade Neoplásica , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Carcinoma Anaplásico da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Carcinoma Anaplásico da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/metabolismo , Nódulo da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/cirurgia , Tireoidectomia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Medicine (Baltimore) ; 98(28): e16343, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305422

RESUMO

To estimate the BRAFV600E mutation frequency in Chinese patients with papillary thyroid carcinoma (PTC), and the diagnostic value of BRAFV600E mutation status in thyroid nodules with indeterminate TBSRTC categories.A total of 4875 consecutive samples for thyroid ultrasound-guided fine-needle aspiration cytology (FNAC) and BRAF mutation analysis were collected from patients at Jiangsu Province Hospital on Integration of Chinese and Western Medicine. Among all the cases, 314 underwent thyroidectomy. According to TBSRTC categories, FNAC was performed for a preoperative diagnosis. ROC of the subject was constructed to evaluate the diagnostic value of these 2 methods and their combination.BRAF mutation in FNAC of thyroid nodules occurred in 2796 samples (57.35%). Of 353 nodule samples from 314 patients with thyroid operation, 333 were pathologically diagnosed as PTC. Of these PTC patients, 292 (87.69%) were found to have BRAF mutation in their preoperative FNAC. In 175 cytologically indeterminate thyroid nodules, BRAF mutation identified 88% of PTC. According to ROC data, BRAF mutation testing had an obviously higher sensitivity (87.69%) and specificity (100.00%) than TBSRTC. Combining BRAF mutation testing and TBSRTC achieved the largest AUC (0.954). For 41 PTC with a negative BRAF mutation in preoperative evaluation, the repeated BRAF mutation testing found out 12 samples with BRAF mutation. The true BRAF mutation rate of Chinese PTC patients was 91.29%.Chinese patients with PTC have a higher frequency of BRAF mutation. The BRAF mutation testing affords a high diagnostic value in thyroid nodules with indeterminate cytology.


Assuntos
Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/metabolismo , Nódulo da Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biópsia por Agulha Fina , Criança , China , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/metabolismo , Sensibilidade e Especificidade , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/terapia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia , Ultrassonografia de Intervenção , Adulto Jovem
10.
Int J Oncol ; 55(1): 21-34, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180559

RESUMO

Emerging studies have indicated that leucine­rich repeat kinase 2 (LRRK2) is associated with thyroid cancer (TC). The present study investigated the effect of LRRK2 on the cell cycle and apoptosis in TC, and examined the underlying mechanisms in vitro. To screen TC­associated differentially expressed genes, gene expression microarray analysis was conducted. Retrieval of pathways associated with TC from the Kyoto Encyclopedia of Genes and Genomes database indicated that the c­Jun N­terminal kinase (JNK) signaling pathway serves an essential role in TC. SW579, IHH­4, TFC­133, TPC­1 and Nthy­ori3­1 cell lines were used to screen cell lines with the highest and lowest LRRK2 expression for subsequent experiments. The two selected cell lines were transfected with pcDNA­LRRK2, or small interfering RNA against LRRK2 or SP600125 (a JNK inhibitor). Subsequently, flow cytometry, terminal deoxynucleotidyl transferase­mediated dUTP­biotin nick end labeling, a 5­ethynyl­2'­deoxyuridine assay and a scratch test was conducted to detect the cell cycle distribution, apoptosis, proliferation and migration, respectively, in each group. The LRRK2 gene was determined to be elevated in TC based on the microarray data of the GSE3678 dataset. The SW579 cell line was identified to exhibit the highest LRRK2 expression, while IHH­4 cells exhibited the lowest LRRK2 expression. LRRK2 silencing, through inhibiting the activation of the JNK signaling pathway, increased the expression levels of genes and proteins associated with cell cycle arrest and apoptosis in TC cells, promoted cell cycle arrest and apoptosis, and inhibited cell migration and proliferation in TC cells, indicating that LRRK2 repression could exert beneficial effects through the JNK signaling pathway on TC cells. These observations demonstrate that LRRK2 silencing promotes TC cell growth inhibition, and facilitates apoptosis and cell cycle arrest. The JNK signaling pathway may serve a crucial role in mediating the anti­carcinogenic activities of downregulated LRRK2 in TC.


Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/biossíntese , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Sistema de Sinalização das MAP Quinases , Neoplasias da Glândula Tireoide/enzimologia , Neoplasias da Glândula Tireoide/genética , Antracenos/farmacologia , Apoptose/fisiologia , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação para Baixo , Ativação Enzimática , Humanos , MAP Quinase Quinase 4/antagonistas & inibidores , MAP Quinase Quinase 4/metabolismo , Neoplasias da Glândula Tireoide/patologia , Transfecção
11.
Biochemistry (Mosc) ; 84(4): 416-425, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31228933

RESUMO

The Q61R mutation of the NRAS gene is one of the most frequent driver mutations of thyroid cancer. Tumors with this mutation are characterized by invasion into blood vessels and formation of distant metastases. To study the role of this mutation in the growth of thyroid cancer, we developed a model system on the basis of thyroid epithelial cell line Nthy-ori 3-1 transduced by a lentiviral vector containing the NRAS gene with the Q61R mutation. It was found that the expression of NRAS(Q61R) in thyroid epithelial cells has a profound influence on groups of genes involved in the formation of intercellular contacts, as well as in processes of epithelial-mesenchymal transition and cell invasion. The alteration in the expression of these genes affects the phenotype of the model cells, which acquire traits of mesenchymal cells and demonstrate increased ability for survival and growth without attachment to the substrate. The key regulators of these processes are transcription factors belonging to families SNAIL, ZEB, and TWIST, and in different types of tumors the contribution of each individual factor can vary greatly. In our model system, phenotype change correlates with an increase in the expression of SNAIL2 and TWIST2 factors, which indicates their possible role in regulating invasive growth of thyroid cancer with the mutation of NRAS(Q61R).


Assuntos
Transição Epitelial-Mesenquimal , GTP Fosfo-Hidrolases/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias da Glândula Tireoide/genética , Transcriptoma , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , GTP Fosfo-Hidrolases/genética , Humanos , Proteínas de Membrana/genética , Mutagênese Sítio-Dirigida , Fenótipo , Transdução de Sinais , Fatores de Transcrição da Família Snail/metabolismo , Células Epiteliais da Tireoide/citologia , Células Epiteliais da Tireoide/metabolismo , Fatores de Transcrição Twist/metabolismo
12.
Nat Commun ; 10(1): 2764, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235699

RESUMO

Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAFV600E and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Carcinoma Anaplásico da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Transcriptoma/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Medicina de Precisão/métodos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/genética , Análise de Sobrevida , Carcinoma Anaplásico da Tireoide/mortalidade , Carcinoma Anaplásico da Tireoide/patologia , Carcinoma Anaplásico da Tireoide/terapia , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia , Regulação para Cima
13.
Anticancer Res ; 39(6): 2811-2819, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177118

RESUMO

BACKGROUND/AIM: Recent knowledge implicates a differential expression of the insulin-like growth factor-I (IGF-I) mRNA splice variants (i.e., IGF-IEa, IGF-IEb and IGF-IEc) in cancerous tissues, implying possible specific roles of the encoded IGF-I protein isoforms in cancer biology. In particular, there is growing evidence that the IGF-IEc isoform may play a distinct biological role in various types of cancers. The present study investigated whether IGF-IEc expression is associated with a particular type of thyroid cancer. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded tissue specimens of different types of thyroid cancers from 92 patients were assessed for IGF-IEc expression by immunohistochemistry. In addition, thyroid cancer biopsies of different TNM staging histological types were evaluated for mRNA expression of the IGF-IEc transcript by real-time polymerase chain reaction (PCR). RESULTS: From the total number of 92 samples, 2 were anaplastic, 10 medullary, 4 hyperplasias of C-cells, 11 follicular, 5 hurtle cell carcinomas, 2 poorly differentiated, 5 nodular hyperplasias, 1 lymphoma and 52 were papillary thyroid cancers. The age of cancer diagnosis or tumor size did not significantly affect the IGF-IEc expression. Among all types of cancers, IGF-IEc was expressed in papillary differentiated thyroid cancer. Its expression/localization was mainly cytoplasmic and significantly associated with TNM staging and the presence of muscular and capsule cancerous invasion (p<0.05). Similarly, a differential profile was revealed regarding the mRNA expression of the IGF-IEc transcript, that exhibited a higher expression in aggressive compared to the non-aggressive papillary cancers. CONCLUSION: IGF-IEc isoform expression in thyroid cancer is positively associated with more advanced stages of papillary thyroid cancer.


