violet radiation (UVR) and chemical exposures was followed by searches for potential TP53 mutational signatures in excess lung tumors arising in Japanese A-bomb survivors and radon-exposed uranium miners (Vahakangas and others 1992; UNSCEAR 1993; Taylor and others 1994b; Venitt and Biggs 1994; Bartsch and others 1995; Lo and others 1995; Rabes and others 2000). Subsequently, attention was also given to TP53 mutations in liver tumors arising in excess in patients receiving the alpha-emitting radiographic contrast agent Thorotrast (Iwamoto and others 1999). Interpretation of these data are problematical, and although one study of lung tumors from uranium miners was suggestive of a possible codon-specific mutational signature of radiation (Taylor and others 1994b), this finding was not confirmed by others (Venitt and Biggs 1994; Bartsch and others 1995; Lo and others 1995). The studies on liver tumors from Thorotrast patients provide some comment on secondary TP53 mutation and possible instability effects but, overall, the studies cited above do not give consistent evidence that TP53 is a primary target for ionizing radiation.
A cytogenetic-molecular data set is available on papillary thyroid cancer (PTC) (Bongarzone and others 1997) arising in excess in 131I-exposed children in areas contaminated by the Chernobyl accident (UNSCEAR 2000a). These mechanistic studies were guided by the knowledge that chromosomally mediated rearrangement and activation of the ret proto-oncogene is a frequently early arising feature of PTC (Richter and others 1999). Three different forms of ret gene rearrangement have been characterized at the cytogenetic and molecular levels (i.e., ret/PTC1, ret/PTC2, and ret/PTC3), and the prevalence of these events has been investigated in post-Chernobyl childhood PTC (Klugbauer and others 1995; Bongarzone and others 1997; Williams 1997; Smida and others 1999a, 1999b). As expected, ret activation events were found to be recurrent in Chernobyl-associated childhood PTC, and a similarly high frequency has been reported in adult thyroid cancer of patients with a history of radiation (Bounacer and others 1997). These studies suggest that the spectra of ret mutations differ between tumors of adults and children. Some investigations suggest that ret/PTC3 events in post-Chernobyl childhood cases are more frequent than expected. However this view is questioned by the study of 191 cases by Rabes and colleagues (2000), which provides evidence that the spectrum of ret rearrangements may be dependent on postirradiation latency, degree of tumor aggression, and possibly, dose to the thyroid.
At present, causal relationships between ret gene rearrangement, childhood PTC, and radiation remain somewhat uncertain. However, a possible clue to radiation causation is the finding that breakpoints in the majority of ret rearrangements carry microhomologies and short direct or inverted repeats characteristic of the involvement of nonhomologous endjoining (NHEJ) mediated misrepair (Klugbauer and others 2001). Other investigations have reported that TP53 gene mutation does not play a significant role in the development of post-Chernobyl PTC (Nikiforov and others 1996; Smida and others 1997).
Some informative molecular data are also available for basal cell skin carcinomas (BCCs) arising in X-irradiated tinea capitis patients (Burns and others 2002). In five out of five tumors analyzed there was evidence of DNA loss events which encompassed the Ptch gene (the gatekeeper for BCC development) plus the closely linked XPA gene.
Overall, the studies summarized above, together with reports on the cytogenetic characterization of acute myeloid leukemias in A-bomb survivors (Nakanishi and others 1999) and radiotherapy-associated solid tumors (Chauveinc and others 1997) do not provide clear evidence on the causal gene-specific mechanisms of radiation tumorigenesis. In general however, they do support a monoclonal basis for postirradiation tumor development and suggest that the characteristics of induced tumors are similar to those of spontaneously arising neoplasms of the same type. A possible exception to this is that an excess of complex chromosomal events and microsatellite sequence instability was observed in late-expressing myeloid leukemias arising in A-bomb survivors exposed to high radiation doses (Nakanishi and others 1999); these data are discussed later in this chapter.
Although radiation-induced tumors from experimental animals have been available for study for many years, it is only through advances in cytogenetics, molecular biology, and mouse genetics that it has become possible to investigate early events in the tumorigenic process. The most informative data on such early events derives from studies of tumors induced in F1 hybrid mice in which specific DNA loss events may be analyzed by loss of heterozygosity for genomically mapped polymorphic microsatellites.
Early studies with radiation-induced thymic lymphoma provided evidence of recurrent RAS gene activation and some indication that the RAS gene mutational spectra differs between X-ray and neutron-induced lymphoma (Sloan and others 1990). Other molecular studies include the finding of recurrent chromosome (chr) 4 deletions in thymic and nonthymic lymphomas (Melendez and others 1999; Kominami and others 2002) and T-cell receptor (Tcr) gene rearrangements and chromosomal events in thymic lymphoma. However, the above and other somatic mutations in mouse lymphoma have yet to be specifically associated with initial radiation damage.
The situation in mouse acute myeloid leukemia (AML; Silver and others 1999) is clearer. AML-associated, region-specific deletion of chr2 has been shown by cytogenetic analysis of in vivo irradiated bone marrow cell populations to be a direct consequence of radiation damage; clonal pre-