Scientists from the Johns Hopkins Kimmel Cancer Center have created a
statistical model that measures the proportion of cancer incidence,
across many tissue types, caused mainly by random mutations that occur
when stem cells divide. By their measure, two-thirds of adult cancer
incidence across tissues can be explained primarily by “bad luck,” when
these random mutations occur in genes that can drive cancer growth,
while the remaining third are due to environmental factors and inherited
genes.
“All cancers are caused by a combination of bad luck, the environment
and heredity, and we’ve created a model that may help quantify how much
of these three factors contribute to cancer development,” says Bert
Vogelstein, M.D., the Clayton Professor of Oncology at the Johns Hopkins
University School of Medicine, co-director of the Ludwig Center at
Johns Hopkins and an investigator at the Howard Hughes Medical
Institute.
“Cancer-free longevity in people exposed to cancer-causing agents, such
as tobacco, is often attributed to their ‘good genes,’ but the truth is
that most of them simply had good luck,” adds Vogelstein, who cautions
that poor lifestyles can add to the bad luck factor in the development
of cancer.
The implications of their model range from altering public perception
about cancer risk factors to the funding of cancer research, they say.
“If two-thirds of cancer incidence across tissues is explained by random
DNA mutations that occur when stem cells divide, then changing our
lifestyle and habits will be a huge help in preventing certain cancers,
but this may not be as effective for a variety of others,” says
biomathematician Cristian Tomasetti, Ph.D., an assistant professor of
oncology at the Johns Hopkins University School of Medicine and
Bloomberg School of Public Health. “We should focus more resources on
finding ways to detect such cancers at early, curable stages,” he adds.
In a report on the statistical findings, published Jan. 2 in
Science,
Tomasetti and Vogelstein say they came to their conclusions by
searching the scientific literature for information on the cumulative
total number of divisions of stem cells among 31 tissue types during an
average individual’s lifetime. Stem cells “self-renew,” thus
repopulating cells that die off in a specific organ.
It was well-known, Vogelstein notes, that cancer arises when
tissue-specific stem cells make random mistakes, or mutations, when one
chemical letter in DNA is incorrectly swapped for another during the
replication process in cell division. The more these mutations
accumulate, the higher the risk that cells will grow unchecked, a
hallmark of cancer. The actual contribution of these random mistakes to
cancer incidence, in comparison to the contribution of hereditary or
environmental factors, was not previously known, says Vogelstein.
To sort out the role of such random mutations in cancer risk, the Johns
Hopkins scientists charted the number of stem cell divisions in 31
tissues and compared these rates with the lifetime risks of cancer in
the same tissues among Americans. From this so-called data scatterplot,
Tomasetti and Vogelstein determined the correlation between the total
number of stem cell divisions and cancer risk to be 0.804.
Mathematically, the closer this value is to one, the more stem cell
divisions and cancer risk are correlated.
“Our study shows, in general, that a change in the number of stem cell
divisions in a tissue type is highly correlated with a change in the
incidence of cancer in that same tissue,” says Vogelstein. One example,
he says, is in colon tissue, which undergoes four times more stem cell
divisions than small intestine tissue in humans. Likewise, colon cancer
is much more prevalent than small intestinal cancer.
“You could argue that the colon is exposed to more environmental
factors than the small intestine, which increases the potential rate of
acquired mutations,” says Tomasetti. However, the scientists saw the
opposite finding in mouse colons, which had a lower number of stem cell
divisions than in their small intestines, and, in mice, cancer incidence
is lower in the colon than in the small intestine. They say this
supports the key role of the total number of stem cell divisions in the
development of cancer.
Using statistical theory, the pair calculated how much of the variation
in cancer risk can be explained by the number of stem cell divisions,
which is 0.804 squared, or, in percentage form, approximately 65
percent.
Finally, the research duo classified the types of cancers they studied
into two groups. They statistically calculated which cancer types had an
incidence predicted by the number of stem cell divisions and which had
higher incidence. They found that 22 cancer types could be largely
explained by the “bad luck” factor of random DNA mutations during cell
division. The other nine cancer types had incidences higher than
predicted by "bad luck" and were presumably due to a combination of bad
luck plus environmental or inherited factors.
“We found that the types of cancer that had higher risk than predicted
by the number of stem cell divisions were precisely the ones you’d
expect, including lung cancer, which is linked to smoking; skin cancer,
linked to sun exposure; and forms of cancers associated with hereditary
syndromes,” says Vogelstein.
“This study shows that you can add to your risk of getting cancers by
smoking or other poor lifestyle factors. However, many forms of cancer
are due largely to the bad luck of acquiring a mutation in a cancer
driver gene regardless of lifestyle and heredity factors. The best way
to eradicate these cancers will be through early detection, when they
are still curable by surgery,” adds Vogelstein.
The scientists note that some cancers, such as breast and prostate
cancer, were not included in the report because of their inability to
find reliable stem cell division rates in the scientific literature.
They hope that other scientists will help refine their statistical model
by finding more precise stem cell division rates.
The research was funded by the Virginia and D. K. Ludwig Fund for
Cancer Research, the Lustgarten Foundation for Pancreatic Cancer
Research, the Sol Goldman Pancreatic Cancer Research Center, and the
National Institutes of Health’s National Cancer Institute (grants
P30-CA006973, R37-CA43460, RO1-CA57345 and P50-CA62924).
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