THE GENOTYPE OF THE HUMAN CANCER CELL - IMPLICATIONS FOR RISK ANALYSIS

An extremely large database describes genotypes associated with the hu man cancer phenotype and genotypes of human populations with genetic p redisposition to cancer. Aspects of this database are examined from th e perspective of risk analysis, and the following conclusions and hypo theses are proposed: (1) The genotypes of human cancer cells are chara cterized by multiple mutated genes. Each type of cancer is characteriz ed by a set of mutated genes, a subset from a total of more than 80 ge nes, that varies between tissue types and between different tumors fro m the same tissue. No single cancer-associated gene nor carcinogenic p athway appears suitable as an overall indicator whose induction serves as a quantitative marker for risk analysis. (2) Genetic defects that predispose human populations to cancer are numerous and diverse, and p rovide a model for associating cancer rates with induced genetic chang es. As these syndromes contribute significantly to the overall cancer rate, risk analysis should include an estimation of the effect of puta tive carcinogens on individuals with genetic predisposition. (3) Gene activation and inactivation events are observed in the cancer genotype at different frequencies, and the potency of carcinogens to induce th ese events varies significantly. There is a paradox between the observ ed frequency for induction of single mutational events in test systems and the frequency of multiple events in a single cancer cell, suggest ing events are not independent. Quantitative prediction of cancer risk will depend on identifying rate-limiting events in carcinogenesis. Hy perproliferation and hypermutation may be such events. (4) Four sets o f data suggest that hypermutation may be an important carcinogenic pro cess. Current mechanisms of risk analysis do not properly evaluate the potency of putative carcinogens to induce the hypermutable state or t o increase mutation in hypermutable cells. (5) High-dose exposure to c arcinogens in model systems changes patterns of gene expression and ma y induce protective effects through delay in cell progression and othe r processes that affect mutagenesis and toxicity. Paradigms in risk an alysis that require extrapolation over wide ranges of exposure levels may be flawed mechanistically and may underestimate carcinogenic effec ts of test agents at environmental levels, Characteristics of the huma n cancer genotype suggest that approaches to risk analysis must be bro adened to consider the multiplicity of carcinogenic pathways and the r elative roles of hyperproliferation and hypermutation. Further, estima tion of risk to general human populations must consider effects on hyp ersusceptible individuals. The extrapolation of effects over wide expo sure levels is an imprecise process.