Dysplastic Crypts

~ 22,000



4.6 Insights following from this analysis

In this chapter we applied the tools developed in Chapter 3 to study the dynamics of colorectal cancer initiation. We calculate the rate of dysplastic crypt formation as a consequence of inactivating both alleles of the APC tumor suppressor gene. This can either happen in normal cells or in cells that have already acquired one of the two genetic instabilities, MSI or CIN. If the rate of triggering genetic instability in a cell is high and if the cost of genetic instability is not too large, then inactivation of APC will frequently occur in cells that are genetically unstable. In this case, genetic instability is the first phenotypic modification of a cell on the way to cancer.

It is interesting to compare the two types of instability, MSI and CIN. MSI, being associated with subtle changes in the genome, is probably less of a liability for the cell than CIN. In other words, CIN cells are more likely to produce non-viable offspring than MSI cells. At the same time, it may be possible that CIN is easier to trigger (for instance, if it requires a change in a single allele of many genes). Our analysis shows that if inactivation of MSI genes (either by point mutation or by methylation) occurs at a sufficiently fast rate - around 10~6 per cell division, then MSI can precede APC inactivation in a significant number of cases. Regarding CIN, the crucial questions are (i) how many dominant CIN genes can be found in the human genome, (ii) how fast are CIN genes inactivated, and (iii) what are the costs of CIN. A more detailed analysis of costs and benefits of CIN is given in Chapters 6 and 7.

Our calculations show that important insights could be derived by carefully monitoring the incidence rate of dysplastic crypts in patients as function of age. With or without early genetic instability, the abundance of dysplastic crypts should grow approximately as a second power of time. The two rate limiting steps can either refer to two mutations of APC, or one mutation of APC and one CIN mutation. In the case of CIN, LOH of the second allele of APC is not rate limiting. Hence, two rate limiting steps for the inactivation of a tumor suppressor gene can be compatible with an additional genetic instability mutation.

Several further insights emerge from our analysis.

Fraction of dysplastic crypts with CIN or MSI. About 87% of sporadic colorectal cancers have CIN while the rest have MSI. Assuming that CIN and MSI are irreversible, we conclude that the maximum fraction of dysplastic crypts with CIN should be 87%, while the maximum fraction of dysplastic crypts with MSI should be 13%. This provides certain restrictions on the possible parameter values of our model (see Table 2b).

Epigenetic factors. If we assume that MSI genes in sporadic colorectal cancer are inactivated only by point mutation or LOH events, then the fraction of dysplastic crypts with MSI is very low. We get higher fractions of MSI if we assume that MSI genes can also be inactivated by methylation and if methylation of MSI genes is fast compared to point mutation or LOH. Thus, methylation events could play a crucial role in the formation of sporadic MSI cancers.

Competition among crypts. Another interesting possibility is that dysplastic crypts can be lost and replaced by normal crypts. In this case, many dysplastic crypts could be produced, but only a part of them is retained so that the actual number of dysplastic crypts stays low. To our knowledge, the competitive dynamics of crypts in a colon has not been investigated experimentally.

No MSI in FAP. Our model predicts that the fraction of MSI dysplastic crypts in FAP patients is close to zero. A significant number of dysplastic crypts will contain CIN. This is consistent with experiments observations.

The number of dysplastic crypts. We calculated both the absolute numbers and relative proportions of dysplastic crypts with or without genetic instabilities. An interesting empirical project is to measure the abundance of such dysplastic crypts as function of age. This will provide crucial information on the dynamics of colorectal cancer initiation.

A more precise description of the mutation spectrum. The mutation spectrum of the APC gene is far from random (one reason being that the APC gene is long and multi-functional). The type of the second APC mutation may depend on where the first APC mutation took place [Lam-lum et al. (1999); Rowan et al. (2000)]. Our model is well suited to take this into account. Here is a simple way to differentiate between two kinds of point mutations. Let us assume that the total probability of a point mutation is u (as in the basic model), and there are two kinds of mutations, (i) With probability a mutation happens such that the second allele can only be inactivated by a point mutation, (ii) With probability u2, a mutation happens which can be followed by another point mutation or an LOH event. We have ui+u2 = u. These two scenarios can be incorporated in our calculations adding a new level of complexity to the basic theory.

The cells at risk of cancer. In this first model we assumed that only stem cells are at risk of cancer. Another possibility is that both stem cells and large numbers of differentiated cells in a crypt are running the risk of acquiring cancerous mutations. In its present form, this analysis would predict that the expected number of dysplastic crypts in persons of 70 years of age is enormous and biologically implausible. In order to correctly include the possibility of cancer initiation in partially differentiated cells, one needs to perform a calculation similar to that presented in the next chapter.

Chapter 5

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