On the nature of susceptibility to cancer. The presidential address.

The most prominent factor determining susceptibility to cancer is age. However, there is little evidence that the aging process per se increases susceptibility to cancer. Rather, age provides the time necessary for the accumulation of cellular events required for the development of neoplasia. The variations in the patterns of cancer incidence rates seen with age can be explained by alterations in conditions of exposure to carcinogenic stimuli. There is no evidence that the pool of susceptible individuals in a population is limited. Cancer occurs as a random event in a population with greater or lesser frequency according to the presence of risk factors. In populations with an increased frequency of cancer such as those with genetic abnormalities, immune deficiency syndromes, or altered hormonal states, the risk of developing cancer is never generalized to all tissues but is characteristic of particular tissues at risk. Any circumstance of internal or external origin that disturbs homeostasis of particular tissues at risk. Any circumstance of internal or external origin that disturbs homeostasis over a prolonged period of time increases the susceptibility to cancer for the tissue concerned. Susceptibility to cancer does not mean that cancer is inevitable. Only a small number of those susceptible to cancer by virtue of a special risk factor develop the disease. Furthermore, most patients who develop cancer have no determinable risk factors. Although all evidence points to a multifactorial, multistage process, the rate of somatic mutation appears to be the key determinant factor in susceptibility to cancer. This concept is supported by research studies showing that the onset of atherosclerosis is initiated by somatic mutations, and the finding that the same chemical mutagens can advance the development of both diseases.