Page 59 - 20dynamics of cancer

44 CHAPTER 3

Inherited MSI by loss APC or K-RAS
MMR of 2nd TGF -RII Late Stage
Mutation MMR allele -catenin IGF-II, BAX Mutations

Figure 3.3 Genetic changes in HNPCC progression. Approximately 2–4 percent
of colorectal cancers follow this pathway.

causes increased mutation in repeated DNA sequences, such as those
in microsatellite regions. This failure to repair mismatches in repeats
causes repetitive microsatellites to change their length at a much higher
rate than normal during DNA replication. The observed fluctuations in
microsatellite length lead to the name microsatellite instability (MSI) for
defects in MMR. Genes with repetitive sequences seem to be at greater
risk for mutation in MSI tumors.
Most colorectal tumors have either MSI or CIN, but not both. Some
form of accelerated mutation may be needed for progression to aggres-
sive colorectal cancer (Jass et al. 2002a; Kinzler and Vogelstein 2002).

HNPCC PATHWAY
Individuals who inherit defects in MMR develop hereditary nonpoly-
posis colorectal cancer (HNPCC) as well as other cancers that together
make up Lynch’s syndrome (Boland 2002). Some of the genetic steps
in HNPCC progression and the rates of transition between stages differ
from the classical pathway (Figure 3.3).
Typically, individuals inherit one defective allele at a locus involved in
MMR. Heterozygous cells are usually normal for MMR. A somatic muta-
tion to the second allele at the affected locus leads to loss of function in
a component of the MMR system. The elevated rate of mutation causes
MSI and frameshift mutations in genes with repeated sequences.
Mutation to APC or β-catenin initiates adenomatous growth. With
MSI, the mutational spectrum to these genes differs from the classical
pathway, which often begins with a mutated copy of APC followed by an
LOH event to knock out both functional copies of the gene. In HNPCC,
there are more mutations to β-catenin instead of APC, and mutations to
APC more often result from frameshifts in repetitive regions caused by
failure of MMR (Jass et al. 2002a, 2002b). These differences are consis-
tent with the observation that MMR deficient tissues rarely have CIN and