Costs and benefits of chromosomal instability

Chapter 4 discussed mathematical models which demonstrated that genetic instability can sometimes speed up the generation of a mutant cell which can give rise to cancer. This underlines the verbal arguments which were first presented in Lawrence Loeb's mutator phenotype hypothesis [Loeb et al. (1974)]: the multi-stage nature of cancer initiation and progression requires genetic instability; otherwise a sufficient number of mutations cannot be generated during the life time of a human being.

The mutator phenotype hypothesis, however, considers genetic instability in general and in all its forms. Do the same arguments apply to all types of instabilities? As reviewed in Chapters 1 and 4, genomic instability can be divided into two broad categories: small scale mutations (such as MSI) and gross chromosomal abnormalities (such as CIN). After a mutant cell has been generated, it needs to give rise to clonal expansion for the cancer to be established. If the instability induces the generation of subtle sequence changes, the process of clonal expansion is not likely to be influenced to a significant degree, and the result derived in Chapter 5 still holds. If the instability induces destructive genomic changes, such as imbalances in genes and chromosome numbers, then clonal expansion can be compromised significantly. Although the cells can undergo uncontrolled growth, genome destruction can result in frequent cell death and this could counteract the establishment of a cancer. Therefore, while CIN can speed up the generation of a cell with an inactivated tumor suppressor gene, it might impair the growth of these cells and slow down clonal expansion. In the light of this tradeoff, what is the overall effect of CIN on the establishment and progression of a cancer? This is the subject of the current chapter.

6.1 The effect of chromosome loss on the generation of cancer

We study the role of chromosomal instability in the context of the inacti-vation of tumor suppressor genes (TSP). We will concentrate on a specific event, namely, the chromosome loss event [Thiagalingam et al. (2001)]. Other features of CIN such as mitotic recombination or chromosome duplication, may contribute to an activation of oncogenes or gene dosage effects [Luo et al. (2000); Tischfield and Shao (2003); Wijnhoven et al. (2001)], but such events cannot turn off a TSP. Thus, focusing on cancers with a TSP allows us to isolate one feature of CIN, and identify its role in cancer progression.

Fig. 6.1 Two mechanisms of a TSP inactivation. First, one allele of the TSP must be inactivated by a small-scale event, e.g. a point mutation. Then, there are two possibilities. Either the second allele experiences another small-scale hit (the phenotype with two inactivated copies of the gene is represented by a black circle). Or, the whole chromosome containing the second, functional copy of the TSP could be lost (this phenotype is represented by a black semicircle).

Let us start our quantitative study by identifying exactly how loss of chromosomes may influence the inactivation of a TSP, see Figure 6.1 [Ko-marova and Wodarz (2004)]. In a normal cell (an empty circle), both maternal and paternal chromosomes are present, and both alleles of the TSP are intact. An inactivating mutation can occur which turns off one of the alleles of the TSP (this is represented by a half of the circle turning black). The corresponding phenotype is denoted by TSP+,/~. For "classical" TSP's

Fig. 6.1 Two mechanisms of a TSP inactivation. First, one allele of the TSP must be inactivated by a small-scale event, e.g. a point mutation. Then, there are two possibilities. Either the second allele experiences another small-scale hit (the phenotype with two inactivated copies of the gene is represented by a black circle). Or, the whole chromosome containing the second, functional copy of the TSP could be lost (this phenotype is represented by a black semicircle).

there is no noticeable change in function of such cells; both alleles must be inactivated before a phenotypic change is observed. This second event, the inactivation of the remaining allele of the TSP, can happen in two ways. First of all, another inactivating small-scale event could occur (both halves of the circle become black). Alternatively, the second allele can be lost by a loss-of-chromosome event (this is depicted by means of a "missing" half of a circle). This will unmask the mutated copy of the TSP and lead to a phenotypic change in the cell.

Clonal expansion

Normal cells

-/First TSP cell

Normal cells

-/First TSP cell

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