MUTATIONS, TISSUE ACCUMULATIONS, AND SERUM LEVELS OF P53 IN PATIENTS WITH OCCUPATIONAL CANCERS FROM ASBESTOS AND SILICA EXPOSURE

In order to determine the relationship between mutations, tissue accum ulations, and serum levels of p53 in occupational cancers, we used den aturing gradient gel electrophoresis and DNA sequencing of exons 5-9 o f the p53 gene, immunohistochemical analysis for tissue identification of mutant p53 protein, and enzyme-linked immunosorbent assay for seru m levels of mutant p53 protein to examine for such alterations in a co hort of individuals with workplace exposure to asbestos or silica, and resultant lung cancers or mesotheliomas. DNA analysis detected mutati ons in 5 of 18 (28%) tumors, and tissue accumulations of protein were detected in 7 of 20 (35%) tumors; the agreement between mutational and immunohistochemical analyses was significant (<(kappa)over cap> = 0.6 2, P = 0.002). Serum elevations of protein were detected in 4 of 11 (3 6%) cases with available serum samples; the agreement between tissue a lterations and serum elevations was also significant (<(kappa)over cap > = 0.71, P = 0.017). In addition, based on the analysis of banked sam ples, serum results tended to be consistent over time prior to the dia gnosis of disease (positive predictive value = 0.67, negative predicti ve value = 0.83). These results suggest that serum levels of p53 are r easonably accurate in reflecting tissue alterations in p53 at the gene and/or protein level and may be early biomarkers of disease risk. (C) 1997 Wiley-Liss, Inc.