L. Ceolin | Universidade Federal do Rio Grande do Sul (original) (raw)

Papers by L. Ceolin

International Journal of Oncology, 2012

Thyroid carcinoma is the most common malignant endocrine neoplasia. Differentiated thyroid carcin... more Thyroid carcinoma is the most common malignant endocrine neoplasia. Differentiated thyroid carcinomas (DTCs) represent more than 90% of all thyroid carcinomas and comprise the papillary and follicular thyroid carcinoma subtypes. Anaplastic thyroid carcinomas correspond to less than 1% of all thyroid tumors and can arise de novo or by dedifferentiation of a differentiated tumor. The etiology of DTCs is not fully understood. Several genetic events have been implicated in thyroid tumorigenesis. Point mutations in the BRAF or RAS genes or rearranged in transformation (RET)/papillary thyroid carcinoma (PTC) gene rearrangements are observed in approximately 70% of papillary cancer cases. Follicular carcinomas commonly harbor RAS mutations and paired box gene 8 (PAX8)-peroxisome proliferator-activated receptor γ (PPARγ) rearrangements. Anaplastic carcinomas may have a wide set of genetic alterations, that include gene effectors in the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and/or β-catenin signaling pathways. These distinct genetic alterations constitutively activate the MAPK, PI3K and β-catenin signaling pathways, which have been implicated in thyroid cancer development and progression. In this context, the evaluation of specific genes, as well as the knowledge of their effects on thyroid carcinogenesis may provide important information on disease presentation, prognosis and therapy, through the development of specific tyrosine kinase targets. In this review, we aimed to present an updated and comprehensive review of the recent advances in the understanding of the genetic basis of follicular cell-derived thyroid carcinomas, as well as the molecular mechanisms involved in tumor development and progression.

Arquivos Brasileiros de Endocrinologia & Metabologia, 2012

Resistance to thyroid hormone (RTH) is a rare autosomal dominant inherited disorder characterized... more Resistance to thyroid hormone (RTH) is a rare autosomal dominant inherited disorder characterized by end-organ reduced sensitivity to thyroid hormone. This syndrome is caused by mutations of the thyroid hormone receptor (TR) β gene, and its clinical presentation is quite variable. Goiter is reported to be the most common finding. A close association of TRβ mutations with human cancers has become apparent, but the role of TRβ mutants in the carcinogenesis is still undefined. Moreover, higher TSH levels, described in RTH syndrome, are correlated with increased risk of thyroid malignancy, whereas TSH receptor stimulation is likely to be involved in tumor progression. We report here an illustrative case of a 29 year-old patient with RTH caused by a mutation in exon 9 (A317T) of TRβ gene, who presented multicentric papillary thyroid cancer. We review the literature on this uncommon feature, and discuss the potential role of this mutation on human tumorigenesis, as well as the challenges in patient follow-up. Arq Bras Endocrinol Metab. 2012;56(1):67-71 SUMÁRIO A síndrome da resistência aos hormônios tireoidianos (RHT) é caracterizada por redução da sensibilidade aos hormônios da tireoide. A apresentação clínica é variável, sendo a presença de bócio a manifestação mais frequentemente descrita. A associação de mutação no receptor β e neoplasias em humanos vem sendo demonstrada recentemente, porém o mecanismo pelo qual a mutação desse receptor está envolvida na carcinogênese não está completamente definido. Além disso, níveis elevados de TSH sérico, descritos na RHT, estão associados a aumento do risco de câncer de tireoide, e o estímulo do TSH está provavelmente envolvido na patogênese desses carcinomas. Este artigo relata o caso de um homem de 29 anos com RHT, com análise molecular demonstrando mutação no éxon 9, códon 317, e carcinoma papilar de tireoide. Revisamos a literatura dos casos relatados os quais descrevem associação entre RHT e câncer de tireoide e discutimos os desafios do tratamento e seguimento desses pacientes. Arq Bras Endocrinol Metab. 2012;56(1):67-71

