Increased proliferative activity caused by loss of p21^WAF1/CIP1 expression and its clinical significance in patients with early-stage gastric carcinoma

BACKGROUND. Recurrences of gastric carcinoma are likely to take on a variety forms, even after patients undergo curative resection for early-stage gastric carcinoma. It is important to identify the biologic markers that predict tumor progression and survival in these patients. Proliferating cell nuclear antigen (PCNA) acts as a processivity factor for DNA polymerase δ, which is involved directly in DNA synthesis, and the PCNA level is correlated with the proliferative state of cells. p21^WAF1/CIP1 interacts with PCNA to inhibit DNA synthesis and plays a central role in regulating the cell cycle. The authors investigated patients with early-stage gastric carcinoma to determine the clinical significance of proliferative activity and p21 expression. METHODS. Tissue specimens from 133 Japanese patients with early-stage gastric carcinoma that invaded the submucosal layer were immunostained with a monoclonal antibody against PCNA and p21^WAF1/CIP1, and the correlations between the PCNA labeling index and p21^WAF1/CIP1 expression as well as clinicopathologic factors were investigated. RESULTS. The PCNA labeling index varied from 9.9% to 81.4%, (mean, 31.2%). The incidence of p21 positive expression was 87 of 133 patients (65.4%). The patients with a high labeling index had a significantly higher rate of lymph node metastasis (P < 0.01) and loss of p21^WAF1/CIP1 expression (P < 0.05) compared with the patients with a low labeling index. The 5-year survival rate for patients in the high labeling index group (87.0%) was significantly lower compared with the 5-year survival rate for the patients in the low labeling index group (98.6%; P < 0.05). CONCLUSIONS. Loss of p21^WAF1/CIP1 expression contributes to the amplification of proliferative activity in patients with early-stage gastric carcinoma. Estimation of the proliferative activity of early-stage gastric carcinoma provides information on lymph node metastasis and prognosis. Even after patients undergo curative resection, those with early-stage gastric carcinoma should be followed closely.