In summary, although studies with radiation-associated human tumors have yet to yield unambiguous data on the nature of causal gene and chromosomal mutations, animal studies are providing valuable guidance on the issue. Three principal points may be made. First, mechanistic studies on murine1 AML, lymphoma or sarcoma in Tp53+/− mice, intestinal adenoma in Apc+/− mice, medulloblastoma in Ptch+/− mice, and renal carcinoma in Tsc-2+/− rats all argue that the induction of critical cellular events by radiation occurs early in the tumorigenic process—a conclusion that is consistent with previous judgments on the issue. Second, the cytogenetic and molecular data cited for AML and intestinal tumors provide evidence for early monoclonal development of characteristic radiation-induced pre-neoplastic changes implying an initial, single-cell target. Third, for induction of AML and intestinal, medulloblastoma, and renal tumors, the radiation-associated events are predominantly DNA losses targeting specific genomic regions harboring critical genes. This in vivo DNA deletion mechanism is consistent with that understood in greater detail from in vitro somatic mutation systems. Also, many of the radiation-associated DNA loss events recorded in tumors are of cytogenetic dimensions. It is therefore possible to draw parallels with in vitro data on chromosome aberration induction where the predominant importance of DNA DSB induction and postirradiation error-prone NHEJ repair has been used in this report to argue against the proposition of a low-dose threshold in the dose-response.
Evidence on the single-cell origin of radiogenic animal tumors, the in vivo gene or chromosomal loss mechanism for tumor initiation that appears to apply, and the close parallels that may be drawn with mechanisms and dose-response for in vitro induction of gene or chromosomal mutations argue in favor of a no-threshold relationship between radiation dose and in vivo tumor risk. In the examples cited, there is generally concordance between gene loss or mutational events recorded in spontaneous and radiation-associated tumors of a given type; although the data are more limited, such concordance tends to apply to other tumorigenic agents. A degree of gene specificity for different tumor types is also evident.
An obvious caveat to this conclusion is the degree to which these limited mechanistic data provide support for broad judgments about radiation risk at low doses. For example, the data cited on the tolerance of aneuploidy in the bone marrow of irradiated Trp53-deficient mice can explain the high-frequency development of lymphoma but may not be wholly relevant to other tissues and/or other genetic settings. Data discussed in the following section on the potentially powerful effects of genetic background on tumorigenic risk in irradiated mice also caution against a dogmatic approach to judgments about low-dose risk that are based on current mechanistic knowledge. In this respect, the following section summarizes data concerning novel aspects of radiation response that may have relevance to unconventional mechanisms of radiation tumorigenesis.
As noted earlier in this chapter, the spontaneous development of tumors is frequently accompanied by the acquisition of genomic instability phenotypes that serve to promote the mutational evolution of more aggressive neoplastic clones. This form of genomic instability is increasingly well understood, and many of the responsible tumor gene mutations have been identified. Also noted in Chapter 2 is the large body of data showing that initial radiation-induced lesions are processed rapidly and expressed as chromosome aberrations at first postirradiation mitoses. However, during the last decade, evidence has accumulated that under certain experimental conditions, the progeny of cells surviving radiation appear to express an excess of new chromosomal and gene mutations over many postirradiation cell generations. This feature of cellular response (reviewed in Chapter 2) is generically termed radiation-induced persistent genomic instability. There are a variety of different manifestations of this phenomenon, and the developing field has been the subject of a number of recent reviews (Morgan and others 1996; Mothersill and Seymour 1998b; Wright 2000). The available data do not allow for generalizations on the onset and duration of such phenomena. On the basis of these data and previous reports of high-frequency neoplastic cell transformation (Clifton 1996), it has been suggested that epigenetic changes affecting a substantial fraction of irradiated cells can serve to destabilize their genomes and that the elevated postirradiation mutation rates in cell progeny, rather than gene-specific initial mutations, act to drive radiation tumorigenesis (Little 2000; Wright 2000). This section of the chapter focuses attention on in vivo studies of induced genomic instability that address the relevance of the phenomenon to radiation tumorigenesis.
Radiation-induced genomic instability in hematopoietic cells was first revealed by studies showing a persistent excess of chromatid-type aberrations in the progeny of mouse bone marrow cells irradiated in vitro with α-particles and subsequently grown in culture (Kadhim and others 1992). Alpha particles were considered to be substantially more effective than low-LET radiation in inducing this form of genomic instability (Wright 2000), which has also been reported in the progeny of cells that had not been traversed by an α-particle track (i.e., a bystander effect for instability; Lorimore and others 1998). Posttransplantation growth in vivo of in vitro irradiated bone marrow cells was also re-