Methylation Status of Genes in Papillary Thyroid Carcinoma

Abstract

To determine the methylation status of gene promoter regions using methylation-specific polymerase chain reaction in genes encoding for thyrotropin receptor (TSHR), E-cadherin (ECAD), sodium iodide symporter protein (NIS-L), ataxia telangiectasia mutated (ATM), and death-associated protein kinase (DAPK) proteins and if methylation status correlates with patient variables, tumor factors, or outcome measures among patients with papillary thyroid carcinoma. Design: Database query and retrospective medical chart review for patients with well-differentiated thyroid cancer and nonmalignant thyroid conditions treated at our institutions (1996-2004). Methylation-specific polymerase chain reaction was performed, and results were compared with controls for these genes. Methylation status was then compared with patient variables, tumor factors, and outcome measures for patients with thyroid carcinoma and controls. Patients: The study population comprised 32 patients with papillary thyroid carcinoma and 27 controls. Results: In our patients, all 5 genes were methylated more frequently in papillary thyroid carcinoma than in controls. NIS-L trended toward a more advanced stage at presentation. NIS-L methylation in cancer cells was not associated with methylation in adjacent benign tissue, unlike the other 4 genes. Neither age nor sex affected methylation status, and methylation status did not correlate with extent of the primary tumor or presence of nodal metastasis at diagnosis. Tumors recurred less frequently in patients with TSHR methylation than in patients with unmethylated TSHR promoter regions. Conclusions: Promoter methylation may be a marker for malignancy in thyroid carcinoma. Furthermore, methylation status of tumors as determined by methylationspecific polymerase chain reaction may help in determining patient prognosis.

DNA Methylation Signatures Identify Biologically Distinct Thyroid Cancer Subtypes

“…Interestingly, thyroid tumors have also been shown to present aberrant promoter hypermethylation at endocrine-related genes such us the solute carrier family 5 (sodium iodide symporter), member 5 (SLC5A5) and the TSH receptor (THSR) has been shown to be frequently repressed by aberrant DNA promoter hypermethylation in thyroid cancer (8 -10). Other examples of genes frequently hypermethylated in thyroid cancer include the apoptosis-related cysteine protease (CASP8) (11) and the ataxia telangiectasia mutated (ATM) (8). Several of these genes have also been identified in our study, which supports the reliability of our experimental design and confirms the notion that aberrant promoter methylation is a relevant molecular alteration in thyroid cancer.…”

“…It is worth mentioning that, because both genes play an important role in iodine uptake, it has been proposed that tumors displaying aberrant hypermethylation at their gene promoters could be good candidates for receiving demethylating agents in conjunction with TSH-promoted radioiodine therapy (10). Other examples of genes frequently hypermethylated in thyroid cancer include the apoptosis-related cysteine protease (CASP8) (11), the tissue inhibitor of metalloprotease 3 (TIMP3) (12,13), the ataxia telangiectasia mutated gene (ATM) (8), and RAS association domain family protein 1 (RASSF1) (14).…”

Correlation between BRAF mutation and promoter methylation of TIMP3, RARβ2 and RASSF1A in thyroid cancer

“…No significant correlation was found with methylation values and age groups by non-parametric Wilcoxon testing. 6,8,[11][12][13][14][15][16][17][18] Among these 19 genes, PAK3, NISCH and KIF1A were previously only tested in a small set of thyroid cancer samples by our group as a part of our comprehensive approach to discover methylated genes in cancer. 8 Three of the 22 genes, MINT1, DCC and AIM1, have not been tested in thyroid cancer to date.…”

5-Aza-2′-Deoxycytidine Has Minor Effects on Differentiation in Human Thyroid Cancer Cell Lines, But Modulates Genes That Are Involved in Adaptation In Vitro

“…Epigenetic silencing of several genes in thyroid tumors has been reported (41), such as the TSHR (7-9) and NIS (10,11). Based on these observations, a re-expression of these hypermethylated genes might be expected using demethylating agents such as 5-AzadC.…”

“…Epigenetic alterations are a common finding in thyroid tumors (7), and epigenetic silencing of a number of genes has been reported, including hypermethylation of thyroid differentiation genes such as the thyrotropin receptor (TSHR) (7)(8)(9)(10) and NIS (10,11). Based on these observations, re-expression of these hypermethylated genes might result after treatment with demethylating agents or other chromatin-modifying drugs such as inhibitors of histone deacetylases (HDAC).…”