Point Mutations and Radiation Carcinogenesis

Abstract

In his recent summary of a symposium, Fry (1) poses the question: Are deletions and perhaps changes in suppressor genes more important in radiation carcinogenesis than are point mutations? Microdosimetric considerations indicate that this should, at least frequently, be the case. Carcinogenesis and oncological cell transformation induced by low-LET radiation are often greatly reduced by dose protraction (administration of the absorbed dose at a low rate or in more than one fraction). Whatever repair or modification may be the reason, this implies action by at least two events (passages of a high-energy electron and its 6 rays). At the absorbed doses that are employed in experimental radiobiology, or that are low enough so as not to cause prompt death in human populations, there is negligible probability that two electrons pass through a codon, gene, or nucleosome. Even if energy is transported from transfer points, joint action in a volume having a diameter as large as 100 nm must be discounted. Experimental data extend downward only to about 300 nm where the event frequency in the case of 60Co 'y radiation is about 1 Gy-1 (it is less at higher photon energies) (2). It is evident that in smaller sites the event frequency continues to decrease at a rate that is appreciably faster than the square of the site diameter, the reason being that in passing through such small volumes many electrons produce no events with a corresponding increase of lineal energy produced by the others. In 100-nm sites the event frequency is thus substantially less than 0.1 Gy-1. Hence, at absorbed doses of a few grays (and probably much higher), there is a negligible probability that two energy deposits in a 100-nm volume are due to two electrons rather than to one electron. On the basis of conservative assumptions it thus appears that the production of point mutations is quite unlikely to be due to multiple events. It is therefore dose-rate independ nt and cannot be a major cause of radiation carcinogenesis when it is reduced by dose protraction. These considerations are based on the assumption that it is improbable that a point mutation occurs at a given location predominantly when this location is at the end of a broken chromosome and the mutation is caused by union with another chromosome fragment. However, two-hit processes can cause deletions resulting in the loss of suppressor genes. In this case the two sublesions responsible can occur at various locations in a much larger volume where on the average many events occur at moderate absorbed doses. In 1-Am sites the event frequency is about 20 Gyfor 60Co y rays and near 5 Gy-' for orthovoltage X rays, and it increases with the square of the site diameter. Although these considerations do not exclude the possibility that a dose-rate-independent linear component of the initial phase of cell transformation is due to point mutation, an alternate explanation is that in this case dual injury is caused by a single electron (2). An example of the importance of deletions affecting suppressor genes is the causation of colorectal cancer as described recently by Kinsler et al. (3).