Hyeon Kook Lee

Tumour suppressor gene expression correlates with gastric cancer prognosis

The loss of tumour suppressor genes (TSGs) is a key event in many human cancers, including gastric carcinoma. Many TSG candidates have been studied, but their roles in gastric carcinogenesis remain unclear. To clarify the clinical significance of TSG expression in gastric carcinoma, the expression of various TSG candidates (p53, E‐cadherin, FHIT, smad4, rb, VHL, PTEN, MGMT, p16, and KAI1), as well as other proteins (bcl‐2, MUC1, MUC2, MUC5AC, MUC6, CEA, CD44, β‐catenin, C‐erbB2, and cyclin B2), was evaluated immunohistochemically in 329 consecutive gastric carcinomas using the tissue array method. The overexpression of p53 and MUC1 (p < 0.01) and the loss of expression of smad4 (p = 0.04), FHIT (p = 0.03), MGMT (p = 0.01), E‐cadherin, KAI1, and PTEN (p < 0.01) were found to be significantly associated with poor gastric carcinoma prognosis. Seven out of eight survival‐associated proteins were found to be protein products of TSGs. The gastric carcinomas were divided into five groups according to the grade of alteration in TSG expression. No TSG expression loss was found in 32 cases (TSG1). One TSG loss was found in 47 cases (TSG2), two in 67 cases (TSG3), three or four in 64 cases (TSG4), and five, six, or seven in 38 cases (TSG5). The grade of TSG expression was confirmed to be significantly associated with WHO classification (p = 0.04), pTNM stage, lymphatic invasion, and patient survival (p < 0.01 for the latter three). By multivariate analysis, the grade of TSG expression was found to be significantly and independently associated with patient survival (p < 0.01). In conclusion, the findings of this study suggest that the cumulative loss of TSG expression in gastric carcinoma is important in determining patient survival. Copyright

Distinct Clinical Features and Outcomes of Gastric Cancers with Microsatellite Instability

Microsatellite instability (MSI) is a hallmark of the DNA mismatch repair deficiency that is one of the pathways of gastric carcinogenesis. Clinicopathologic characteristics of MSI+ gastric cancers remain unclear. To determine the correlation between MSI status and clinical features, we analyzed 327 consecutive gastric cancers for the occurrence of MSI in the BAT-26 marker. Because it has been proven that MSI at BAT-26 reflects the MSI+ phenotype, cancers with alteration at BAT-26 were categorized as having the MSI+ phenotype. The expressions of hMLH1, hMSH2, p53, MUC1, MUC2, and CEA were evaluated immunohistochemically using the tissue array method. The MSI+ phenotype was found in 9.5% (31/327) of gastric cancers examined. MSI+ gastric cancers were significantly associated with older age, antral location, Borrmanns gross Type II, intestinal subtype, lower prevalence of lymph node metastasis, and lower pTNM stage (P < .05). By multivariate logistic regression, MSI+ gastric cancers had a lower prevalence of lymph node metastasis independent of tumor invasion (P < .001). MSI+ gastric cancers displayed frequent frameshift mutations of transforming growth factor-β type II receptor (90.3%), BAX (61.3%), hMSH3 (38.7%), and E2F4 (61.3%) genes and diminished hMLH1 (24/31) or hMSH2 (4/31) expressions. The MSI+ phenotype correlated with patient survival in advanced gastric carcinoma (P = .046). In conclusion, MSI+ phenotype in gastric cancers was found to have distinct clinicopathologic characteristics and to be predictive of a favorable outcome in advanced carcinoma.

