Context: It remains inconclusive whether mutations in thyroid hormone receptor (TR) genes naturally occur in thyroid cancer and whether these genes could be suppressors of this cancer.

Objective: To further examine mutations of TR and TR genes in thyroid cancer, and to also examine their methylation as an epigenetic silencing mechanism in thyroid cancer.

Experimental Design: Instead of using cDNA sequencing approach used in previous studies, we used genomic DNA to directly sequence the coding regions of the TR and TR genes to search mutations in various differentiated thyroid tumors and used methylation-specific PCR to analyze promoter methylation of these genes. Allelic zygosity status at TR was also analyzed.

Results: We found no TR gene mutation in 17 papillary thyroid cancers (PTC) and 11 follicular thyroid cancers (FTC) and no TR gene mutation in 16 PTC and 12 FTC. We also found no methylation of the TR gene in 33 PTC, 31 FTC, 20 follicular thyroid adenomas (FTA), and 10 thyroid tumor cell lines. In contrast, we found hypermethylation of the TR gene in 10/29 (34%) PTC, 22/27 (81%) FTC, 5/20 (25%) FTA, and 3/10 (30%) thyroid tumor cell lines, with the highest prevalence in FTC. We additionally examined loss of heterozygosity at TR and found it in 3/9 (33%) PTC and 3/9 (33%) FTC.

Conclusions: Mutation is not common in TR genes, whereas hypermethylation of the TR gene as an alternative gene silencing mechanism is highly prevalent in thyroid cancer, particularly FTC, consistent with a possible tumor suppressor role of this gene for FTC.