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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HEALTHY CELL WITH ONLY ONE NORMAL Rb GENE COPY
mutation at Rb locus
in maternal chromosome
nondisjunction
causes
chromosome
loss
chromosome
loss, then
chromosome
duplication
normal Rb gene
in paternal chromosome
POSSIBLE WAYS OF ELIMINATING NORMAL Rb GENE
mitotic
recombination
event
gene
conversion
during mitotic
recombination
deletion
point
mutation
Figure 20–21 Six ways of losing the
remaining good copy of a tumor
suppressor gene through a change in
DNA sequences. A cell that is defective
in only one of its two copies of a tumor
suppressor gene—for example, the Rb
gene—usually behaves as a normal,
healthy cell; the diagrams below show how
this cell may lose the function of the other
gene copy as well and thereby progress
toward cancer. A seventh possibility,
frequently encountered with some tumor
suppressors, is that the gene may be
silenced by an epigenetic change, without
alteration of the DNA sequence,
as illustrated in Figure 20–22. (After
W.K. Cavenee et al., Nature 305:779–784,
1983. With permission from Macmillan
Publishers Ltd.)
the chromosome carrying the remaining normal copy may be lost from the cell
through errors in chromosome segregation; or the normal gene, along with
neighboring genetic material, may be replaced by a mutant version through
either a mitotic recombination event or a gene conversion that accompanies it (see
MBoC6 m20.31/20.21
p. 286).
Figure 20–21 summarizes the range of ways in which the remaining good copy
of a tumor suppressor gene can be lost through a DNA sequence change, using the
Rb gene as an example. It is important to note that, except for the point mutation
mechanism illustrated at the far right, these pathways all produce cells that carry
only a single type of DNA sequence in the chromosomal region containing their
Rb genes—a sequence that is identical to the sequence in the original mutant
chromosome.
Epigenetic changes provide another important way to permanently inactivate
a tumor suppressor gene. Most commonly, the gene may become packaged into
heterochromatin and/or the C nucleotides in CG sequences in its promoter may
become methylated in a heritable manner (see pp. 404–405). These mechanisms
can irreversibly silence the gene in a cell and in all of its progeny. Analysis of methylation
patterns in cancer genomes shows that epigenetic gene silencing is a frequent
event in tumor progression, and epigenetic mechanisms are now thought
to help inactivate several different tumor suppressor genes in most human cancers
(Figure 20–22).
Systematic Sequencing of Cancer Cell Genomes Has Transformed
Our Understanding of the Disease
Methods such as those we have described above shone a spotlight on a set of cancer-critical
genes that were identified in a piecemeal fashion. Meanwhile, the rest
of the cancer cell genome remained in darkness: it was a mystery how many other
mutations might lurk there, of what types, in which varieties of cancer, at what
frequencies, with what variations from patient to patient, and with what consequences.
With the sequencing of the human genome and the dramatic advances
in DNA sequencing technology (see Panel 8–1, pp. 478–481), it has become possible
to see the whole picture—to view cancer cell genomes in their entirety. This
transforms our understanding of the disease.
Cancer cell genomes can be scanned systematically in several different ways.
At one extreme—the most costly, but no longer prohibitively so—one can determine
a tumor’s complete genome sequence. More cheaply, one can focus just on
the 21,000 or so genes in the human genome that code for protein (the so-called
exome), looking for mutations in the cancer cell DNA that alter the amino acid
sequence of the product or prevent its synthesis (Figure 20–23). There are also
efficient techniques to survey the genome for regions that have undergone