Prognostic significance of Bcl-2 and p53 expression in gastric cancer

Background and aimsApoptosis regulates cell death and influences cell proliferation and therefore may play an important role in development or growth of various malignant tumors. The Bcl-2 and p53 are closely linked in the regulation of apoptosis. We investigated the prognostic significance of Bcl-2 and p53 expression in patients with gastric cancer.Patients and methodsImmunohistochemistry was used to study Bcl-2 and p53 expression in 308 consecutive patients with gastric cancer.ResultsBcl-2 expression was positive in 39 patients (12.7%) and showed a significant negative correlation with depth of invasion and lymph node metastasis. p53 expression was observed in 105 patients (34.1%) and was significantly associated with depth of invasion, lymph node metastasis, distant metastasis, and intestinal type. Patients with Bcl-2+ tumors showed a trend to better 5-year survival rate (81%) than those with Bcl-2− negative tumors (71%). The 5-year survival rate in p53 positive cases (60%) was significantly lower than that in p53-negative cases (78%). In addition, p53 expression showed a significantly poorer prognosis in both diffuse and intestinal types. In multivariate analysis restricted to patients with R0 resection p53 expression was an independent prognostic factor (relative risk: 2.063). In combined assessment of p53 and Bcl-2 expression the group with p53+/Bcl-2− tumors showed significantly worse 5-year survival (57%) than the other groups, while best survival was seen in the group with p53+/Bcl-2+ tumors (100%).Conclusionp53 expression is an unfavorable prognostic factor in gastric cancer. Bcl-2 expression may have possible prognostic value when combined with p53 expression.

Expression of gastrin and its receptor in human gastric cancer tissues

Purpose: Gastrin is a growth factor of cancerous and normal cells of the gastrointestinal tract, and its effect is known to be mediated by gastrin/cholecystokinin B (CCKB) receptor. This study was performed to investigate the prognostic significance and the expression profiles of gastrin and gastrin receptor in human gastric carcinoma tissues. Methods: We analyzed the expressions of gastrin and gastrin receptor by immunohistochemical staining using anti-gastrin Ab (Sigma, St. Louis, MO, USA) and anti-gastrin receptor Ab (Aphton Corp., Woodland, CA, USA) in 279 gastric adenocarcinoma patients. Patients’ clinicopathologic features and prognoses were analyzed. Results: The gastrin expression rate in these patients was 47.7% (133/279) and the gastrin receptor expression rate was 56.5% (158/279). Gastrin expression was significantly higher in men than in women (54.3% vs. 34.1%), and higher in differentiated gastric adenocarcinoma than in the undifferentiated type (55.1% vs. 43.0%). The gastrin receptor expression rate was also significantly higher in men than in women (61.2% vs. 47.3%), and was higher in the differentiated type than in the undifferentiated type (72.9% vs. 46.5%), and significantly higher in the intestinal type than in the diffuse type (75.2% vs. 42.9%). Gastrin and gastrin/CCKB receptor expressions were not found to be significant prognostic factors in themselves. When focused on correlation between the co-expression of gastrin and gastrin/CCKB receptor and the survival, the prognosis of patients positive for both gastrin and gastrin receptor was significantly poorer than for those negative for gastrin and gastrin receptor in diffuse-type gastric cancer patients. However, multivariate analysis showed that only TNM stage was an independent prognostic factor of survival in diffuse-type gastric cancer patients. Conclusions: This study shows that the expression rates of gastrin and gastrin receptor are high (about a half) in gastric carcinoma tissues, and that there is an association between gastrin and gastrin receptor expression. We also found that patients with diffuse-type gastric carcinoma tissues expressing both gastrin and gastrin receptor have a poorer prognosis than those negative for both, which suggests that gastrin acts as an autocrine growth factor in a subgroup of gastric carcinomas.

Transcriptional repression of the human p53 gene by cobalt chloride mimicking hypoxia

The switch to an angiogenic phenotype is known to be a fundamental determinant of neoplastic growth and tumor progression. We herein report that the transcription of the human p53 gene was repressed by treatment with a hypoxia‐mimicking concentration of cobalt chloride and alone by hypoxia‐inducible factor 1α. Analyses of serial deletions, site‐directed mutageneses and heterologous promoter systems showed that the site responsible for the repression by both factors was the E‐box element in the promoter of the p53 gene. These results alongside previous data suggest that the loss of p53 including the transcriptional repression may play an important role in the angiogenic switch during tumorigenesis.

E2F1 activates the human p53 promoter and overcomes the repressive effect of hepatitis B viral X protein (Hbx) on the p53 promoter.

