Page 61 - 20dynamics of cancer

46 CHAPTER 3

A two-step mechanism may begin carcinogenesis in all hypermethy-
lation pathways: reduction of apoptosis followed by increase in somatic
mutation (Jass et al. 2002a). The order may be important. High somatic
mutation rate in cells with normal apoptotic processes may often lead
to increased cell death rather than accumulation of genetic change, be-
cause normal cells often undergo apoptosis if they cannot repair genetic
damage. If apoptosis is lost first, then somatic mutations can be main-
tained.
With loss of apoptosis, cells accumulate in the aberrant crypt. In typi-
cal hypermethylation pathways, cellular accumulation causes hyperplas-
tic growth with a characteristic sawtoothed or serrated morphology (Jass
et al. 2002b; Jass 2003; Park et al. 2003). Hyperplasia means that the
aberrant tissue retains a more or less orderly internal structure, whereas
dysplasia means disordered cellular organization in the aberrant tissue.
About 95 percent of aberrant crypt foci are hyperplastic and serrated
(Jass et al. 2002a). The other 5 percent are dysplastic and lack serration.
The dysplastic group may often follow the classical pathway in Figure 3.2
via mutation of the APC pathway, which may abrogate apoptosis and
cause accumulation of cells at the top of aberrant crypts (Kinzler and
Vogelstein 2002). By contrast, hyperplastic crypts seem to accumulate
cells lower down in the crypt, suggesting an alternative to APC muta-
tion as an initiating event that abrogates apoptosis (Jass et al. 2002a).
Alternative initiating events that interfere with apoptosis include K-RAS
mutation and hypermethylation silencing of HPP1/TPEF.
Most hyperplastic aberrant crypts do not progress. However, a sub-
sequent disruption of the DNA repair system leads to elevated somatic
mutation rates, and may drive the tissue through the next stages of pro-
gression. Morphologically, serrated and hyperplastic precursor lesions
sometimes show heterogeneous dysplastic outgrowths, such as serrated
adenomas. Those dysplastic outgrowths usually have some form of ele-
vated mutation, and progress relatively rapidly to cancer, causing a low
adenoma to carcinoma ratio for this pathway (Jass et al. 2002a).
Jass and colleagues describe two hypermethylation syndromes. The
two syndromes can be distinguished by the mechanism that elevates
somatic mutation rates (Jass et al. 2002b, 2002a).
In the first syndrome, promoter methylation of hMLH1 disrupts the
MMR system, leading to high somatic mutation rate and high levels of mi-
crosatellite instability (MSI-H). These cases do not have inherited hMLH1