Progression and multiple events in radiation carcinogenesis of rat skin.

The multistage theory of carcinogenesis specifies that cells progress to cancer through a series of discrete, irreversible genetic alterations, but data on radiation-induced cancer incidence in rat skin suggests that an intermediate repairable alteration may occur. Data are presented on cancer induction in rat skin exposed to the following radiations: 1. an electron beam (LET = 0.34 kev/mu), 2. a neon ion beam (LET = 45 kev/mu) and 3. an argon ion beam (LET = 125 kev/mu). The latter 2 beams were generated by the Bevalac at the Lawrence Berkeley Laboratory, Berkeley, CA. About 6.0 cm2 of skin was irradiated per rat. The rats were observed every 6 weeks for at least 78 weeks and tumors were scored at first occurrence. Several histological types of cancer, including squamous and basal cell carcinomas, were induced. The total cancer yield was fitted by the quadratic equation, and the equation parameters were estimated by linear regression for each type of radiation. Analysis of the DNA from the electron-induced carcinomas indicated that K-ras and/or c-myc oncogenes were activated in all tumors tested. In situ hybridization indicated that the cancers contain subpopulations of cells with differing amounts of c-myc and H-ras amplification. The results are consistent with the idea that ionizing radiation produces stable, carcinogenetically relevant lesions via 2 repairable events at low LET and via a non-repairable, linked event pathway at high LET; either pathway may advance the cell by 1 stage in the multistage model.