Page 64 - 20dynamics of cancer

MULTISTAGE PROGRESSION 49

to carcinoma ratio to about 1:1. The HNPCC pathway lacks chromoso-
mal instability, instead using the malfunction in DNA repair to raise the
mutation rate. This pathway accounts for only about 2–4 percent of
colorectal cancers.
Third, hypermethylation silences MMR, causing a high somatic muta-
tion rate in repeated sequences. The morphological pathway and the set
of mutated genes differ from HNPCC, even though both pathways have
MMR defects. In this hypermethylation pathway, the initiating stages
that abrogate apoptosis may focus on regulatory systems other than APC
and β-catenin. Morphologically, initiation leads to hyperplastic crypts,
followed by dysplastic outgrowths from these aberrant crypt foci. Sub-
sequent mutations and gene silencing depend both on changes to re-
peated DNA sequences and on methylation and silencing of other genes.
After initiation and progression through the early dysplastic adenoma
stage, progression may be rapid, causing a low adenoma to carcinoma
ratio. As in HNPCC, this sequence lacks chromosomal instability. About
10–15 percent of colorectal cancers follow this pathway.
Fourth, hypermethylation may silence DNA repair systems other than
MMR. The characteristics of progression roughly follow those in the
third pathway with loss of MMR by methylation. However, the partic-
ular type of DNA repair affected determines the particular genes subse-
quently mutated during progression. Jass et al. (2002b) have argued that
perhaps 20 percent of colorectal cancers follow these various routes of
progression. However, supporting data remain weaker for this pathway
than for the previous three.

3.5 Changes during Progression

Multistage progression simply means that transformation to cancer
does not happen in a single step. That vague definition leaves open what
actually happens. In the next three sections, I briefly outline some of the
details.
My ultimate goal is to formulate and test hypotheses about the pro-
cesses that shape quantitative aspects of cancer incidence. I will show
in the following chapters that, in the absence of knowing everything that
affects progression, we can still learn a great deal if we formulate and
test hypotheses in the proper way. For now, I give a brief abstract of the