Win

2 nju normal x.

CIN v

Fig. 4.3 Mutation-selection network of sporadic colorectal cancer initiation including CIN and MSI. From the initial wild-type state, Xo, the crypt can change to state Xi as in Figure 4.1, acquire a CIN mutation (the arrow down) or an MSI mutation (the arrow up). The line Xo —► Xi —> X2 is identical to the process in Figure 4.1 of developing a dysplastic crypt with no genetic instabilities. The bottom row of the diagram corresponds to CIN cells acquiring the first, and then the second, mutation (loss) of the APC gene; the second copy can be lost by a point mutation or by an LOH event whose rate is much larger for CIN cells than it is for normal or MSI cells. The state Y2 corresponds to a CIN dysplastic crypt. The top row is the development of an MSI dysplastic crypt. The MSI phenotype is characterized by an increased point mutation rate, u. The state Z2 is an MSI dysplastic crypt. Red arrows denote faster steps. Note that it takes only one leap (down) to go to a CIN state from a state with no genetic instability, because CIN genes are dominant-negative. It takes two steps to acquire MSI (up) because both copies of an MSI gene need to be inactivated before any phenotypic changes happen.

Table 4.3 The three major classes of homogeneous states.

Quantity

Definition

Point mutation rate

Rate of LOH

Xo,Xl, X_2

non-CIN, non-MSI

u

Po

Y0,Y1,Y2

0 0

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