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Genetic and Immunohistochemical Analyses of p53 Independently Predict Regional Metastasis of Gastric Cancers¹

Laboratory of Comparative Carcinogenesis [Y-H. S.] and Data Management Services, Inc. [W. G. A.], National Cancer Institute, Frederick Cancer Research and Development Center, NIH, Frederick, Maryland 21702; Epidemiology Unit, Centro per lo Studio e la Prevenzione Oncologica, A.O. Careggi, 50131 Florence, Italy [D. P., C. S., G. M.]; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892 [N. E. C., J. F. F.]; Department of Pathology, University of Florence, 50134 Florence, Italy [A. A., G. N.]; and International Agency for Research on Cancer, 69372 Lyon Cedex 08, France [J. M. R.]

Either p53 gene mutation or immunohistochemical detection of p53 protein has not been consistently shown to have prognostic significance in human cancers, including gastric carcinomas. One hypothesis to explain this inconsistency is that some p53 mutations and p53 protein accumulation are not indicative of tumor progression. To test this hypothesis, we categorized p53 status in 105 gastric carcinomas according to types of mutations, numerical scores of immunohistochemical staining (IHC), or combinations thereof. The p53 status was then correlated with metastasis to liver or peritoneum. Gastric cancers with no p53 mutations were significantly less likely to metastasize than tumors with mutations. Intermediate IHC scores were inversely associated with metastasis. A substantial number of gastric cancers (31 of 105) showed positive p53 immunostaining without detectable mutations (p53-/IHC+), which suggested an accumulation of wild-type p53 protein, and also a significantly lower risk for metastasis. After adjusting for depth of invasion and lymph node involvement, the p53-/IHC+ combination predicted low metastatic risk better than either p53- or IHC+ with intermediate scores. These findings suggest that an accumulation of wild-type p53 protein occurs in gastric cancer cells and represents a stress-response mechanism that lowers metastatic potential.

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