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Promoter methylation of TGFβ receptor I and mutation of TGFβ receptor II are frequent events in MSI sporadic gastric carcinomas
Author(s) -
Pinto Mafalda,
Oliveira Carla,
Cirnes Luis,
Carlos Machado José,
Ramires Maria,
Nogueira Ana,
Carneiro Fátima,
Seruca Raquel
Publication year - 2003
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.1327
Subject(s) - microsatellite instability , methylation , receptor , biology , cancer research , transforming growth factor , dna methylation , microbiology and biotechnology , mutation , gene , medicine , endocrinology , gene expression , genetics , microsatellite , allele
Transforming growth factor beta (TGFβ) 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 TGFβ. TGFβ RII mutations occur in many types of malignancy. TGFβ 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 TGFβ RI gene using a methylation‐sensitive enzyme followed by polymerase chain reaction (PCR), and TGFβ RII mutations (BAT‐RII and a GT 3 ) in order to determine the frequency of alteration of the TGFβ 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 TGFβ 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 TGFβ 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 TGFβ 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 TGFβ 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 TGFβ ( TGFβ RI promoter hypermethylation and TGFβ 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 TGFβ in this setting. Copyright © 2003 John Wiley & Sons, Ltd.