neoplastic growth of carrier cells has also been reported (Hayata and others 1983; Breckon and others 1991; Bouffler and others 1997). These deletions, which are characteristic of ~90% of AML induced by various radiation qualities, have been analyzed in detail, and a putative myeloid suppressor gene target was identified within a chr2 interval of ~1 centimorgan (cM; 1 centimorgan equals about 1 million base pairs; Clark and others 1996; Silver and others 1999). Site-specific breakage of chr2 is characteristic of early radiation-induced events in AML, and there are cytogenetic and molecular data that support the involvement of telomere-like repeat (TLR) sequence arrays in chr2 breakage and rearrangement at fragile sites (Finnon and others 2002). Initial hypotheses on this form of postirradiation chromosomal fragility centered on increased recombinational activity of such TLR sequence arrays (Bouffler and others 1997). However, the data of Finnon and colleagues (2002) are more consistent with a mechanism of domain-specific chromosomal rearrangement involving chromatin remodeling that is mediated by TLR-associated matrix attachment sequences.

With regard to radiation-induced osteosarcoma, Nathrath and colleagues (2002) have provided evidence for the involvement of two tumor-suppressor gene loci, but whether these loci are direct targets for radiation remains to be determined.

Mouse genetic models of tumorigenesis have also proved to be instructive about the nature of radiation-associated early events in tumor induction. In these models, the germline of the host mouse carries an autosomal deficiency in a given tumor-suppressor or gatekeeper gene, thus exposing the remaining functional (wild-type) copy to spontaneous or induced mutation and thereby tumor initiation (see “Genetic Susceptibility to Radiation-Induced Cancer”). The nature of these tumor gene-inactivating events has been studied in models of different tumor types.

In mice deficient in the Trp53 tumor suppressor gene (Trp53+/− and Trp53/), quantitative tumorigenesis studies implied that loss of the wild-type (wt) gene of Trp53+/− heterozygotes was a critical early event for the radiation induction of lymphoma and sarcoma (Kemp and others 1994). Molecular analysis confirmed the loss of wt Trp53 from tumors but also showed a high frequency of concomitant duplication of mutant (m) Trp53—such duplication was much less frequent in spontaneous tumors (Kemp and others 1994). Subsequent cytogenetic studies showed that Trp53+/− mice were highly prone to radiation-induced whole chromosome loss and gain (aneuploidy), and that the molecular data on tumorigenesis could be explained by radiation-induced loss of the whole chromosome (chr11) bearing wt Trp53, with duplication of the copy bearing mTrp53 being necessary to regain cellular genetic balance (Bouffler and others 1995). Thus, in this genetic context, Trp53 loss and tumorigenesis were relatively high-frequency events dependent upon the cellular tolerance of aneuploidy. However a recent study poses questions about whether Trp53 is indeed a direct target for radiation tumorigenesis in these knockout mice (Mao and others 2004). This study has raised the hypothesis that after radiation, the wt Trp53 gene in +/− mice activates the Fbxw7 gene, leading to genome instability, aneuploidy, and thereby increased Trp53 loss.

Radiation-induced intestinal tumorigenesis has been studied in F1 hybrid mice of the Apc+/− genotype (Luongo and Dove 1996; van der Houven van Oordt and others 1999; Haines and others 2000). In this mouse model, DNA may be sampled from very small, early arising adenomas, thus focusing attention on early clonal events in tumor development (Levy and others 1994). Loss of wt Apc with the whole of the encoding chr18 is a relatively common early event in spontaneous intestinal tumorigenesis in Apc+/− mice. However, in tumors arising in low-LET-irradiated mice, the spectrum of wt Apc loss events was dominated by interstitial chromosome deletions. One study (Haines and others 2000) implicated a second chr18 locus in these early radiation-associated losses and also identified loss of the Dpc4 gene as a common secondary event in spontaneous and induced tumors. In some genetic backgrounds, mammary, ovarian, and skin tumors also arise in excess in Apc+/− mice (van der Houven van Oordt and others 1999).

The same molecular genetic approach to experimental radiation tumorigenesis has been used in tumor-prone rodents that are heterozygous for the Ptch and Tsc-2 tumor-suppressor genes.

Mice deficient in the patched gene (Ptch+/−) are susceptible to both spontaneous and radiation-induced BCC and medulloblastoma (Hahn and others 1998; Aszterbaum and others 1999; Pazzaglia and others 2002). Of particular note are the recent data of Pazzaglia and colleagues (2002) showing that neonatal mice are highly susceptible to X-ray-induced medulloblastoma and that the predominant mutational event in these tumors is loss of Ptch+.

Loss of Tsc-2+ was similarly observed in many X-ray-induced renal carcinomas of Tsc-2+/− rats (Hino and others 2002), although intragenic deletions and point mutations were also observed. Importantly, the data available in this rodent genetic model (Hino and others 2002) reveal different spectra of tumor-associated Tsc-2+ mutations in spontaneous, X-ray, and ethylnitrosourea (ENU) induced renal carcinomas, which strongly suggests that the wt gene in target kidney cells is a direct target for carcinogens. As predicted from in vitro studies on somatic mutagenesis (Thacker 1986), tumors induced by the powerful point mutagen ENU were not characterized by Tsc-2+ gene loss events.

Studies with gene knockout mice are providing further evidence on the role of DNA damage response genes in determining the in vivo radiosensitivity of cells and tissue, together with the impact on growth or development and spontaneous tumorigenesis (Deng and Brodie 2001; Kang and others 2002; Spring and others 2002; Worgul and others 2002). It is expected that such animal genetic models will, in due course, yield more detailed information on the in vivo mechanisms of radiation tumorigenesis.

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