Clinical Correlations

There are many ways in which mutations in cancer-promoting genes can occur. The predisposition to cancer can be inherited, as in patients with Li-Fraumeni syndrome, whose cells contain a germ-line mutation ofp53, one of the cell cycle checkpoint regulators described above. Cells from patients with chronic myelogenous leukaemia often contain an abnormal chromosome resulting from a translocation between chromosomes 9 and 22, the so-called Philadelphia chromosome (Rowley, 1973). This abnormal fusion juxtaposes two genes, which code for the proteins BCR and the Abl tyrosine kinase, and results in aberrant activity and subcellular localization of the Abl protein. In breast cancer, BRCA1 is mutated at specific sites in the gene. Such mutations are largely inherited.

In contrast to germ-line or inherited mutations, 'sporadic' cancers also can arise when a mutation occurs in a previously normal somatic cell. In this regard, environmental factors are thought to play major roles as mutagens or carcinogenic agents. For example, the relationship between tobacco smoke and lung cancer is well documented (Henderson et al., 1991). Anilines used in rubber tyre production are linked to the development of bladder cancer, while exposure to solar ultraviolet rays can cause melanoma (Case et al., 1993; Armstrong et al., 1997). Hundreds of chemical carcinogens that exist in food and products in daily use can either directly or through the production of secondary metabolites irreversibly alter a normal cell's DNA. So-called 'lifestyle' factors can also play a role. A link has been made between consumption of a diet high in animal fats and prostate cancer (Tzonou et al., 1999). In women, reproductive history and the resulting cumulative lifetime exposure to oestrogen correlate with an increased risk of breast cancer (Hankinson et al., 1995). How environmental factors trigger the activation and mutation of cancer-causing genes is, in many cases, still unclear. Subsequent chapters will detail what is known about a very complicated and intricate process.

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