Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

CANCER-CRITICAL GENES: HOW THEY ARE FOUND AND WHAT THEY DO
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(A)
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the inevitable DNA replication errors that occur in the patient’s cells. However, as
discussed previously, these individuals are at risk, because the accidental loss or
inactivation of the remaining good gene copy will immediately elevate the spontaneous
mutation rate by a hundredfold MBoC6 m20.47/20.35 or more (discussed in Chapter 5). These
genetically unstable cells then can presumably speed through the standard processes
of mutation and natural selection that allow clones of cells to progress to
malignancy.
This particular type of genetic instability produces invisible changes in the
chromosomes—most notably changes in individual nucleotides and short expansions
and contractions of mono- and dinucleotide repeats such as AAAA… or
CACACA…. Once the defect in HNPCC patients was recognized, the epigenetic
silencing or mutation of mismatch repair genes was found in about 15% of the
colorectal cancers occurring in people with no inherited predisposing mutation.
Thus, the genetic instability found in many colorectal cancers can be acquired
in at least two ways. The majority of the cancers display a form of chromosomal
instability that leads to visibly altered chromosomes, whereas in the others the
instability occurs on a much smaller scale and reflects a defect in DNA mismatch
repair. Indeed, many carcinomas show either chromosomal instability or defective
mismatch repair—but rarely both. These findings clearly demonstrate that
genetic instability is not an accidental by-product of malignant behavior but a
contributory cause—and that cancer cells can acquire this instability in multiple
ways.
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Figure 20–35 Chromosome
complements (karyotypes) of colon
cancers showing different kinds of
genetic instability. (A) The karyotype
of a typical cancer shows many gross
abnormalities in chromosome number
and structure. Considerable variation can
also exist from cell to cell (not shown).
(B) The karyotype of a tumor that has a
stable chromosome complement with
few chromosomal anomalies; the genetic
abnormalities are mostly invisible, having
been created by defects in DNA mismatch
repair. All of the chromosomes in this figure
were stained as in Figure 4–10, the DNA of
each human chromosome being marked
with a different combination of fluorescent
dyes. (Courtesy Wael Abdel-Rahman and
Paul Edwards.)
The Steps of Tumor Progression Can Often Be Correlated with
Specific Mutations
In what order do K-Ras, p53, Apc, and the other identified colorectal cancer-critical
genes mutate, and what contribution does each of them make to the asocial
behavior of the cancer cell? There is no single answer, because colorectal cancer
can arise by more than one route: thus, we know that in some cases, the first mutation
can be in a DNA mismatch repair gene; in others, it can be in a gene regulating
cell proliferation. Moreover, as previously discussed, a general feature such as
genetic instability or a tendency to proliferate abnormally can arise in a variety of
ways, through mutations in different genes.
Nevertheless, certain sets of mutations are particularly common in colorectal
cancer, and they occur in a characteristic order. Thus, in most cases, mutations
inactivating the Apc gene appear to be the first, or at least a very early step, as they
are detected at the same high frequency in small benign polyps as in large malignant
tumors. Changes that lead to genetic and epigenetic instability are likely also
to arise early in tumor progression, since they are needed to drive the later steps.
Activating mutations in the K-Ras gene occur later, as they are rare in small
polyps but common in larger ones that show disturbances in cell differentiation
and histological pattern.
Inactivating mutations in p53 are thought to come later still, as they are rare
in polyps but common in carcinomas (Figure 20–36). We have seen that loss
of p53 function allows cancer cells to endure stress and to avoid apoptosis and
cell-cycle arrest. Additionally, loss of p53 is related to the heightened activation