Radiation has at its core a fundamental dichotomy in its effects on humans—on the one hand, it is frequently and successfully used to treat cancer; on the other hand, it can cause cancer. What explains this dichotomy? It all comes down to whether the dose of radiation is large enough to kill cells, or whether it is small enough to leave the cell alive with some damage that does not get repaired. Cancer therapy is all about killing cancer cells by causing so much damage that the cell cannot repair it all and dies from lethal chromosomal aberrations. A standard course of radiotherapy consists of 2 Gy fractions of radiation delivered 5 days a week for about 6 weeks. This regimen gives the maximum probability of killing the cancer cells while not causing excessive damage to normal tissues that also get irradiated.

The carcinogenic (cancer-causing) effects of radiation are due to the presence of unrepaired or misrepaired DNA damage that can lead to mutations or altera­tions in the ability of some genes to be expressed. Radiation is not very effective at causing small mutations in individual bases of DNA—most of these get repaired. But it is very good at causing DSBs that lead to deletions of whole sections of a chromosome, and sometimes these deleted sections may contain important genes (14). The formation of chromosomal aberrations is a type of damage from radiation leading to many of its biological effects (15). To understand why that is important, we have to explore the molecular underpinnings of cancer.

Cancer is the result of an evolutionary process in which a normal cell under­goes genetic changes that eventually cause it to transform into a malignant cell that can develop into a malignant cancer in a human. A single mutation is not capable of causing a cell to transform from a normal cell into a malignant cell. Instead, there are a number of individual genetic changes that occur in a process known as multistep carcinogenesis. Cancer is sometimes considered to develop in three stages—initiation, promotion, and progression. Ionizing radiation, along with many toxic chemicals, is known as an initiator because it causes mutations that begin the long process of cancer. Other genetic changes occur during the process of promotion to push the cell closer to the edge of becoming fully malig­nant. Progression is the continued uncontrolled growth of the altered cells to form a malignant tumor. For most solid tumors, there is a latency period of 10 to 60 years from the time of exposure to radiation (initiation) to the development of a malignant tumor. It is notably shorter for leukemia, taking only 5 years or so, but the risk is over by about 15 years (7). After the Chernobyl nuclear accident (see Chapter 10), it was discovered that thyroid cancer also develops within a few years, a similar latency period to that of leukemia. Both of these cancers occur primarily in children, so it may be the result of very rapid proliferation of cells that accounts for the shorter latency period in these cancers. But what are these genetic changes that transform a normal cell into a malignant cell?