DNA Methylation in Thyroid Tumorigenesis

Abstract

Thyroid cancer is the most common endocrine cancer with 1,690 deaths each year. There are four main types of which the papillary and follicular types together account for >90% followed by medullary cancers with 3% to 5% and anaplastic carcinomas making up <3%. Epigenetic events of DNA hypermethylation are emerging as promising molecular targets for cancer detection. Our immediate and long term goal is to identify DNA methylation markers for early detection of thyroid cancer. This pilot study comprised of 21 patients to include 11 papillary thyroid cancers (PTC), 2 follicular thyroid cancers (FTC), 5 normal thyroid cases, and 3 hyperthyroid cases. Aberrant promoter methylation was examined in 24 tumor suppressor genes using the methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) assay and in the NIS gene using methylation-specific PCR (MSP). The frequently methylated genes were CASP8 (17/21), RASSF1 (16/21) and NIS (9/21). In the normal samples, CASP8, RASSF1 and NIS were methylated in 5/5, 4/5 and 1/5 respectively. In the hyperthyroid samples, CASP8, RASSF1 and NIS were methylated in 3/3, 2/3 and 1/3 respectively. In the thyroid cancers, CASP8, RASSF1, and NIS were methylated in 9/13, 10/13, and 7/13 respectively. CASP8, RASSF1 and NIS were also methylated in concurrently present normal thyroid tissue in 3/11, 4/11 and 3/11 matched thyroid cancer cases (matched for presence of both normal thyroid tissue and thyroid cancer), respectively. Our data suggests that aberrant methylation of CASP8, RASSF1, and NIS maybe an early change in thyroid tumorigenesis regardless of cell type.

DKK3 is a potential tumor suppressor gene in papillary thyroid carcinoma

“…Over the past several years, many TSGs have been found to be epigenetically inactivated in PTC, indicating that epigenetic silencing of TSGs is a major molecular alteration in the tumorigenesis of thyroid carcinoma (Lal et al 2006, Xing 2007, Yin et al 2010b, Stephen et al 2011). It has recently been shown that the methylation of DKK3 gene family contributes to carcinogenesis and serves as a potential biomarker for the diagnosis of several human malignancies (Veeck et al 2008, Vander Meide et al 2011.…”

“…DNA methylation is a common epigenetic event observed in mammalian genomes, and it often mediates transcriptional repression (Aleqria-Torres et al 2011). It has been reported that many TSGs are hypermethylated in PTC (Lal et al 2006, Xing 2007, Yin et al 2010b, Stephen et al 2011.…”

DNA Methylation Signatures Identify Biologically Distinct Thyroid Cancer Subtypes

“…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).…”

Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in oligodendroglial tumors

“…CASP8, a gene located at 2q33–34 that encodes caspase 8, was found to be methylated in 70.5% of the current series. The most upstream protease of the activation cascade of caspases responsible for the execution‐phase of cell apoptosis, methylation of the CASP8 gene has been reported to be a common epigenetic characteristic in thyroid cancer and breast cancer 24, 25.…”