Promoter methylation of TGFbeta receptor I and mutation of TGFbeta receptor II are frequent events in MSI sporadic gastric carcinomas.

Abstract

Transforming growth factor beta (TGFbeta) is a potent inhibitor of cell growth, whose action is transduced through interaction between type I (RI) and type II (RII) receptors. Abnormal expression of these receptors has been identified in several human cancers and was found to be associated with resistance to TGFbeta. TGFbeta RII mutations occur in many types of malignancy. TGFbeta RI hypermethylation has been suggested as a cause of abnormal or absent expression of this receptor in cancer. This study has analysed the methylation status of the promoter region of the TGFbeta RI gene using a methylation-sensitive enzyme followed by polymerase chain reaction (PCR), and TGFbeta RII mutations (BAT-RII and a GT(3)) in order to determine the frequency of alteration of the TGFbeta receptors in a series of 40 sporadic gastric carcinomas (SGCs), 25 of which showed microsatellite instability (MSI) and 15 of which were microsatellite stable (MSS). Methylation in the promoter region of the TGFbeta RI gene was detected in 20 of the 40 (50%) SGCs (64% of the MSI cases and 26.7% of the MSS); 17 of the 40 (42.5%) cases had mutations in the BAT-RII region of the TGFbeta RII gene (68% in the MSI cases; 0% in the MSS). In total, 25 of the 40 (62.5%) SGCs had alterations in at least one of the TGFbeta receptors (84% of the cases in the MSI group, in contrast with 16% of the MSS cases) (p = 0.0003). The clinicopathological features of the cases were also studied and significant associations were found between the presence of alterations in TGFbeta receptors and the age of the patients (p = 0.046), size (p = 0.011), and proliferative rate of the tumours (p = 0.048). In conclusion, alterations in the receptors of TGFbeta (TGFbeta RI promoter hypermethylation and TGFbeta RII mutations) are frequent events in MSI SGC and are associated with large size and high proliferative activity of the tumours, in keeping with loss of the growth inhibitory effects of TGFbeta in this setting.