Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Chemoprevention: genetic & molecular basis

WN Hittelman PhD

University of Texas M D Anderson Cancer Center, Houston, TX,

AIM: Chemoprevention trials using cancer as the primary endpoint require large numbers of patients and long follow-up times, limiting the number of trials that can be performed. The aim of these studies is to characterize molecular and cellular biomarkers that can be used in association with chemoprevention trials to identify individuals at high cancer risk who would benefit from intervention and to assess treatment effect at the tissue level. METHODS: Tissue biopsies were obtained from the target tissue (e.g., oral cavity, larynx, lung) of subjects with premalignant lesions before and following chemopreventive treatment (e.g., retinoids, vitamin E, interferon) and assessed for genetic changes (chromosome in situ hybridization, LOH and mutation analysis), proliferation (Ki67 or PCNA immunocytochemistry), and expression of regulatory factors (p53 by immunocytochemistry). RESULTS: Genetic instability, clonal outgrowths, and dysregulation of proliferation were found in premalignant lesions and normal appearing epithelium throughout the aerodigestive tract of chronic smokers, were associated with the extent of tobacco exposure, and persisted for years following tobacco cessation. While the degree of abnormal biomarker expression was correlated with the degree of histologic change, a high degree of inter-subject variation was evident. Those individuals with the highest degree of genetic instability, LOH, and p53 expression in oral and laryngeal lesions were shown prospectively to be selectively resistant to short-term chemopreventive treatment and to be at highest risk for cancer development. Complete clinical and histologic response to combination treatment was associated with decreases in proliferation and transient decreases in p53 expression, however genetically-defined clones were found to persist in the target tissue. The continued presence of p53 expression, genetic instability, and LOH in the lesions was associated with subsequent relapse and progression to carcinoma. CONCLUSIONS: These results suggest that chronic carcinogen exposure leads to the development of clonal outgrowths throughout the exposed epithelial field and that genetic and phenotypic biomarkers can be used to identify individuals at highest carcinoma risk, to assess the likelihood and extent of response to current interventions, and to identify new targets and strategies for chemopreventive treatment.

KEY WORDS: chemoprevention, aerodigestive tract cancer, biomarkers.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on anticancer strategies.