The functional effect of the interaction of E2F1 and hepatitis B virus X protein (HBx) on the promoter of human p53 gene was studied using chloramphenicol acetyl transferase (CAT) assay. E2F1 activated the p53 promoter through E2F1 binding site. As previously reported, HBx repressed the p53 promoter through E‐box. When E2F1 was cotransfected with HBx, E2F1 overcame the repressive effect of HBx on the p53 promoter through the E2F1 site. However, in the thymidine kinase ( tk ) heterologous promoter system with the E2F1 binding sites, cotransfection of E2F1 and HBx showed a strong synergistic activation. An in vitro interaction assay showed that E2F1 and HBx physically bind with each other. Analyses of the interaction domain with the GAL4 fusion protein showed that the pRb‐binding domain of E2F1 was necessary for the functional interaction of these two proteins. Taken together, these results imply the functional inhibitory action of E2F1 on the HBV life cycle and HBV‐mediated hepatocellular carcinogenesis (HCC). Therefore, the normal or enhanced function of E2F1 gene would be important in controlling the HBx function in HCC.

A Clinicopathological Analysis of Recurrent Gastric Cancer.

PURPOSE This study was designed to investigate the correlation between the clinicopathologic characteristics and the recurrence pattern of gastric cancer and to define survival difference according to treatment modality after diagnosis of recurrence. MATERIALS AND METHODS We retrospectively reviewed the medical records of 4184 patients who had undergone radical surgery for primary gastric cancer from 1986 through 1996. Clinicopathologic factors were analyzed for the relationship of each factor with the pattern of recurrence. And the survival after diagnosis of recurrence was compared among the treatment modalities. RESULTS Recurrence pattern was confirmed in 1141 patients. Loco-regional recurrence occurred in 291 patients (20.1%), peritoneal recurrence in 383 (26.5%), distant recurrence in 290 (20.1%), and mixed recurrence in 177 (12.3%), respectively. Early recurrence (less than 2 years) occurred in 767 (69.3%), intermediate recurrence (2~5 years) in 286 (25.8%), and late recurrence (more than 5 years) in 54 (4.9%). In multivariate analysis, T stage, N stage, size of tumor and perineural invasion were independent prognostic factors for recurrence. Median survival from diagnosis of recurrence was 24.2 months in the curative operation group, 7.7 months in the chemotherapy group, 7.1 months in the non-curative operation group and 3.3 months in the conservative treatment group, respectively (p=0.000). CONCLUSION The clinicopathological analysis of recurrent gastric cancer showed recurrent patterns and prognostic factors. Curative resection is suggested to have survival benefit in recurrent gastric cancer patients, although it was possible in patients with limited extent of disease.

Usefulness of a FDG-PET Scan in Assessing Recurrent Gastric Cancer

Purpose: For curative resection of recurrent gastric cancer, it is imperative that there be no unrecognized foci of tumoral disease outside the operation field. PET (positron emission tomography) with FDG (18 fluoro-2 deoxy-D-glucose) is a whole-body imaging technique that exploits the increased rate of glycolysis in tumor cells to detect disease. The authors evaluated the usefulness of FDG-PET in assessing resectability of recurrent gastric cancer. Materials and Methods: Seven patients with recurrent gastric cancer were studied with FDG-PET from December 1998 to October 2000. All FDG-PET images were interpreted in conjunction with conventional diagnostic methods. All imaging results were correlated with the pathological diagnosis and clinical outcome. Results: A final diagnosis of recurrence was obtained at 14 sites in all 7 patients by histology or clinical follow up. Locoregional recurrence, including distant metastasis, developed in 6 of 7 patients and distant recurrence in only one. FDG-PET detected all recurrent sites (5 locoregional and 5 distant) in 5 patients without peritoneal recurrence, but did not detect peritoneal seeding in 2 patients with peritoneal recurrence. The accuracy of FDG-PET in estimating resectability was (5/7), and that of CT and PET together was (6/7). A curative resection could be performed in three of the recurrent patients (2 locoregional and 1 distant recurrence). Conclusion: Our results suggest that FDG-PET may be useful for detecting locoregional and distant recurrence of gastric cancer and for selecting appropriate treatment. However, considering that FDG-PET was limited in detecting peritoneal seeding and determining the exact anatomical extension of tumor, it should be used in conjunction with other anatomical images.