Epigenetics in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) shows a remarkably distinctive ethnic and geographic distribution among the world suggesting that genetic susceptibility backgrounds cooperate with the environmental risk factors in etiology of NPCs. Among the environmental factors, much attention has been focused on a well-documented association with Epstein-Barr virus (EBV), which can be detected in 100% undifferentiated NPCs. During the passing decade, increasing evidence has shown that epigenetic changes play an important role at the early stage of carcinogenesis. Epigenetic changes could also serve as a surrogate for mutations or chromosomal alterations in inactivating tumor suppressor genes (TSGs) in the tumor development. In the present work, we mainly focused on the study of methylation of NPC-related genes, including cellular TSGs and EBV-encoded gene, which may unravel the molecular basis of its tumorigenesis and thereby expand the prospects for the development of diagnostic and prognostic markers. First, CDH13, which encodes cell adhesion molecule H-cadherin, was found to be methylated in 89.7% of NPC primary tumors, while only methylated in 10% normal nasopharyngeal epithelia (p<0.05). The potential of detecting methylation from nasopharyngeal swabs was then investigated. The high sensitivity (81%) and specificity (0% false positives) of detecting CDH13 methylation from nasopharyngeal swabs suggests it could be utilized as a tentative auxiliary tool for early diagnosis. We next explored another candidate TSG, RASSF2 which can bind directly to K-Ras and function as a negative effector of Ras protein. Promoter methylation of one of RASSF2 isoform, RASSF2A, could be detected in 80% NPC cell lines and 50.9% of primary tumors, but not in any of the normal epithelia. RASSF2A expression was found to be correlated with its promoter methylation. In addition, patients with methylated RASSF2A presented a higher frequency of lymph node metastasis (P