Endocrine Related Cancer, 2010

The possible role of RET variants in modifying the natural course of medullary thyroid carcinoma ... more The possible role of RET variants in modifying the natural course of medullary thyroid carcinoma (MTC) is still a matter of debate. Here, we investigate whether the RET variants L769L, S836S, and G691S/S904S influence disease presentation in hereditary or sporadic MTC patients. One hundred and two patients with hereditary MTC and 81 patients with sporadic MTC attending our institution were evaluated. The frequencies of RET polymorphisms in hereditary MTC were as follows: L769L, 17.3%; S836S, 7.95%; and S904S/G691S, 18.2%. No associations were observed between these polymorphisms and pheochromocytoma, hyperparathyroidism, lymph node, or distant metastasis. However, patients harboring the S836S variant were younger than those without this allele (17G8.2 vs 28.6G14.4 years, PZ0.01), suggesting that these patients had metastases at a young age. Accordingly, the cumulative frequency of local and/or distant metastases as estimated by Kaplan-Meier curves showed that lymph node and distant metastases occurred earlier in patients harboring the S836S variant (PZ0.003 and PZ0.026 respectively). The S836S allele frequency was higher in sporadic MTC patients than in controls (10.5 vs 3.1%, PZ0.01). Individuals harboring the S836S variant were younger (38.6G13.3 vs 48.5G16.7 years, PZ0.02) and showed a higher percentage of lymph node and distant metastases (PZ0.02 and PZ0.04 respectively). Kaplan-Meier estimates of lymph node and distant metastases yielded distinct curves for patients with or without the S836S allele (PZ0.002 and PZ0.001 respectively). Additional analyses using a COX regression model showed that the S836S variant was independently associated with metastatic disease (hazard ratio 2.82 (95% confidence interval 1.51-5.26), PZ0.001). In conclusion, the RET S836S variant is associated with early onset and increased risk for metastatic disease in patients with hereditary or sporadic MTC.

European Journal of Endocrinology, 2014

Background: RET polymorphisms have been involved in the clinical presentation and prognosis of mu... more Background: RET polymorphisms have been involved in the clinical presentation and prognosis of multiple endocrine neoplasia type 2 (MEN2)-associated medullary thyroid carcinoma. Objective: To investigate the effect of RET variants on the penetrance of pheochromocytoma (PHEO) in MEN2 patients. Methods: The RET variants L769L, S836S, and G691S/S904S were evaluated in a cohort of 153 MEN2 patients attending a tertiary teaching hospital. A comparison of RET variant frequencies between patients with and without PHEO was performed. Kaplan-Meier curves and Cox regression analysis were used to estimate the effect of RET variants on the age-dependent penetrance. Results: A total of 48 (31.4%) patients presented with MEN2-associated PHEOs. The mean age at diagnosis was 35.5G13.4 years, 60.4% of patients were women, and 92.8% had RET mutations at codon 634. The frequencies of RET polymorphisms were as follows: 20.1% L769L, 4.75% S836S, and 17.3% S904S/G691S. We did not observe any association between the frequencies of L769L, S836S, or S904S/G691S variants and PHEO development (all PO0.05). However, individuals carrying two RET polymorphic alleles had an increased estimated risk of PHEO (2.63; 95% CI, 1.4-5.0; PZ0.004) and were younger at diagnosis when compared with those with one or no polymorphism (29.6G6.3 and 39.3G14.4 years respectively; PZ0.006). Accordingly, additional analysis using Cox proportional hazard models demonstrated that the presence of two RET variants was associated with an increased risk for early PHEO development (hazard ratio, 5.99 (95% CI, 2.24-16.03); P!0.001). Conclusions: RET polymorphic alleles have an additive effect on the estimated risk of age-related PHEO penetrance in MEN2 patients.

European Journal of Endocrinology, 2012

Objective: RET single nucleotide polymorphisms (SNPs) have been implicated in the pathogenesis an... more Objective: RET single nucleotide polymorphisms (SNPs) have been implicated in the pathogenesis and progression of medullary thyroid carcinoma (MTC). Here, we investigated the influence of multiple RET variants (G691S, L769L, S836S, and S904S) on the risk of MTC and tumor behavior. Design and methods: One hundred and seven MTC patients and 308 cancer-unaffected control individuals were included. SNPs were analyzed using Custom TaqMan Genotyping Assays. Haplotypes based on the combination of allelic variants were inferred using a Bayesian statistical method. Results: The minor allele frequencies in MTC patients were as follows: L769L: 28.0%, S836S: 8.9%, and G691S/S904S: 22.2%. The RET L769L and S836S SNPs were associated with increased risk of MTC (odds ratio (OR)Z1.95, 95% CI: 1.2-3.1, PZ0.005 and ORZ2.29, 95% CI: 1.2-4.5, PZ0.017 respectively). The adjusted OR for individuals harboring haplotypes with three or more polymorphic alleles was 3.79 (95% CI: 1.5-9.5; PZ0.004), indicating an additive effect of these variants on the risk for MTC. Among MTC patients, no significant associations were observed between RET variants and age of diagnosis or tumor size but serum calcitonin levels increased according to the number of risk alleles (PZ0.003). Remarkably, patients carrying haplotypes with three or four risk alleles had increased risk for lymph node and distant metastases at diagnosis (ORZ5.84, 95% CI: 1.1-31.2, PZ0.039). Further analysis using Kaplan-Meier model demonstrated that metastatic disease occurred earlier in individuals harboring multiple risk alleles. Conclusion: Our results demonstrated an additive effect of RET polymorphic alleles on the estimated risk of developing aggressive MTC.