CpG island methylation of tumor-related promoters occurs preferentially in undifferentiated carcinoma.
OBJECTIVE
To understand the role of epigenetic inactivation of tumor-related genes in the pathogenesis of thyroid cancer, we investigated the methylation profile of distinct thyroid neoplasms.


METHODS
We analyzed the methylation pattern of 17 gene promoters in nine thyroid cancer cell lines and in 38 primary thyroid carcinomas (13 papillary thyroid carcinoma [PTC], 10 follicular thyroid carcinoma [FTC], 9 undifferentiated thyroid carcinoma [UTC], 6 medullary thyroid carcinoma [MTC]), 12 goiters, and 10 follicular adenomas (FA) by methylation- specific polymerase chain reaction (PCR). Epigenetic inactivation was validated by expression analysis.


RESULTS
Twelve of these genes (RASSF1A, p16(INK4A), TSHR, MGMT, DAPK, ERalpha, ERbeta, RARbeta, PTEN, CD26, SLC5A8, and UCHL1) were frequently methylated in UTC (15%-86%) and thyroid cancer cell lines (25%-100%). In the more aggressive UTC, the mean methylation index (MI = 0.44) was the highest compared to other thyroid alterations PTC (MI = 0.29, p = 0.123), FTC (MI = 0.15, p = 0.005), MTC (MI = 0.13; p = 0.017), FA (MI = 0.27; p = 0.075) and goiters (MI = 0.23; p = 0.024). Methylation of TSHR, MGMT, UCHL1, and p16 occurred preferentially in UTC and this inactivation was reverted by a demethylating agent.


CONCLUSIONS
Our results show that hypermethylation of several tumor-related gene promoters is a frequent event in UTC. The hypermethylation status may be reversed by DNA demethylating agents. Their clinical value remains to be investigated.
Schagdarsurengin
Undraga
U
AG Tumorgenetik der Medizinischen Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
Gimm
Oliver
O
Dralle
Henning
H
Hoang-Vu
Cuong
C
Dammann
Reinhard
R
D002277:Carcinoma / Q000235:genetics*; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D013964:Thyroid Neoplasms / Q000235:genetics*