Lack of mutations in the thyroid hormone receptor (TR) alpha and beta genes but frequent hypermethylation of the TRbeta gene in differentiated thyroid tumors.
BACKGROUND
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
Our objectives were to examine further mutations of TRalpha and TRbeta genes in thyroid cancer and also to examine their methylation as an epigenetic silencing mechanism in thyroid cancer.


METHODS
Instead of using a cDNA sequencing approach used in previous studies, we used genomic DNA to sequence directly the coding regions of the TRalpha and TRbeta 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 TRbeta was also analyzed.


RESULTS
We found no TRalpha gene mutation in 17 papillary thyroid cancers (PTCs) and 11 follicular thyroid cancers (FTCs), and no TRbeta gene mutation in 16 PTCs and 12 FTCs. We also found no methylation of the TRalpha gene in 33 PTCs, 31 FTCs, 20 follicular thyroid adenomas (FTAs), and 10 thyroid tumor cell lines. In contrast, we found hypermethylation of the TRbeta gene in 10 of 29 (34%) PTCs, 22 of 27 (81%) FTCs, five of 20 (25%) follicular thyroid adenomas, and three of 10 (30%) thyroid tumor cell lines, with the highest prevalence in FTC. We additionally examined loss of heterozygosity at TRbeta and found it in three of nine (33%) PTCs and three of nine (33%) FTCs.


CONCLUSIONS
Mutation is not common in TR genes, whereas hypermethylation of the TRbeta 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.
Joseph
Biju
B
Division of Endocrinology and Metabolism, Department of Meidcine, The Johns Hopkins University School of Medicine, 813 Hunterian Street, Baltimore, Maryland 21287, USA.
Ji
Meiju
M
Liu
Dingxie
D
Hou
Peng
P
Xing
Mingzhao
M
D018263:Adenocarcinoma, Follicular / Q000235:genetics*; D000483:Alleles; D002291:Carcinoma, Papillary / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
D004273:DNA, Neoplasm; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta