leagues (Vogelstein 1990; Fearon and others 1990) with hereditary colon cancer. The progression from normal epithelium to metastatic cancer appears to involve a number of mutations in different oncogenes and tumor-suppressor genes and multiple chromosomal changes.

In the multistage formation of radiation-induced carcinogenesis, it is unclear as to how a single relatively small dose of radiation could result in mutations in so many different genes. The induction of multiple mutations seems highly unlikely, but data from the Japanese atomic-bomb survivors clearly show that a modest dose of radiation can induce many types of solid tumors, including those in the digestive tract. A more likely possibility is that radiation causes mutations in a gene responsible for the stability of the genome, which leads to a mutator phenotype. The multiple mutations and chromosomal changes follow as a cascade because of the induced instability as described below.

Both densely ionizing and sparsely ionizing radiation have been shown to induce chromosomal and mutational changes that appear in the progeny of exposed cells many generations after the initial exposure (Morgan and others 1996). The changes can occur in a high proportion of the surviving irradiated cells even after doses that give an average of only 1 alpha-particle traversal per cell. Examples of radiation-induced changes that are used as indicators of genomic instability are chromosomal aberrations, gene mutations, and even tumor induction in animal-model systems (Kennedy and Little 1984; Seymour and others 1986; Gorgojo and Little 1989; Chang and Little 1992; Kadhim and others 1992, 1994, 1995; Sabatier and others 1992; Martins and others 1993; Marder and Morgan 1993; Selvanayagam and others 1995). The high proportion of initially irradiated cells that transmit the instability phenotype and the variety of events observed suggest that this is not the result of a targeted effect of the initial radiation damage of specific genes, but rather a consequence of more-generalized damage to the cell; whether the initial damage is genetic or epigenetic is an unresolved question. Induced genomic instability is transmissible to progeny cells and can persist for multiple generations. Although this is an attractive hypothesis to account for carcinogenesis by low doses of high linear-energy-transfer radiation, typified by single-particle traversals, the case is far from proved.

INDIVIDUAL AND GENETIC SUSCEPTIBILITY

There is much published evidence that many cancer-predisposing genes are present in the human genome (Sankaranarayanan and Chakraborty 1995). For some tumor types, changes in these genes are responsible for a large fraction of the total cancer frequency. For example, 40% of children with retinoblastoma carry a germ-line mutation in the RB1 gene (Vogel 1979; Cowell and Hogg 1992). The tumor-suppressor gene p53 has been associated either directly or indirectly with at least 50% of human cancers (Hollestein and others 1991), although a causal link is less clear.



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