Journal List > J Korean Thyroid Assoc > v.7(2) > 1056553

Tae, Chi, Kim, Lee, and Youn: Gene Methylation Associated with Differentiated Thyroid Cancer

Abstract

Epigenetic alteration changes expression of many genes, such as tumor suppressor gene and molecular specific gene, without change in DNA sequence. Cancers, including thyroid cancer, often exhibit an aberrant methylation of gene promoter regions, which is associated with loss of gene function. Aberrant methylation plays a fundamental role in tumorigenesis. Methylation of some genes tends to occur in certain types of thyroid cancer. Methylation of TIMP3, SLC5A8, p16, RAR β2, DAPK genes is associated with papillary thyroid cancer. Some studies show that aberrant methylation is related to the BRAF V600E mutation. Methylation of PTEN and RASSF1A genes occurs commonly in follicular thyroid cancer. Methylation of thyroid-specific genes, such as sodium/iodide symporter, thyroid-stimulating hormone receptor, and SLC26A4 which encodes pendrine, also has a relation to thyroid cancer. Methylation of these genes could be utilized as markers to detect early disease, to define prognosis and to predict therapeutic targets of thyroid cancer.

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Fig. 1.
CpG island methylation. (A) In a normal cell, CpG islands have no methylated cytosine residue and allow transcriptional activity. (B) DNA methylation at the 5 position of cytosine has the specific effect of reducing gene expression by gene silencing. Methylated CpG islands contribute to loss of gene function.
jkta-7-118f1.tif
Fig. 2.
Thyroidal iodide-metabolizing molecules. A unique physiological function of thyroid gland is ability to uptake, concentrate and use iodide to synthesize thyroid hormones. This process involves several key protein molecules that are specifically expressed in follicular epithelial cells of the thyroid gland. Thyroid stimulating hormone receptor (TSHR) bound to TSH stimulates iodide transport into the thyroid gland by the sodium iodide symporter (NIS). The function of pendrin is to transport iodide into the follicular lumen from the thyroid cell. The genes of thyroid specific molecules (red arrow) are methylated in the promoter areas in thyroid tumors.
jkta-7-118f2.tif
Table 1.
Methylation of tumor suppressor genes associate with papillary thyroid cancer
Gene Methods nMe/N (%) Clinical signification References
TIMP3 QMSP 122/231 (53%) Extrathyroidal invasion Lymph node metastasis Multifocality Hu et al. 2006
QMSP 22/44 (51%) Lack of tissue inhibitor of metalloproteinase and antagonist of angiogenesis Bralt et al. 2012
SLC5A8 MSP 9/10 (90%) Thyroid tumorigenesis Porra et al. 2005
QMSP 76/231 (33%) Extrathyroidal invasion Multifocality Advanced tumor stage Hu et al. 2006
QMSP 34/86 (40%) Increase of the amount of circulating cf-DNA Zane et al. 2013
P16 MSP 17/35 (48%) No association with clinical characteristics Klm et al. 2010
MSP 18/44 (41%) High AMES risk group Advanced tumor stage Lam et al. 2007
MSP 10/25 (40%) No association with clinical characteristics Mohammadl-asl et al. 2011
MSP 3/12 (25%) Advanced tumor stage Schagdarsurengln et al. 2002
MSP 20/74 (27%) Metastasis High AMES risk group Wang et al. 2013
RAR β 2 QMSP 50/231 (22%) No association with clinical characteristics Hu et al. 2006
QMSP 23/138 (17%) Association with smoking Kiseljak-Vassiliades et al. 2011
DAPK QMSP 78/231 (34%) Multifocality Hu et al. 2006
RUNX3 QMSP 10/12 (83%) Diagnostic marker Ko et al. 2012
Rap1GAP MSP 58/75 (71%) Silencing of gene Zuo et al. 2010

AMES: age–metastasis–extent-size, cf–DNA: cell–free DNA, DAPK: death–associated protein kinase, MSP: methylation specific polymerase chain reaction, nMe/N: number of cases with methylation/total, QMSP: quantitative methylation specific polymerase chain reaction, Rap1GAP: Rap1 GTPase–activating protein, RAR β 2: retinoic acid receptor beta 2, RUNX3: Runt–related transcription factor 3, SLC5A8: solute carrier family 5 member 8, TIMP3: tissue inhibitor of metalloproteinase 3

Table 2.
Methylation of tumor suppressor genes associated with follicular thyroid carcinoma
Gene Methods Frequency (nMe/N [%])
References
FA FTC PTC
PTEN MSP 5/6 (83%) 6/7 (86%) 21/46 (46%) Alvarez-Nuñez et al. 2006
QMSP 5/43 (12%) 25/65 (51%) No exam. Hou et al. 2008
PTC FTC Normal
RASSF1A QMSP 8/13 (62%) 7/10 (70%) 1/4 (25%) Schagdarsurengin et al. 2002
QMSP 6/30 (20%) 9/12 (75%) 0/14 (0%) Xing et al. 2004

FA: follicular adenoma, FTC: follicular thyroid cancer, MSP: methylation specific polymerase chain reaction, nMe/N: number of cases with methylation/total, PTC: papillary thyroid cancer, PTEN: phosphatase and tensin homolog gene, QMSP: quantitative methylation specific polymerase chain reaction, RASSF1A: ras association domain family 1 isoform A

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