Venkataraman GM, Yatin M, Marcinek R, Ain KBRestoration of iodide uptake in dedifferentiated thyroid carcinoma: relationship to human Na+/I- symporter gene methylation status. J Clin Endocrinol Metab 84: 2449-2457

University of Kentucky, Lexington, Kentucky, United States
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.21). 08/1999; 84(7):2449-57. DOI: 10.1210/jc.84.7.2449
Source: PubMed


Disseminated dedifferentiated thyroid epithelial carcinoma, which cannot sufficiently concentrate therapeutic radioiodide, is a terminal disease without any effective systemic treatment or chemotherapy. This is a likely consequence of loss of human sodium-iodide symporter (hNIS) function. We hypothesized that hNIS transcriptional failure in thyroid carcinoma could be consequent to methylation of DNA in critical regulatory regions and could be reversed with chemical demethylation treatment. Analysis of hNIS messenger ribonucleic acid (mRNA) expression in 23 tumor samples revealed that although loss of this expression corresponded to loss of clinical radioiodide uptake, some thyroid carcinomas with hNIS mRNA expression did not concentrate iodide, suggesting additional posttranscriptional mechanisms for loss of hNIS function. In addition, analysis of DNA methylation in CpG-rich regions of the hNIS promoter extending to the first intron failed to define specific methylation patterns associated with transcriptional failure in human thyroid tumor samples. In seven human thyroid carcinoma cell lines lacking hNIS mRNA, treatment with 5-azacytidine or sodium butyrate was able to restore hNIS mRNA expression in four cell lines and iodide transport in two cell lines. Investigation of methylation patterns in these cell lines revealed that successful restoration of hNIS transcription was associated with demethylation of hNIS DNA in the untranslated region within the first exon. This was also associated with restoration of expression of thyroid transcription factor-1. These results suggest a role for DNA methylation in loss of hNIS expression in thyroid carcinomas as well as a potential application for chemical demethylation therapy in restoring responsiveness to therapeutic radioiodide.

