Promoter hypermethylation of TMS1 and DAPK were correlated to low chemosensitivity and poor prognosis in patients with recurrent gastric cancer

Abstract

4280 Background: Promoter hypermethylation plays an important role in the inactivation of tumor suppressor genes during tumorigenesis. Gene silencing associated with aberrant methylation of promoter region CpG islands is an acquired epigenetic alteration that serves as an alternative to genetic defects in the inactivation of tumor suppressor and other genes in human cancers. Target of methylation-induced silencing (TMS1) is a novel CpG island-associated gene and induces apoptosis through activation of caspase-9 and inhibited the survival of human breast cancer cells. Methylation of the apoptosis-associated gene death-associated protein kinase (DAPK) has been recently described in stage I lung cancer, in which it portends a poor prognosis. In the present study, promoter hypermethylation of TMS1 and DAPK were investigated and in gastric cancer specimen and compared to chemosensitivity and patient’s prognosis. Methods: Methylation status of forty-one gastric cancer specimens, all of which were formalin-fixed and paraffin embedded, were studied by methylation specific PCR. All the patients were administered 5-FU based chemotherapy for the treatment of recurrent lesion. Results: Hypermethylation of TMS1 and DAPK was observed 36.7% and 37.1% of the specimen, respectively. In TMS1 (DAPK) unmethylated group, 42.3 (45.5) % of the patients responded to the chemotherapy, while 20.0 (23.1)% responded in TMS1 (DAPK) methylated group. Patients with both TMS1 and DAPK methylated cancer showed significant poor survival than the others (p=0.0452, Log-rank test). Conclusions: Promoter hypermethylation of TMS1 and DAPK were supposed to be negative predictive and prognostic factors in patients with recurrent gastric cancer, probably through preventing apoptosis. No significant financial relationships to disclose.