Assuntos
Processamento Alternativo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Regulação para Cima , Adolescente , Adulto , Idoso , Citoplasma/genética , Citoplasma/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Carga Tumoral , Adulto Jovem
14.
Praxis (Bern 1994) ; 108(8): 535-540, 2019 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-31185849

RESUMO

Benefits of Molecular Analyses in Thyroid Carcinoma Abstract. The widespread access to neck ultrasonography has led to high detection rates of thyroid nodules, whose vast majority will remain clinically silent. In daily practice it is a challenge to filter out the thyroid nodules that require medical attention. This is usually achieved by a combination of sonomorphologic criteria and fine-needle aspiration cytology. In recent years, there is a trend toward deescalation in diagnostic and therapeutic measures for thyroid nodules. Some authors even advocate active surveillance instead of surgical approaches for very low-risk thyroid carcinoma. This approach requires an accurate assessment of the malignant potential of each thyroid nodule. As recent studies have allowed better understanding of molecular pathogenesis of thyroid cancer, the mutational profile of thyroid nodules has emerged as a new tool for assessment of thyroid nodules. Its exact clinical application in daily routine remains, however, unclear.


Assuntos
Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Biópsia por Agulha Fina , Humanos , Mutação , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/genética , Ultrassonografia
15.
Clin Nucl Med ; 44(7): 544-549, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31107749

RESUMO

PURPOSE: Brain metastases (BMs) in patients with differentiated thyroid cancer (DTC) are rare but associated with poor prognosis. We examined risk factors for overall survival (OS) in this population and explored the pattern of genomic alterations. METHODS: Single-institution, retrospective review of all patients with DTC from January 2000 to November 2016 identified 79 patients for analysis. Multiple prognostic factors, including age, gender, distal metastasis (DM), diagnosis time, DM sites, BM diagnosis time, BM number and size, genomic sequencing data, craniectomy, external beam radiation therapy, and kinase inhibitor therapies, were evaluated. Univariate and multivariate analyses were performed. RESULTS: Median survival after BM was 18 months. One- and 3-year survival rates were 63% and 33%, respectively. Univariate analysis identified 4 covariates correlated with prolonged survival: time between DTC diagnosis and BM for less than 3 years (P = 0.01), time from initial DM diagnosis to BM for 22 months or less (P = 0.03), 3 BM sites or fewer (P = 0.002), and craniectomy (P = 0.05). Multivariate model revealed 3 variables associated with OS: DTC diagnosis to BM time of less than 3 years (P = 0.04), craniectomy (P = 0.06), and patients with fewer than 3 BM sites (P = 0.06). The majority of patients with BM had a telomerase reverse transcriptase promoter mutation, However, mutational status was not an independent predictor of survival. CONCLUSIONS: For BM from DTC, time interval between DTC diagnosis and BM, number of BM sites, and craniectomy were independently associated with OS. Further studies are needed to define the role of genomic mutations in advanced cancer.