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Available from: Gopalakrishnan M Venkataraman,
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    • "As compared with normal cells, the malignant cells show major disruptions in their DNA methylation patterns [35]. Methylation happens to thyroid-specific genes, such as those for sodium/iodide symporter (NIS) [36] and thyroglobulin [37]. Pichonet et al found that reporter-gene expression from a plasmid containing only the proximal thyroglobulin gene promoter is sensitive to DNA methylation even in fully differentiated thyrocytes . "
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    ABSTRACT: The overall survival rate of non-radioiodine avid differentiated (follicular, papillary, medullary) thyroid carcinoma is significantly lower than for patients with iodine-avid lesions. The purpose of this study was to evaluate toxicity and efficacy (response and survival) of peptide receptor radionuclide therapy (PRRT) in non-radioiodine-avid or radioiodine therapy refractory thyroid cancer patients. Sixteen non-radioiodine-avid and/or radioiodine therapy refractory thyroid cancer patients, including follicular thyroid carcinoma (n = 4), medullary thyroid carcinoma (n = 8), Hürthle cell thyroid carcinoma (n = 3), and mixed carcinoma (n = 1) were treated with PRRT by using (90)Yttrium and/or (177)Lutetium labeled somatostatin analogs. (68)Ga somatostatin receptor PET/CT was used to determine the somatostatin receptor density in the residual tumor/metastatic lesions and to assess the treatment response. Hematological profiles and renal function were periodically examined after treatment. By using fractionated regimen, only mild, reversible hematological toxicity (grade 1) or nephrotoxicity (grade 1) were seen. Response assessment (using EORTC criteria) was performed in 11 patients treated with 2 or more (maximum 5) cycles of PRRT and showed disease stabilization in 4 (36.4%) patients. Two patients (18.2%) showed partial remission, in the remaining 5 patients (45.5%) disease remained progressive. Kaplan-Meier analysis resulted in a mean survival after the first PRRT of 4.2 years (95% CI, range 2.9-5.5) and median progression free survival of 25 months (inter-quartiles: 12-43). In non-radioiodine-avid/radioiodine therapy refractory thyroid cancer patients, PRRT is a promising therapeutic option with minimal toxicity, good response rate and excellent survival benefits.
    American Journal of Nuclear Medicine and Molecular Imaging 01/2014; 4(1):39-52. · 3.25 Impact Factor
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    • "In some cancers, methylation can occur in particular oncosuppressor genes or in genes involved in specific organ function; in TC, the expression of molecules metabolizing iodine is lost frequently [24] [25] [26] [27]. Among the family of sodium-solute symporters (SLC), SLC5A8 and SLC26A4 (PDS) encode for AIT and Pendrin. "
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    ABSTRACT: In the latest years, high levels of circulating cell-free DNA (cf-DNA) have been found to be associated with cancer diagnosis and progression, and cf-DNA has become a potential candidate as biomarker for tumor detection. cf-DNA has been investigated in plasma or serum of many tumor patients affected by different malignancies, but not yet in thyroid cancer (TC). Furthermore, in TC cells the capability to metabolize iodine is frequently lost. SLC5A8 and SLC26A4 genes are both involved in the iodine metabolism, and SLC5A8 hypermethylation status is associated with the BRAF(V600E) mutation, which is the most frequent genetic event underlying the development of papillary TC. The aim of our study is the development of a new non-invasive tool for the diagnosis and prognosis of TC based on cf-DNA, SLC5A8 and SLC26A4 hypermethylation, and BRAF(V600E) analysis. cf-DNA was measured by quantitative real-time PCR in nine cases of anaplastic thyroid cancer (ATC), 58 medullary thyroid cancers (MTC), five of synchronous medullary and follicular thyroid cancers (SMFC), 23 follicular adenomas (FA), 86 papillary thyroid cancers (PTC). A control group of 19 healthy subjects was taken. Moreover, in the PTC group we analyze the state of hypermethylation of SLC5A8 and SLC26A4, BRAF(V600E) mutation, and their involvement in the loss of function of the thyroid. cf-DNA showed a high ability to discriminate healthy individuals from cancer patients. cf-DNAALU83 and cf-DNAALU244 values were significantly correlated with the histological type of TC (P-value<0.0001). A significant increase in the amount of cf-DNAALU83 and cf-DNAALU244 when methylation occurs was observed (P-value=0.02). A correlation between BRAF(V600E) and cf-DNAALU244/ALU83 was also found (P-value=0.02). According to our experimental results, the panel including cf-DNA, SLC5A8 and SLC26A4 hypermethylation, and BRAF(V600E) analysis appears easy, reproducible, and non-invasive for the diagnosis on TC. Its possible implication in clinical setting remains to be elucidated.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 07/2013; 67(8). DOI:10.1016/j.biopha.2013.06.007 · 2.02 Impact Factor
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    • "Previous studies have reported that aberrant hypermethylation at various genes is associated with thyroid malignancy, including genes involved in the control of cell proliferation and invasion, such as p16INK4A (21), Rassf1A (22), PTEN (23), Rap1GAP (24), TIMP3, RAR-b2, DAPK (15,16,25), CDH1 (26,27), TGFb and CITED1 (28), as well as genes specific to thyroid differentiation, such as Na+/I− symporter (NIS), TSH receptor, pendrin, SL5A8 (29,30) and TTF-1 (31), as reviewed by Catalano et al (32). In the majority of these studies, which were performed by methylation-specific PCR, a considerable overlap was observed in the methylation levels between benign and malignant tumors, with the exception of hypermethylation at RAR-b2 (15,16), NIS (33), TSHR (34), ECAD (26) and ATM (35), which was observed to be more prevalent in patients with papillary thyroid carcinoma than in non-malignant thyroid diseases. However, none of the observed tumor-related gene hypermethylation is considered to be a stand-alone marker for distinguishing malignant from benign tumors. "
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    ABSTRACT: In order to supplement the cytopathological assessment of thyroid tumors, there is a need for new markers to correctly diagnose malignant thyroid lesions and avoid unnecessary and potentially harmful therapies for patients. The immunohistochemical expression of galectin-3 is currently considered to be the most accurate stand-alone marker for thyroid cancer diagnosis. The aim of this study was to establish whether the methylation state of the galectin-3 gene is a candidate molecular marker for thyroid malignancy. Thyroid specimens from 50 patients were analyzed, including 5 normal thyroid, 3 goiters, 39 papillary and 3 anaplastic thyroid carcinoma cases. High-resolution methylation analyses was performed to investigate the methylation state of a large genomic region (from -89 to +408) encompassing the galectin-3 transcriptional start site. Within this region, 5 CpG sites (nucleotide positions +134, +137, +142, +147 and +156) were observed to be differentially methylated among the samples and were further analyzed by the quantitative pyrosequencing technique. The hypomethylation of the +134, +137, +142, +147 and +156 CpG sites was observed to be markedly associated with cancer. Although the methylation degree of each single site was highly variable in non-neoplastic tissues, the average methylation state of the 5 CpG sites clearly distinguished cancer from the nonneoplastic thyroid tissues.
    Oncology letters 07/2013; 6(1):86-90. DOI:10.3892/ol.2013.1312 · 1.55 Impact Factor
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