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

1094 Chapter 20: Cancer
Figure 20–4 The growth of a typical human tumor, such as a tumor of
the breast. The diameter of the tumor is plotted on a logarithmic scale. Years
may elapse before the tumor becomes noticeable. The doubling time of a
typical breast tumor, for example, is about 100 days. However, particularly
virulent tumors may grow much more rapidly.
how this particular translocation promotes the development of CML by creating a
novel hybrid gene encoding a protein that promotes cell proliferation.
Many other lines of evidence, from a variety of cancers, point to the same conclusion:
most cancers originate from a single aberrant cell.
Cancer Cells Contain Somatic Mutations
If a single abnormal cell is to give rise to a tumor, it must pass on its abnormality
to its progeny: the aberration has to be heritable. Thus, the development of
a clone of cancer cells depends on genetic changes. The tumor cells contain
somatic mutations: they have one or more shared detectable abnormalities in
their DNA sequence that distinguish them from the normal cells surrounding the
tumor, as in the example of CML just described. (The mutations are called somatic
because they occur in the soma, or body cells, not in the germ line). Cancers are
also driven by epigenetic changes—persistent, heritable changes in gene expression
that result from modifications of chromatin structure without alteration of
the cell’s DNA sequence. But somatic mutations that alter DNA sequence appear
to be a fundamental and universal feature, and cancer is in this sense a genetic
disease.
Factors that cause genetic changes tend to provoke the development of cancer.
Thus, carcinogenesis (the generation of cancer) can be linked to mutagenesis
(the production of a change in the DNA sequence). This correlation is particularly
clear for two classes of external agents: (1) chemical carcinogens (which typically
cause simple local changes in the nucleotide sequence), and (2) radiation such as
x-rays (which typically cause chromosome breaks and translocations) or ultraviolet
(UV) light (which causes specific DNA base alterations).
As would be expected, people who have inherited a genetic defect in one of
several DNA repair mechanisms, causing their cells to accumulate mutations at an
elevated rate, run a heightened risk of cancer. Those with the disease xeroderma
pigmentosum, for example, have defects in the system that repairs DNA damage
induced by UV light, and they have a greatly increased incidence of skin cancers.
A Single Mutation Is Not Enough to Change a Normal Cell into a
Cancer Cell
An estimated 10 16 cell divisions occur in a normal human body in the course of
a typical lifetime; in a mouse, with its smaller number of cells and its shorter lifespan,
the number is about 10 12 . Even in an environment that is free of mutagens,
mutations would occur spontaneously at an estimated rate of about 10 –6 mutations
per gene per cell division—a value set by fundamental limitations on the accuracy
of DNA replication and repair (see pp. 237–238). Thus, in a typical lifetime, every
single gene is likely to have undergone mutation on about 10 10 separate occasions
in a human, or on about 10 6 occasions in a mouse. Among the resulting mutant
cells, we might expect a large number that have sustained deleterious mutations
in genes that regulate cell growth and division, causing the cells to disobey the
normal restrictions on cell proliferation. From this point of view, the problem of
cancer seems to be not why it occurs, but why it occurs so infrequently.
Clearly, if a mutation in a single gene were enough to convert a typical healthy
cell into a cancer cell, we would not be viable organisms. Many lines of evidence
indicate that the development of a cancer typically requires that a substantial
number of independent, rare genetic and epigenetic accidents occur in the lineage
that emanates from a single cell. One such indication comes from epidemiological
studies of the incidence of cancer as a function of age (Figure 20–6). If a
diameter of tumor (mm)
100
10
1
0.1
death of
patient
(10 12 cells)
tumor first
palpable
(10 9 cells)
tumor first
visible on x-ray
(10 8 cells)
1 10 20 30 40
tumor cell population doublings
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Philadelphia
chromosome
9 22 9q + 22q _
Figure 20–5 The translocation between
chromosomes 9 and 22 responsible
for chronic myelogenous leukemia.
The normal structures of chromosomes
9 and 22 are shown at the left. When a
translocation occurs between them at the
indicated site, the result is the abnormal
pair at the right. The smaller of the two
resulting abnormal chromosomes (22q – ) is
called the Philadelphia chromosome, after
the city where the abnormality was first
recorded.
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