p16(INK4A) promoter hypermethylation and expression of p16(INK4A), cyclin D1, and Rb in papillary thyroid carcinoma

Kim, Yoon Jung; Kim, Hye Soon; Ha, Yu Jin; Lee, Ho Young; Park, Keun Gyu; Kim, Mi Kyung; Kwon, Sun Young

Abstract

BACKGROUND/AIMS
Dysregulation of the cell cycle is believed to be important in human neoplasia. p16(INK4A), a regulator of the retinoblastoma protein, is inactivated by several mechanisms, including hypermethylation of the promoter. The aim of this study was to assess the relationship between p16(INK4A) methylation status and the expression of p16(INK4A), cyclin D1, and retinoblastoma protein in papillary thyroid cancer.
METHODS
Thirty-five surgically resected papillary thyroid cancer cases treated at Keimyung University Dongsan Medical Center from Jan 2003 to Dec 2005 were included in the study. We examined promoter hypermethylation of p16(INK4A) and immunohistochemically analyzed p16(INK4A), cyclin D1, and retinoblastoma protein expression.
RESULTS
Aberrant hypermethylation of 5' CpG islands of the p16(INK4A) gene promoter was observed in 17 (48.6%) out of 35 cases, and the p16(INK4A) protein was lost in 18 (51.4%) cases. With the exception of one case, p16(INK4A) promoter hypermethylation correlated with the loss of p16(INK4A) protein expression (p<0.0001). Overexpression of cyclin D1 was found in 27 (77.1%) cases and retinoblastoma immunostaining was detected in 10 (28.6%) cases. There was an inverse relationship between p16(INK4A) and pRb immunostaining (p<0.018, r=-0.398), and a strong direct correlation between cyclin D1 and pRb immunostaining (p<0.0001, r=0.710). Cyclin D1 expression was significantly associated with the pathologic T stage of cancer (p=0.04).
CONCLUSIONS
These data suggest that promoter hypermethylation is a major mechanism underlying the inactivation of p16(INK4A) and alterations in the p16 (INK4a)/cyclin D1/retinoblastoma pathway, which are thought to be very important in papillary thyroid cancer.