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Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, Maryland [W. P. B., Y. T., J. A. W., C. C. H.]; Department of Pathology, Mayo Clinic, Rochester, Minnesota [T. V. C.]; Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland [W. D. T.]; Department of Pathology, University of Maryland, Baltimore, Maryland [A. B., R. T. J., B. F. T.]; Department of Biochemistry, University of Dundee, Dundee, Scotland [D. P. L.]; Food and Drug Administration, National Institutes of Health, Bethesda, Maryland [R. A. M.]; University of New Mexico Cancer Center, Albuquerque, New Mexico [J. M. S.]; Shanghai Cancer Institute, Shanghai, People's Republic of China3 [J. R. G.]; and Departments of Pharmacology and Toxicology [K. H. V.] and Pathology [Y. S., P. P.], University of Oulu, Oulu, Finland
p53 mutations are common in human lung cancer and frequently generate levels of p53 protein that are detectable by immunohistochemistry. For this reason, p53 protein accumulation is a candidate biomarker, but little is known about its timing or frequency in multistage bronchial carcinogenesis. We studied human lung tissues containing preinvasive squamous neoplasms from 34 donors with and without lung cancer. Nuclear p53 protein was present in 0% of normal mucosas, 6.7% of squamous metaplasias, 29.5% of mild dysplasias, 26.9% of moderate dysplasias, 59.7% of severe dysplasias, 58.5% of carcinomas in situ, 67.5% of microinvasive carcinomas, and 79.5% of invasive tumors. These data indicate that (a) p53 protein accumulates in about 30% of the earliest recognized neoplastic lesions (i.e., mild dysplasia), (b) there is an increasing frequency of p53 protein accumulation starting with mild dysplasia, and (c) p53 protein accumulates infrequently in normal or metaplastic mucosa. In a subset of six patients whose most advanced lesion was carcinoma in situ without evidence of invasive cancer, p53 protein was detected in 0% of normal mucosas, 8.3% of squamous metaplasias, 37.5% of mild dysplasias, 12.5% of moderate dysplasias, 93.8% of severe dysplasias, and 55% of carcinoma in situ lesions. These data show clearly that p53 alterations can occur before invasion and suggest that the frequency is similar to that observed in the full series. Since two-thirds or more of lung cancers have p53 alterations, the timing and frequency of p53 protein accumulation make the p53 tumor suppressor gene an attractive marker for early diagnosis and evaluation of chemoprevention agents.
1 To whom requests for reprints should be addressed, at Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Building 37, Room 2C01, Bethesda, MD 20892.
Received 6/ 1/93. Accepted 9/ 2/93.
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