age, and chromosome fusion (Alvarez and others 1993; Ashley and Ward 1993; Bouffler and others 1993; Day and others 1993; Hastie and others 1990). Even chromosomal rearrangements that appear stable, such as balanced translocations, are not as secure as normal chromosomes and show declines in frequency with time after radiation exposure in vivo (Tucker and others 1997). A frequent result of chromosomal instability in tumor progression is the loss of a chromosome and the reduplication of the homologue; the chromosome number is maintained with the loss of heterozygosity (LOH). That can result in the loss of a normal gene and the duplication of mutant genes. Recent analysis of a large number of tumors indicates that LOH can involve an exceedingly large variety of genome-wide alterations even for a single tumor type (Kerangueven and others 1997).

The processes of mutation, insertion, deletion, rearrangement, loss of heterozygosity, reduced apoptosis, radiation-induced genomic instability, and the continued replication and proliferation of stem cells lead to a number of critical changes in genes along the paths that result in malignancies. Each tissue might require changes in specific genes, possibly in a particular sequential progression, for complete malignancy to emerge. The need for an ordered set of changes leads to the concept of fingerprints: characteristic mutations in tissue-specific rate-limiting genes that need to be altered early to allow tumor progression (Dogliotti 1996).

Mutations In α-Particle-Induced Tumors—The Fingerprints

It would be expected on the basis of in vitro work, that radon alpha-particle-induced cancers of the lung and other tissues would contain characteristic mutations, fingerprints, in critical gatekeeper genes that initiate carcinogenesis (Dogliotti 1996). Genetic changes that occur during tumor progression are likely to involve many genes but would lack characteristic fingerprints. The strongest example of a carcinogenic fingerprint is the detection of C to T mutations at the 3' C in dipyrimidine sites in nonmelanoma skin cancers, representing mispairing at sites of sunlight-induced photoproducts in DNA (Brash and others 1991). Carcinogenesis, however, is a highly selective process in which many genetic changes are pruned by selective constraints before the fully malignant cell types with genetic variability, unregulated growth, and invasive properties emerge. Many large α-particle-induced deletions might therefore be inconsistent with emergence of these properties and be lost from such a population. Deletions with a range of sizes up to complete gene loss, however, have been observed in the Rb and p53 genes in murine tumors induced by ionizing radiation (Zhang and Woloschak 1997). The mutations observed in α-particle-induced tumors will therefore be a subset of the full spectrum of genetic changes that are produced initially. But with the prevalence of genomic instability in tumors, specific deletions and rearrangements might easily become obscured; this would make a search for α-particle-induced fingerprints difficult.

The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement