While inherited cancers shed important light on the classes of genes involved in cancer, the majority of cases of cancer do not result from an obvious inherited predisposition. The major causes of cancer death worldwide arise from tumours in the lung, stomach, liver, colon, and breast. Of these cancers, lung cancer is strongly linked to cigarette smoking, and liver cancer to infection with the hepatitis B virus, with a significant role for alcohol consumption. Cancers of the digestive tract are presumed to be linked to diet, but the precise causation is still poorly understood. Likewise, breast cancer (and prostate cancer in men) is clearly linked to both dietary and hormonal factors. How may these diverse influences act to produce the changes required to generate cancer described above?
Lung cancer is the best-understood example of how a carcinogen in the environment can interact to generate cancer. The risk is clearly linked to the amount of tobacco consumed – there is a dose effect – and the duration of consumption. Smokers who give up tobacco before getting cancer have a decreasing risk of developing the disease after stopping. In terms of a model like the Vogelstein cascade, smoking must be responsible for inducing the first steps of the cascade and continued smoking must also induce the subsequent steps. In older models of carcinogenesis, the initial step was often referred to as initiation and the subsequent steps as a promotion of tumour growth, with a final step, termed transformation. These terms still have value and in the laboratory, agents that convert non-malignant cell growths into cancerous ones are often referred to as transforming the cells. Analysis of tobacco smoke has revealed a host of agents that will result in the transformation of cell culture systems. Detailed study of these smoke constituents has revealed the precise molecular mechanisms at work, down to the mode of interaction with the DNA double helix. One of the key culprits is called benzopyrene, and careful research has demonstrated it will bind to the DNA helix, damaging the structure. Figure 15 shows the benzopyrene molecule bound within a DNA double helix.
As mentioned above, there is clearly a need for DNA damage – an initiating event followed by a generally prolonged period of further damage accumulation, sometimes referred to as promotion – before a final transforming event turns the pre-cancerous lesion into full-blown cancer. In the case of tobacco, the process appears to be driven by continuous exposure to tobacco smoke, which has direct DNA-damaging properties. For other diseases, in particular, breast and prostate cancers, the role of the promoter is taken by the individual’s own hormones. The risk of breast cancer is influenced by duration of exposure of the breast to cyclical female hormones – hence early menarche and fewer pregnancies with no breastfeeding results in increased risk. The inference of this is that the continued cycles of changes in the breast induced by the menstrual cycle magnify any initial DNA damage done by some form of environmental carcinogen. A similar effect is seen in prostate cancer, in that men castrated early in life (for example, eunuchs) have a very low risk of prostate cancer compared to their peers who presumably are exposed to the same environmental carcinogens. A similar role is played by alcohol in liver disease. Alcohol, as already noted, is not a direct carcinogen – it will not damage DNA. However, heavy long-term abuse of alcohol induces cycles of damage and repair in the liver, with increased cell turnover. As with the cyclical changes in the breast, this continually increased activity serves to magnify the harm done by the DNA-damaging agents that must also be present, increasing the opportunity for accumulation of further DNA damage and the development of cancer.