CASE 3 YOU, FROM A TO T: YOUR PERSONAL GENOME

Cancer is usually due to a series of mutations that occur sequentially in a single lineage of somatic cells, as illustrated for colon cancer in Fig. 14.4. Each type of cancer is caused by its own particular sequence of mutations, although mutations in some genes are implicated in several different types of cancer. An example is the p53 gene, the nonmutant product of which detects DNA damage and slows the cell cycle to allow time for DNA repair (Chapter 11). Mutations in p53 are one step in the mutational progression of many different types of cancer, including colon cancer and breast cancer.

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In most individuals with cancer, all the sequential mutations that cause the cancer are spontaneous mutations that take place in somatic cells. They are not transmitted through the germ line, and so there is little or no increased risk of cancer in the offspring. In some families, however, there is a germ-line mutation in one of the genes implicated in cancer that is transmitted from parents to their children. In any child who inherits the mutation, all cells in the body contain the defective gene, and hence the cells already have taken one of the mutational steps that lead to cancer. The effect of such a germ-line mutation is therefore to reduce the number of additional mutations that would otherwise be necessary to produce cancer cells.

Any mutation that increases the risk of disease in an individual is known as a genetic risk factor for that disease. For colon cancer, the major genetic risk factors are mutations in APC, Ras, and p53. For breast cancer, the major genetic risk factors are mutations in the BRCA1 and BRCA2 genes (Case 3: You, from A to T). A risk factor does not cause the disease, but it makes the disease more likely to occur. For the genes implicated in colon cancer, each is a risk factor because when it is mutated, fewer additional mutations are needed to bring about tumor growth.

The DNA sequence of each of our personal genomes can reveal the genetic risk factors that each of us carries, not only for cancer but for many other diseases as well. Not all genetic risk factors are known for all diseases, and a great deal of current research aims to identify new ones. But many genetic risk factors are already known for a large number of common diseases, including high blood pressure, diabetes, inflammatory bowel disease, age-related macular degeneration, Alzheimer’s disease, and many forms of cancer. Therefore, your personal genome can be of great value in identifying diseases for which you carry risk factors, as was the case for Claudia Gilmore (Case 3: You, from A to T).

Our personal genomes can identify only genetic risk factors, however. In many cases, disease risk is substantially increased by environmental risk factors as well, especially lifestyle choices. While there are genetic risk factors for lung cancer, for example, the single biggest environmental risk factor is smoking tobacco. For skin cancer, the greatest environmental risk factor is exposure to the damaging ultraviolet rays in sunlight or in the sunlamps used in tanning beds. For heart disease, it is smoking, lack of physical activity, and obesity. For diabetes, it is an unhealthy diet.

For breast cancer, the environmental risk factors include certain forms of hormone therapy, lack of physical activity, and alcohol. While we may not be able to do much about the genetic risk factors for any of these conditions, knowing that we have them may make us more careful about the lifestyle choices that we make.