Page 63 - 20dynamics of cancer

48 CHAPTER 3

rate of certain types of mutations, leading to a particular spectrum of
mutated genes in subsequent progression.

SUMMARY

I described four pathways to colorectal cancer: mismatch repair mu-
tations leading to microsatellite instability, HNPCC, hypermethylation
with high microsatellite instability, and hypermethylation with low mi-
crosatellite instability. I emphasized the details because colorectal can-
cer provides the greatest insight into multistage progression of disease.
The different pathways highlight the need to classify disease by pathway
rather than solely by tissue location. In particular, the various pathways
have different stages and rates of transition between stages.
In the future, it may be possible to couple better understanding of
distinct colorectal pathways with measurement of age-onset patterns
for each pathway. Of course, we will never have all the genetic details
or perfect measurement of age-onset patterns. But we should be able
to formulate and test comparative hypotheses: pathways with fewer
rate-limiting stages or faster transitions between stages will differ pre-
dictably in age-onset patterns when compared with pathways that have
more stages or slower rates of transition. In the next chapter, I dis-
cuss the great importance of formulating and testing comparative hy-
potheses. For now, I end this section by briefly summarizing the four
colorectal pathways that I have discussed.
First, initiation of the classical pathway usually requires mutation of
APC or β-catenin, leading to dysplastic crypt foci. Further mutations
lead to adenomas, a slow transition to carcinomas, and about a 30:1
ratio of adenomas to carcinomas. Chromosomal instability, loss of het-
erozygosity, and aneuploidy occur. The classical pathway accounts for
the majority of colorectal cancers.
Second, inherited mutations to mismatch repair (MMR) cause hered-
itary nonpolyposis colorectal cancer (HNPCC). This disease follows the
same morphological stages as the classical pathway, but with different
mutations and rates of progression. Mutations usually occur in repeated
regions of genes, because reduced MMR causes increased frameshift mu-
tations in repeated sequences. Progression through the middle stages
occurs more rapidly than in the classical pathway, reducing the adenoma