Sete anos de seguimento de uma paciente jovem com carcinoma papílfero de tireóide e mutação de BRAF e perda de expressão de genes do metabolismo de iodo

BACKGROUND: Recent studies reported that BRAF V600E mutation, the most prevalent genetic event found in papillary thyroid carcinoma, is an independent poor prognostic marker. Additionally, it correlates with a less differentiated tumor stage due to reduced expression of key genes involved in iodine metabolism. We previously described a patient with BRAF V600E mutation in primary tumor and a new mutation (V600E+K601del) in the matched-lymph node metastases. In the present study we report an unusual clinical behavior of PTC and correlate with BRAF mutational status and level of expression of TSHR and NIS. METHODS: Quantitative PCR (qPCR) was used to evaluate the NIS and TSHR level of expression in matched papillary thyroid carcinoma and adjacent normal tissue. RESULTS: In this study, we presented a seven-year follow up of a juvenile papillary thyroid carcinoma patient who had an aggressive tumor harboring BRAF mutation, and failed to conventional therapy. We found a markedly decrease of NIS and TSHR expression in primary PTC compared to adjacent normal thyroid tissue. CONCLUSION: Our findings suggest that BRAF mutational status and decreased NIS and TSHR expression in this patient may reduce radioiodine uptake and lead to a negative response to radioiodine therapy.INTRODUÇÃO: Estudos recentes demonstraram que a mutação V600E no gene BRAF é o evento genético mais freqüentemente encontrado em carcinoma papilífero da tiróide e um marcador de prognóstico independente. Adicionalmente, esta alteração genética tem sido correlacionada com a redução de expressão de genes envolvidos no metabolismo do iodo. Previamente, nosso grupo descreveu uma paciente com a mutação V600E no gene BRAF no tumor primário e uma mutação nova (V600E+K601del) em metástases pareadas. Neste estudo, reportamos um carcinoma papilífero com um comportamento clínico incomum e correlacionamos com a presença de mutação no gene BRAF e os níveis de expressão de TSHR e NIS. MÉTODO: Análise de expressão dos genes NIS e receptor de TSH (TSHR) através da técnica de PCR em tempo real. RESULTADOS: Descrevemos sete anos de acompanhamento de uma paciente jovem que apresentava um tumor com comportamento agressivo e baixa resposta aos tratamentos convencionais. Uma acentuada diminuição da expressão do TSHR e a ausência de expressão de NIS foram observadas no tumor primário desta paciente quando comparada com o tecido tiroidiano normal adjacente. CONCLUSÃO: Nossos dados sugerem que as mutações encontradas nesta paciente no gene BRAF com conseqüente perda de expressão dos genes NIS e TSHR podem ter reduzido a captação de iodo radioativo e a resposta ao tratamento.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Federal University of São Paulo Division of Genetics and Division of Endocrinology Genetic Bases of Thyroid Tumor LaboratoryUNIFESP, Division of Genetics and Division of Endocrinology Genetic Bases of Thyroid Tumor LaboratorySciEL

ABI3 ectopic expression reduces in vitro and in vivo cell growth properties while inducing senescence

<p>Abstract</p> <p>Background</p> <p>Mounting evidence has indicated that <it>ABI3 </it>(ABI family member 3) function as a tumor suppressor gene, although the molecular mechanism by which ABI3 acts remains largely unknown.</p> <p>Methods</p> <p>The present study investigated <it>ABI3 </it>expression in a large panel of benign and malignant thyroid tumors and explored a correlation between the expression of ABI3 and its potential partner ABI3-binding protein (ABI3BP). We next explored the biological effects of <it>ABI3 </it>ectopic expression in thyroid and colon carcinoma cell lines, in which its expression was reduced or absent.</p> <p>Results</p> <p>We not only observed that <it>ABI3 </it>expression is reduced or lost in most carcinomas but also that there is a positive correlation between <it>ABI3 </it>and <it>ABI3BP </it>expression. Ectopic expression of <it>ABI3 </it>was sufficient to lead to a lower transforming activity, reduced tumor <it>in vitro </it>growth properties, suppressed <it>in vitro </it>anchorage-independent growth and <it>in vivo </it>tumor formation while, cellular senescence increased. These responses were accompanied by the up-regulation of the cell cycle inhibitor <it>p21 </it>^WAF1and reduced ERK phosphorylation and <it>E2F1 </it>expression.</p> <p>Conclusions</p> <p>Our result links <it>ABI3 </it>to the pathogenesis and progression of some cancers and suggests that ABI3 or its pathway might have interest as therapeutic target. These results also suggest that the pathways through which <it>ABI3 </it>works should be further characterized.</p

Investigation of Braf mutation in a series of papillary thyroid carcinoma and matched-lymph node metastasis reveals a new mutation in metastasis

