Page 62 - 20dynamics of cancer

MULTISTAGE PROGRESSION 47

? MMR Repair
Methylation Methylation Mutations,
HPP1/TPEF hMLH1 Methylations

Hyperplastic Dysplastic
Normal Serrated Serrated Cancer
Epithelium
Crypts Adenomas

Figure 3.4 Morphological sequence in hypermethylated MSI-H cancers. Up to
15 percent of colorectal cancers follow this pathway.

mutations and differ significantly from the HNPCC pathway. Although
there is much variation, the sequence in Figure 3.4 may be typical for
MSI-H tumors that are not HNPCC. Many common attributes of the clas-
sical pathway are rare in this sequence. For example, these cancers have
relatively low frequencies of mutations to the APC pathway, suggesting
some other initiating event such as apoptotic loss via methylation of
HPP1/TPEF. These cancers also have fewer mutations to K-RAS and p53,
and usually do not have chromosomal instability or significantly altered
karyotypes.
The second hypermethylation syndrome follows the same morpho-
logical pathway in Figure 3.4, but has little or no MSI. The early hyper-
plastic, serrated morphology suggests an initiating event that abrogates
apoptosis and acts in the lower portion of the crypt. The genetics of
the various subsequent steps appear to be heterogeneous. The genetic
heterogeneity may arise because, in particular cases, hypermethylation
knocks out different DNA repair genes (Jass et al. 2002a). Elevated
somatic mutation rate for a particular spectrum of genes follows, the
particular spectrum depending on the DNA repair system reduced by
methylation. Increased somatic mutation can lead to rapid progression
from dysplastic serrated adenomas to carcinomas.
A high MSI pathway may begin after methylation and suppression of
the MMR gene hMLH1. By contrast, a low MSI pathway may follow after
promoter methylation and suppression of the DNA repair gene MGMT .
The enzyme MGMT removes promutagenic adducts from guanine nu-
cleotides. Several common carcinogens create such adducts, typically
in the distal colon and rectum. Loss of MGMT probably increases the