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

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MBoC6 n20.250/20.24
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CANCER-CRITICAL GENES: HOW THEY ARE FOUND AND WHAT THEY DO
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Many Cancers Have an Extraordinarily Disrupted Genome
Cancer genome analysis reveals, first of all, the scale of gross genetic disruption
in cancer cells. This varies greatly from one type of cancer and one cancer patient
to another, both in severity and in character. In some cases, the karyotype—the
set of chromosomes as they appear at mitosis—is normal or nearly so, but many
point mutations are detected in individual genes, suggesting a failure of the
repair mechanisms that normally correct local errors in the replication or maintenance
of DNA sequences. Often, however, the karyotype is severely disordered,
with many chromosome breaks and rearrangements. In some breast cancers, for
example, genome sequencing reveals an astonishing scene of genetic chaos (Figure
20–24), with hundreds of chromosome breaks and translocations, resulting in
many deletions, duplications, and amplifications of parts of the genome. In such
cells, the normal machinery for avoidance or repair of DNA double-strand breaks
is evidently somehow defective, destabilizing the genome by giving rise to broken
chromosomes whose fragments then rejoin in random combinations. From the
pattern of changes, one can infer that this disruptive process has occurred repeatedly
during the evolution of the tumor, with a progressive increase of genetic disorder.
Breast cancers showing the most extreme chromosome disorder are usually
hard to treat and have a gloomy prognosis.
One survey of more than 3000 individual cancer specimens showed that on
average 24 separate blocks of genetic material were duplicated in each tumor,
amounting to 17% of the normal genome, and 18 blocks were deleted, amounting
to 16% of the normal genome. Many of these changes were found repeatedly,
suggesting that they contain cancer-critical genes whose loss (tumor suppressor
genes) or gain (oncogenes) confers a selective advantage.
Whole-genome analysis also helps to explain some cancers that seem, at first
sight, to be exceptions to the general rules. An example is retinoblastoma, with
its early onset during childhood. If cancers in general require an accumulation of
many genetic changes and are thus diseases of old age, what makes retinoblastoma
different? Whole-genome sequencing confirms that in retinoblastoma, the
tumor cells contain loss-of-function mutations in the Rb gene; but, astonishingly,
they contain practically no mutations or genome rearrangements that affect any
other oncogene or tumor suppressor gene. Instead, they contain many epigenetic
modifications, which alter the level of expression of many known cancer-critical
genes—as many as 15 in one well-analyzed case.
Many Mutations in Tumor Cells are Merely Passengers
Cancer cells generally contain many mutations in addition to gross chromosome
abnormalities: point mutations can be scattered over the genome as a whole at
a rate of about one per million nucleotide pairs, in addition to the abnormalities
copy number (blue)
17
16
15
14
18
13
19
12
20
highly
amplified
regions
21
11
22
10
X
9
1
8
intrachromosomal
rearrangement (green)
7
2
6
3
5
4
17
16
15
14
18
13
19
12
20
21
11
interchromosomal
rearrangement (purple)
BREAST CANCER 1 BREAST CANCER 2
22
10
X
9
1
8
7
2
6
3
5
4
Figure 20–24 The chromosomal
rearrangements in breast cancer
cells. The results of an extensive DNA
sequencing analysis performed on two
different primary tumors are displayed
as “Circos plots.” In each plot, the
reference DNA sequences of the 22
autosomes and single sex chromosome
(X) of a normal human female (3.2 billion
nucleotide pairs) are aligned end-to-end
to form a circle. Colored lines within
the circle are then used to indicate the
chromosome alterations found in the
particular primary tumor. As indicated,
purple lines connect sites at which two
different chromosomes have become
joined to create an interchromosomal
rearrangment, while green lines connect
the sites of rearrangements found within a
single chromosome. The intrachromosomal
rearrangements can be seen to
predominate, and most join neighboring
sections of DNA that were originally located
within 2 million nucleotide pairs of each
other. The increases in copy number,
shown in blue, reveal the amplified DNA
sequences (see the highly amplified regions
indicated). (Adapted from P.J. Stephens et
al., Nature 462:1005–1010, 2009.)