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 AS A MICROEVOLUTIONARY PROCESS
1095
Figure 20–6 Cancer incidence as a function of age. The number of newly
diagnosed cases of colon cancer in women in England and Wales in 1 year
is plotted as a function of age at diagnosis, relative to the total number
of individuals in each age group. The incidence of cancer rises steeply
as a function of age. If only a single mutation were required to trigger the
cancer and this mutation had an equal chance of occurring at any time, the
incidence of this cancer would be the same at all ages. Analyses of this type
suggest that the development of a solid tumor instead requires five to eight
independent accidents (“hits”) that occur randomly over time. This calculation
assumes that the mutation rate remains constant as a cancer evolves, where
in fact it often increases (see p. 1097). (Data from C. Muir et al., Cancer
Incidence in Five Continents, Vol. V. Lyon: International Agency for Research
on Cancer, 1987.)
single mutation were responsible for cancer, occurring with a fixed probability per
year, the chance of developing cancer in any given year of life should be independent
of age. In fact, for most types of cancer, the incidence rises steeply with age—
as would be expected if cancer is caused by a progressive, random accumulation
of a set of mutations in a single lineage of cells.
As discussed later, these indirect arguments have now been confirmed by systematically
sequencing the genomes of the tumor cells from individual cancer
patients and cataloging the mutations that they contain.
Cancers Develop Gradually from Increasingly Aberrant Cells
For those cancers known to have a specific external cause, the disease does
not usually become apparent until long after exposure to the causal agent. The
incidence of lung cancer, for example, does not begin to rise steeply until after
decades of heavy smoking (Figure 20–7). Similarly, the incidence of leukemias
in Hiroshima and Nagasaki did not show a marked rise until about 5 years after
the explosion of the atomic bombs, and industrial workers exposed for a limited
period to chemical carcinogens do not usually develop the cancers characteristic
of their occupation until 10, 20, or even more years after the exposure. During
this long incubation period, the prospective cancer cells undergo a succession
of changes, and the same presumably applies to cancers where the initial genetic
lesion has no such obvious external cause.
The concept that the development of a cancer requires a gradual accumulation
of mutations in a number of different genes helps to explain the well-known phenomenon
of tumor progression, whereby an initial mild disorder of cell behavior
evolves gradually into a full-blown cancer. Chronic myelogenous leukemia again
provides a clear example. It begins as a disorder characterized by a nonlethal
overproduction of white blood cells and continues in this form for several years
before changing into a much more rapidly progressing illness that usually ends
in death within a few months. In the early chronic phase, the leukemic cells are
distinguished mainly by the chromosomal translocation (the Philadelphia chromosome)
mentioned previously, although there may well be other, less visible
incidence rate per 100,000
180
160
140
120
100
80
60
40
20
0
10 20 30 40 50 60 70 80
age (years)
MBoC6 m20.07/20.06
cigarettes smoked per year (billions)
6000
5000
4000
3000
2000
1000
GLOBAL CIGARETTE
CONSUMPTION
GLOBAL LUNG
CANCER DEATHS
CAUSED BY
SMOKING
(ESTIMATE)
LUNG CANCERS
UNRELATED
TO TOBACCO
1880 1920 1960 2000
2000
1500
1000
500
0
lung cancer deaths per year (thousands)
Figure 20–7 Smoking and the onset of
lung cancer. A major increase in cigarette
smoking (red line) has caused a dramatic
rise in lung cancer deaths (green line), with
a lag time of about 35 years. Because
global cigarette smoking peaked in 1990,
global lung cancer deaths are expected to
decline after a similar lag. (Data from R.N.
Proctor, Nat. Rev. Cancer 1:82–86, 2001).