Assuntos
Adenocarcinoma/patologia , Neoplasias Encefálicas/secundário , Oncogenes , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adulto , Idoso , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Atenção Terciária à Saúde/estatística & dados numéricos , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genética
16.
BMC Med Genet ; 20(1): 92, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138213

RESUMO

BACKGROUND: This study aimed to establish an artificial neural network (ANN) model based on variant pathways to predict the risk of thyroid cancer. METHODS: The RNASeq data of 482 thyroid cancer samples were downloaded from the TCGA database. The samples were divided into low-risk and high-risk groups, followed by identification of differentially expressed genes (DEGs). Co-expression analysis and pathway enrichment analysis were then performed. The variant pathways were screened according to the functional deviation score of each pathway, and an ANN model was established. Finally, the efficiency of the ANN model for risk assessment was validated by survival analysis and analysis of an independent microarray dataset (GSE34289) for thyroid cancer. RESULTS: In total, 190 DEGs (85 up-regulated and 105 down-regulated) were identified between the low-risk and high-risk groups. Ten risk-related variant pathways were identified between the low-risk and high-risk groups, which were related to inflammatory and immune responses. Based on these variant pathways, an ANN model was built, consisting of an input layer, two hidden layers, and an output layer, corresponding to 15, 8, 5, and 1 neuron, respectively. Survival analysis showed that this model could effectively distinguish the samples with different risks. Analysis of microarray dataset GSE34289 showed that the accuracy of this model for predicating low-risk and high-risk samples was 77.5 and 86.0%, respectively. CONCLUSIONS: This study suggests that the ANN model based on variant pathways can be used for effectively evaluating the risk of thyroid cancer.


Assuntos
Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Redes Neurais (Computação) , Neoplasias da Glândula Tireoide/genética , Biomarcadores Tumorais/genética , Análise por Conglomerados , Humanos , Fatores de Risco , Transdução de Sinais/genética
17.
Eur J Endocrinol ; 181(1): 1-11, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042674

RESUMO

Objective: Follicular-derived thyroid cancers generally have a good prognosis, but in a minority of cases, they have an aggressive behavior and develop distant metastases, with an increase in the associated mortality. None of the prognostic markers currently available prior to surgery can identify such cases. Methods: TERT promoter and BRAF gene mutations were examined in a series of 436 consecutive TIR-4 and TIR-5 nodes referred for surgery. Follow-up (median: 59 months, range: 7-293 months) was available for 384/423 patients with malignant nodes. Results: TERT promoter and BRAF mutations were detected in 20/436 (4.6%) and 257/434 thyroid nodules (59.2%), respectively. At the end of the follow-up, 318/384 patients (82.8%) had an excellent outcome, 48/384 (12.5%) had indeterminate response or biochemical persistence, 18/384 (4.7%) had a structural persistence or died from thyroid cancer. TERT promoter mutations correlated with older age (P < 0.0001), larger tumor size (P = 0.0002), oxyntic and aggressive PTC variants (P = 0.01), higher tumor stages (P < 0.0001), distant metastases (<0.0001) and disease outcome (P < 0.0001). At multivariate analysis, TERT promoter mutation was not an independent predictor of disease outcome. TERT promoter mutation- (OR: 40.58; 95% CI: 3.06-539.04), and N1b lymph node metastases (OR: 40.16, 95% CI: 3.48-463.04) were independent predictors of distant metastases. BRAF mutation did not predict the outcome, and it correlated with a lower incidence of distant metastases (P = 0.0201). Conclusions: TERT promoter mutation proved an independent predictor of distant metastases, giving clinicians the chance to identify many of the patients who warranted more aggressive initial treatment and closer follow-up.


Assuntos
Carcinoma Papilar, Variante Folicular/genética , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Telomerase/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patologia , Adulto , Fatores Etários , Carcinoma Papilar, Variante Folicular/patologia , Feminino , Humanos , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Carga Tumoral
18.
Cancer Sci ; 110(7): 2180-2188, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31046163

