Inherited Lack of Death Receptor 4 (DR4) Expression in Gastric Carcinoma through Gene Promoter Methylation
KH Lee, SS Kim, Y Kim, JS Kim, MH Cho, YM Lee, JH Lee. Seonam University, College of Medicine, Namwon, Jeollabukdo, Republic of Korea; Chonnam National University Medical School, Gwangju, Republic of Korea
Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent because of its selective toxicity in cancer cells. TRAIL sensitivity is suggested to be affected by the expression balance between pro-apoptotic death receptors (DR4 and DR5) and anti-apoptotic decoy receptors (DcR1 and DcR2). Promoter methylation status of death receptors in gastric cancer has never been studied in a large series. In this study we investigated the frequency of promoter methylation in DR4, DR5, DcR1, DcR2 and caspase-8, the next signaling step, in early and advanced gastric carcinoma.
Design: Promoter methylation of DR4, DR5, DcR1, DcR2 and caspase-8 was evaluated in 62 early gastric cancers (EGCs) and 60 advanced gastric cancers (AGCs) from 122 patients who had undergone gastrectomy. Methylation status was also examined in normal mucosa samples from 24 patients with benign gastric pathology. The methylation status of five gene promoters was determined by bisulfite modification and methylation-specific PCR (MSP).
Results: Sixty one (98.4%) cases of 62 EGCs and 50 (83.3%) cases of AGCs exhibited promoter methylation of DR4. Of the 62 EGCs, 1 (1.6%), 7 (11.3%), 10 (16.1 %) and 12 (18.3%) cases were methylated for DR5, DcR1, DcR2 and Caspase-8. Promoter methylation was seen in 0 (0%), 6 (10.0%), 14 (16.7%) and 10 (16.0%) cases of 60 AGCs for each promoter. Interestingly, 24 (100%) cases of 24 normal samples showed promoter methylation of DR4. With other genes, 0 (0%), 4 (16.05), 5 (20.8%), 1 (4.2%) cases of 24 normal samples demonstrated methylation for each gene promoters. Hypomethylation rather than hypermethylation of DR4 was observed in the progression of gastric tumor to more invasive carcinoma. Difference between the frequencies of other gene promoter methylation was not statistically significant (p>0.05, respectively).
Conclusions: We authors showed high promoter methylation rate of DR4 in gastric carcinoma in relation with its constituitive methylation in gastric normal mucosa. Lack of gene expression through promoter methylation in proapoptotic death receptors may contribute to TRAIL insensitivity of gastric cancer. Knowledge on the promoter methylation status of death receptors in gastric carcinoma in the present study will contribute to new, patient-tailored, treatment strategies for gastric cancer patients.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 95, Tuesday Afternoon