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. Design: 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. Main outcome: Twelve of these genes (RASSF1A, p16(INK4A), TSHR, MGMT, DAPK, ER alpha, ER beta, RAR beta, 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.