p53 Biomarker and intervention in occupational cancer.
Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, R01-OH-007590, 2007 Nov; :1-7
Research Methods for Occupational Cancer are needed to develop early markers of adverse health effects from workplace exposures and to devise ways for interrupting the pathways between workplace exposures and resultant cancers. The p53 tumor suppressor gene is a potential target for both of these approaches. Certain occupational exposures can produce mutations in p53 which cause the generation of an immune response with circulating p53 autoantibodies, even before the occurrence of clinically detectable cancers, so that these autoantibodies may serve as useful early markers of adverse effects. In addition, certain short protein sequences from p53 have been shown in vitro to cause mutant p53 to revert to normal function resulting in the death of cancer cells containing mutant p53, suggesting that this may be a useful approach for interrupting the pathway between workplace exposures that produce p53 mutations and resultant cancers. The purpose of this study was to examine both of these approaches for occupational cancers in two related projects. In the first project, the presence of p53 autoantibodies was determined by ELISA in the banked serum samples from asbestosis cases collected between 1980 and 1987 and cancer mortality for the cohort was followed up to 2002. P53 autoantibodies were detected in 26. 5% of the individuals who subsequently developed cancer compared to 7.4% of the individuals who did not, a statistically significant difference (p=0.015), representing a positive predictive value of 0.76 and an average lead time to diagnosis of 3.5 years. In addition, in a repeat measures Cox proportionate hazards model, p53 autoantibody status was found to be highly statistically significantly predictive of subsequent. development of cancer (hazard ratio=5.5, 95%CI=2.8=10.9). Furthermore, p53 autoantibody status was found to be statistically significantly associated with p53 mutational status of the resultant tumors (Cohen's kappa=0.78, p=0.01). These results suggest that p53 autoantibodies are good predictors of cancer development in high-risk asbestosis cases and thus can be used as early markers of adverse health effects to identify those workers requiring more aggressive preventive interventions. In the second project, we determined that a C-terminal p53 protein sequence ( delivered as a peptide or as a mini-gene) was highly effective in producing apoptosis in premalignant and malignant cells with p53 mutations both in vitro in cell culture and in vivo in animal models via triggering of the FADD/caspase 8/caspase 3 pathway. In the animal studies, survival in the treatment groups was statistically significantly increased compared to the controls (p=0.01). Further structure-function studies of the protein sequence led to the development of an improved peptide with enhanced biological activity composed of a tetrameric palindrome of the C-terminal p53 sequence. Studies in vitro in cell culture and in vivo in animal models have confirmed the improved cytotoxic effect of this peptide in killing human mutant p53 cancer cells, including those that could develop from workplace exposures such as asbestos. These results suggest that this p53 peptide could be a novel and effective intervention for the chemotherapy or chemoprophylaxis of mutant p53 cancers produced by occupational carcinogens.
Biomarkers; Cancer; Carcinogens; Carcinogenesis; Carcinogenicity; Cancer-rates; Disease-incidence; Epidemiology; Exposure-assessment; Exposure-levels; Growth-factors; Growth-rate; Lung-cancer; Lung-disease; Mathematical-models; Mutagens; Mutagenesis; Pneumoconiosis; Pulmonary-cancer; Pulmonary-system-disorders; Pathogenesis; Pathogenicity; Radiation-effects; Radiation-exposure; Risk-analysis; Risk-factors;
Author Keywords: PDGF; TGF; pneumoconiosis severity; pneumoconiosis progression
Paul Brandt-Rauf, M.D., Sc.D., Dr.P.H., Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 60 Haven Avenue, New York, NY 10032
Final Grant Report
NTIS Accession No.
Research Tools and Approaches: Cancer Research Methods
National Institute for Occupational Safety and Health
Columbia University Health Sciences