Page 58 - 20dynamics of cancer

MULTISTAGE PROGRESSION 43

CHROMOSOMAL INSTABILITY
About 85 percent of colorectal tumors have major chromosomal aber-
rations. Often, part of a chromosome or a whole chromosome is lost
(Rajagopalan et al. 2003). A lost chromosome is usually replaced by
duplication of the remaining chromosome from the original pair. Dupli-
cation creates two copies of the same allele at a locus, with loss of one
of the original parental alleles. This is called loss of heterozygosity, or
LOH, because the remaining duplicated pair is homozygous.
LOH accelerates the genetic changes that drive carcinogenesis (Nowak
et al. 2002). For example, a mutation to one allele of p53 leaves one
original copy intact. By itself, the single mutation to one allele often
does not cause severe problems. But the good copy may disappear if its
chromosome is lost, and the remaining chromosome duplicates leaving
two copies of the mutated allele. In chromosomally unstable genomes,
chromosomal losses causing LOH happen much more rapidly than do
typical mutations. The common genetic pathway of change is often a
mutation to one allele at a low rate followed by loss of the other allele
by LOH at a relatively rapid rate.
Chromosomal instability (CIN) arises from mutations and other ge-
nomic changes that abrogate the normal controls on chromosome du-
plication and segregation in mitosis (Rajagopalan et al. 2003). Because
CIN increases the rate at which genetic changes occur, CIN can acceler-
ate the sequence of genetic events that drive carcinogenesis. Most tu-
mors of solid tissue have CIN. But it remains controversial whether CIN
arises early in carcinogenesis and thus plays a key role in driving genetic
change, or CIN develops late in tumorigenesis as the genome becomes
increasingly disrupted by the later stages of carcinogenesis. Probably
there are pathways of progression that depend on CIN and those that
do not.

3.4 Alternative Pathways to Colorectal Cancer

MICROSATELLITE INSTABILITY
Approximately 15 percent of colorectal tumors do not have CIN or
widespread chromosomal abnormalities (Rajagopalan et al. 2003). In-
stead, these tumors usually have mutations in their mismatch repair
(MMR) system, a component of DNA repair (Boland 2002). Loss of MMR