BV UNIFESP: Teses e dissertaçõe

High Prevalence of BRAF Mutation in a Brazilian Cohort of Patients With Sporadic Papillary Thyroid Carcinomas Correlation With More Aggressive Phenotype and Decreased Expression of Iodide-Metabolizing Genes

BACKGROUND: Although several studies undoubtedly demonstrated that BRAF mutation is an important genetic event in the pathogenesis of papillary thyroid carcinoma (PTC), its prognostic significance and correlation with less differentiated states remains unclear. It has been suggested that the discrepancy may be at least partially due to the insufficient number of cases analyzed, epidemiologic factors, and a combination of different variants of PTC included in these studies. METHODS: in this context, the prevalence of the BRAF mutation in a Brazilian cohort of PTCs (n = 120) was first assessed and correlated with clinicopathologic features. the BRAF exon 15 mutation was evaluated by direct sequencing. Furthermore, using quantitative polymerase chain reaction, the issue of whether the expression level of the iodide-metabolizing genes (NIS and TSHR) was correlated with BRAF mutational status was investigated. RESULTS: A high prevalence of the BRAF mutation was found in PTC cases (48%). the BRAF mutation was found to be significantly associated with the classic variant of PTC (66%; P < .0001), although it was found in the follicular variant as well (21%). Subtype stratification demonstrated that the BRAF V600E mutation was associated with tumor size, extrathyroid invasion, the presence of lymph node metastasis and risk of disease recurrence, and mortality in patients with the classic variant of PTC. Moreover, the expression levels of NIS and TSHR were remarkably lower in PTCs harboring the BRAF V600E mutation. CONCLUSIONS: These findings provide further evidence that BRAF might be associated with a more aggressive phenotype and less differentiated state due to decreased expression of iodide-metabolizing genes. the search for a BRAF mutation in the current study population appears to be valuable for predicting prognosis and guiding management in patients with PTC. Cancer 2009;115:972-80. (c) 2009 American Cancer Society.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Genet Bases Thyroid Tumor Lab, Div Endocrinol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Div Genet, Genet Bases Thyroid Tumor Lab, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Genet Bases Thyroid Tumor Lab, Div Endocrinol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Div Genet, Genet Bases Thyroid Tumor Lab, BR-04039032 São Paulo, BrazilFAPESP: 05/60330-8Web of Scienc

Gene expression profiling of papillary thyroid carcinoma identifies transcripts correlated with BRAF mutational status and lymph node metastasis

Purpose: To identify papillary thyroid carcinoma (PTC)-associated transcripts, we compared the gene expression profiles of three Serial Analysis of Gene Expression libraries generated from thyroid tumors and a normal thyroid tissue.Experimental Design: Selected transcripts were validated in a panel of 57 thyroid tumors using quantitative PCR (qPCR). An independent set of 71 paraffin-embedded sections was used for validation using immunohistochemical analysis. To determine if PTC-associated gene expression could predict lymph node involvement, a separate cohort of 130 primary PTC (54 metastatic and 76 nonmetastatic) was investigated. the BRAF(V600E) mutational status was compared with qPCR data to identify genes that might be regulated by abnormal BRAF/MEK/extracellular signal-regulated kinase signaling.Results: We identified and validated new PTC-associated transcripts. Three genes (CST6, CXCL14, and DHRS3) are strongly associated with PTC. Immunohistochemical analysis of CXCL14 confirmed the qPCR data and showed protein expression in PTC epithelial cells. We also observed that CST6, CXCL14, DHRS3, and SPP1 were associated with PTC lymph node metastasis, with CST6, CXCL14, and SPP1 being positively correlated with metastasis and DHRS3 being negatively correlated. Finally, we found a strong correlation between CST6 and CXCL14 expression and BRAF(V600E) mutational status, suggesting that these genes may be induced subsequently to BRAF activation and therefore may be downstream in the BRAF/MEK/extracellular signal-regulated kinase signaling pathway.Conclusion: CST6, CXCL14, DHRS3, and SPP1 may play a role in PTC pathogenesis and progression and are possible molecular targets for FTC therapy.Universidade Federal de São Paulo, Genet Bases Thyroid Tumor Lab, Div Genet, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Div Endocrinol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Div Head & Neck Surg, BR-04039032 São Paulo, BrazilUniv São Paulo, Sch Med, Dept Surg, São Paulo, BrazilJohns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21205 USAUniversidade Federal de São Paulo, Genet Bases Thyroid Tumor Lab, Div Genet, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Div Endocrinol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Div Head & Neck Surg, BR-04039032 São Paulo, BrazilWeb of Scienc

Doença de Hungtinton, herança autossômica dominante

Herança que necessita somente de um gene mutado para o desenvolvimento da doença, como por exemplo a Coreia de Huntington, uma doença neurodegenerativa acarretada por uma mutação do gene huntintina localizado no cromossomo 4. Neste trabalho foi realizado uma peça teatral exemplificando um caso clínico de um portador da doença de Huntington