Epigenetic inactivation of retinoid X receptor genes in non-small cell lung cancer and the relationship with clinicopathologic features

Retinoid X receptors (RXRs) are nuclear receptors for retinoids that play a critical role in the regulation of growth and differentiation in normal and tumor cells. Deregulation of RXR expression has been reported in non-small cell lung cancer (NSCLC); however, the mechanism underlying the impaired expression of RXRs in lung cancer is not known. Aberrant methylation of promoter CpG islands is known to be a major mechanism for inactivation of tumor suppressor genes. We investigated the methylation status of the RXR genes in 139 surgically resected NSCLCs and correlated the results with the clinicopathologic characteristics of the patients. Methylation in the tumors was detected in all three genes: RXRA, 5.7%; RXRB, 4.3%; RXRG, 23.7%. Reverse transcriptase-polymerase chain reaction analysis showed that RXRG methylation correlates with mRNA expression. Methylation of the RXRG gene was not significantly associated with the prognosis of patients. When the patients were categorized by smoking status, however, the effect of RXRG methylation on prognosis was significantly different between never- and ever-smokers (P = 0.003, test for homogeneity). Specifically, RXRG methylation was associated with a significantly worse survival in never-smokers; a trend to better survival outcome was observed for ever-smokers, although not statistically significant. This finding suggests that methylation-associated downregulation of the RXRG gene may play a differential role in the carcinogenesis of NSCLCs according to smoking status, but further studies are needed to confirm this.