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Promoter methylation and protein expression of the Slit2 and Robo1 genes in resected esophageal squamous cell carcinoma.

10032 Background: Recent epigenetic studies suggest that the slit-robo pathway is involved in tumorigenesis of a number of human cancers and a role of SLIT2 as a tumor suppressor gene. In view of lack of epigenetic studies of SLIT2 and ROBO1 genes in squamous cell esophageal carcinoma (ESCC), we investigate whether promoter methylation is responsible for aberrant protien expression of SLIT2 and ROBO1 and whether promoter methylation and aberrant protein expression of these two genes are related to prognosis after resection for ESCC.


METHODS
We analyzed promoter methylation of SLIT2 and ROBO1 using methylation-specific polymerase chain reaction (MSP) and their protein expression using immunohistochemistry in 60 resected tumor specimens. The Pearson χ2 test was used to compare promoter methylation and protein expression of SLIT2 and ROBO1 among patients with different clinicopathological parameters. Concordance analysis was performed between promoter methylation and protein expression of these two genes.


RESULTS
Promoter methylation of SLIT2 and ROBO1 was observed in 43 (71.6%) and 16 (26.6%) of the 60 resected specimens, respectively (P = 0.002). Aberrant protein expression of SLIT2 and ROBO1 was observed in 51 (85%) and 23 (38.3%), respectively (P < 0.001). Promoter methylation of SLIT2 correlated well with smoking (P = 0.046), betel nut chewing (P = 0.032), staging (P = 0.018) and tumor (T) factor (P < 0.001) of the TNM system and its aberrant protein expression correlated well with betel nut chewing (P = 0.038), staging (P = 0.025) and nodal (N) involvement (P = 0.004). Promoter methylation and protein expression of ROBO1 did not correlate with any of these clinicopathologic parameters. A concordance rate of 88.2% and 74.2% was present between expression of SLIT2 and ROBO1 protein and their promoter methylation (P < 0.001) and (P = 0.004), respectively.


CONCLUSIONS
Aberrant expression of SLIT2 and ROBO1 protein is frequently associated with the presence of ESCC, with SLIT2 a more predominant one. Promoter methylation is one of the major mechanisms responsible for aberrant protein expression of these two genes in resected ESCC. Promoter methylation and aberrant protein expression of SLIT2 may predict prognosis after resection for ESCC. No significant financial relationships to disclose.