RESUMO

Novel diagnostic and prognostic biomarkers of cancers are needed to improve precision medicine. Circular RNAs act as important regulators in cancers at the transcriptional and posttranscriptional levels. The circular RNA circMAN1A2 is highly expressed in nasopharyngeal carcinoma according to our previous RNA sequencing data; however, the expression and functions of circMAN1A2 in cancers are still obscure. Therefore, in this study, we evaluated the expression of circMAN1A2 in the sera of patients with nasopharyngeal carcinoma and other malignant tumors and analyzed its correlations with clinical features and diagnostic values. The expression levels of circMAN1A2 were detected by quantitative real-time PCR, and the correlations of clinical features with circMAN1A2 expression were analyzed by χ2 tests. Receiver operating characteristic curves were used to evaluate the clinical applications of circMAN1A2. The results showed that circMAN1A2 was upregulated in nasopharyngeal carcinoma, oral cancer, thyroid cancer, ovarian cancer, and lung cancer, with areas under the curves of 0.911, 0.779, 0.734, 0.694, and 0.645, respectively, indicating the good diagnostic value of circMAN1A2. Overall, our findings suggested that circMAN1A2 could be a serum biomarker for malignant tumors, providing important insights into diagnostic approaches for malignant tumors. Further studies are needed to elucidate the mechanisms of circMAN1A2 in the pathogenesis of cancer.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias/genética , RNA/genética , Regulação para Cima , Biomarcadores Tumorais/genética , Detecção Precoce de Câncer , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Masculino , Neoplasias Bucais/sangue , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/genética , Carcinoma Nasofaríngeo/sangue , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/genética , Neoplasias/sangue , Neoplasias/diagnóstico , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Sequenciamento Completo do Exoma
19.
Indian J Cancer ; 56(2): 173-175, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31062739

RESUMO

A 41 year old man presented with a familial history of multiple endocrine neoplasia type 2A (MEN2A) and severe hypertension. Rearranged during transfection (RET) gene sequencing confirmed a Cys634Tyr mutation of TGC to TAC. Total thyroidectomy and bilateral neck dissection were performed and the pathological assessment revealed a medullary thyroid carcinoma (MTC), 0.6 cm in size on the right side (number of lymph nodes: 0/2, 0/15, 0/12, and 0/8 in areas VI, II, III, and IV, respectively) and a papillary thyroid carcinoma (PTC), 0.2 cm in size on the left side (numbers of lymph nodes: 2/6, 0/3, 0/10, and 0/6 in areas VI, II, III, and IV, respectively). There were no pathological changes in the MTC observed in the thyroid tissues on the left side. We believe that the follow-up of patients with both MTC and PTC should utilize a combination of the respective principles for rational disease reassessment.


Assuntos
Carcinoma Neuroendócrino/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Proteínas Proto-Oncogênicas c-ret/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Carcinoma Neuroendócrino/patologia , Mutação em Linhagem Germinativa , Humanos , Linfonodos/patologia , Masculino , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia
20.
Oncol Rep ; 41(6): 3270-3280, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002347

RESUMO

Leucine­rich­alpha­2­glycoprotein 1 (LRG­1) has been reported to be associated with multiple malignancies. However, its participation in thyroid carcinoma progression remains unclear. In the present study, the biological function and underlying molecular mechanisms of LRG­1 in thyroid carcinoma were investigated. It was found that LRG­1 was overexpressed in thyroid carcinoma tissues, and high LRG­1 expression predicted poor patient survival and late tumor stage. As shown in the mouse xenograft study, knockdown of LRG­1 significantly attenuated thyroid cancer growth in vivo. Based on wound healing, Transwell, proliferation and apoptosis assays, it was found that the knockdown of LRG­1, using shLRG­1, inhibited cell migration and invasion, but did not affect proliferation and apoptosis in thyroid cancer cells. Furthermore, LRG­1 also induced epithelial­mesenchymal transition (EMT) in thyroid carcinoma cells. Western blot analysis revealed that this tumor­promoting bioactivity of LRG­1 was attributed to its selective activation of MAPK/p38 signaling. All of these findings indicate that LRG­1 plays a deleterious role in the progression of thyroid carcinoma. LRG­1 may serve as a promising biomarker for predicting prognosis in thyroid carcinoma patients, and LRG­1­based therapy may be developed into a novel strategy for the treatment of thyroid carcinoma.


Assuntos
Biomarcadores Tumorais/genética , Transição Epitelial-Mesenquimal/genética , Glicoproteínas/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Idoso , Animais , Apoptose/genética , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Glicoproteínas/antagonistas & inibidores , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , Transdução de Sinais , Neoplasias da Glândula Tireoide/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/genética
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