As one example, the receptor for the extracellular signal protein epidermal growth factor (EGF) can be activated by a deletion that removes part of its extracellular domain, causing it to be active even in the absence of EGF (Figure 20–19). It thus produces an inappropriate stimulatory signal, like a faulty doorbell that rings even when nobody is pressing the button. Mutations of this type are frequently found in the most common type of human brain tumor, called glioblastoma.
As another example, the Myc protein, which acts in the nucleus to stimulate cell growth and division (see Chapter 17), generally contributes to cancer by being overproduced in its normal form. In some cases, the gene is amplified— that is, errors of DNA replication lead to the creation of large numbers of gene copies in a single cell. Or a point mutation can stabilize the protein, which normally turns over very rapidly. More commonly, the overproduction appears to be due to a change in a regulatory element that acts on the gene. For example, a chromosomal translocation can inappropriately bring powerful gene regulatory sequences next to the Myc protein-coding sequence, so as to produce unusually large amounts of Myc mRNA. Thus, in Burkitt’s lymphoma, a translocation brings the Myc gene under the control of sequences that normally drive the expression of antibody genes in B lymphocytes. As a result, the mutant B cells tend to proliferate excessively and form a tumor. Different specific chromosome translocations are common in other cancers.
Studies of Rare hereditary Cancer Syndromes First Identified Tumor Suppressor Genes
Identifying a gene that has been inactivated in the genome of a cancer cell requires a different strategy from finding a gene that has become hyperactive: one cannot, for example, use a cell transformation assay to identify something that simply is not there. The key insight that led to the discovery of the first tumor suppressor gene came from studies of a rare type of human cancer, retinoblastoma, which arises from cells in the retina of the eye that are converted to a cancerous state by an unusually small number of mutations. As often happens in biology, the discovery arose from examination of a special case, but it turned out to reveal a gene of widespread importance.
Retinoblastoma occurs in childhood, and tumors develop from neural precursor cells in the immature retina. About one child in 20,000 is afflicted. One form of the disease is hereditary, and the other is not. In the hereditary form,
Figure 20–19 Mutation of the epidermal growth factor (EGF) receptor can make it active even in the absence of EGF, and consequently oncogenic. Only one of the possible types of activating mutations is illustrated here.
NORMAL, HEALTHY INDIVIDUAL HEREDITARY RETINOBLASTOMA NONHEREDITARY RETINOBLASTOMA occasional cell inactivates one of its two good Rb genes excessive cell proliferation leading to retinoblastoma excessive cell proliferation leading to retinoblastoma
RESULT: MOST PEOPLE WITH INHERITED RESULT: ONLY ABOUT 1 IN 30,000 RESULT: NO TUMOR multiple tumors usually arise independently, affecting both eyes; in the nonhereditary form, only one eye is affected, and by only one tumor. A few individuals with retinoblastoma have a visibly abnormal karyotype, with a deletion of a specific band on chromosome 13 that, if inherited, predisposes an individual to the disease. Deletions of this same region are also encountered in tumor cells from some patients with the nonhereditary disease, which suggested that the cancer was caused by loss of a critical gene in that location.