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Cell that does not get hit by a mutation event still has one good copy of the RB gene

One-hit cells sit quietly without dividing

FIGURE 33.2 The two-hit model for tumor formation. The first hit, an inherited defect in a tumor suppressor gene in every cell in an individual's body, does not itself result in cancer. It is only when an additional mutation event (the second hit) takes out the second copy of the tumor suppressor gene in a single cell that loss of regulation of cell division occurs and the cell begins to divide in an uncontrolled fashion. It is unlikely but possible for defects to develop in both copies of a tumor suppressor gene in the same cell in an individual who did not start out in possession of a defective copy, but such events are very rare. In an individual who has inherited an RB copy with the first hit already present, most cells will retain their protective good copy and only rare cells will receive a second hit and become cancer cells. Second hits like this can happen independently more than once in the same individual bearing an inherited tumor suppressor defect. The two-hit hypothesis for tumor formation was proposed by Dr. Alfred Knudson.

One mechanism by which the second copy can be lost is through deletion of one copy of the RB gene. When this happens the cell is left with only one copy of RB and that copy is detective. This one cell is no longer heterozygous.

This process of losing the remaining normal allele is referred to as loss of heterozygosity (LOH). It is a common event at many sites in the genome in human tumors. It is important to realize that the normal product of the RB gene plays a crucial role in the nondividing cells in the retina. This protein, the RB protein, is required to block cells from starting the mitotic cell cycle. In its absence, cell proliferation begins and the cell starts on the path to tumorigenesis.

If mutations are going on throughout our lifetimes, can't a cell sometimes have separate mutations hit both alleles of the same gene even though the person does not carry a mutated allele in all of their cells? In both inherited and sporadic retinoblastoma both copies of the gene are defective. They differ only in whether it takes one mutational hit, or two hits both falling on the same cell, to bring about a functional defect. The sporadic form is quite rare (about 1/40,000) because it is so unlikely that both copies of a gene will be knocked out in the same cell, and two hits on different cells will not cause tumors because each of those two cells will still retain one good copy. Because it is so unlikely that this double hit will happen even once to a particular person, the chances become vanishingly small that someone with two normal copies of the RB gene will have a double hit happen independently in two different cells at different times. Thus sporadic cases of RB characteristically present with a tumor in only one eye. The inherited form is found in only those who have inherited a first hit, but it is likely that they will experience a second hit more than once and end up with multiple tumors originating from different cells at different points in time. Thus individuals with inherited forms of RB are more likely to end up with tumors in both eyes.

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