'Bad
luck' of random mutations plays predominant role in cancer, study shows
Johns Hopkins Medicine, Science Daily
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 incidents 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).
Story Source:
The above story is based on materials provided by Johns Hopkins Medicine. Note:
Materials may be edited for content and length.
Journal Reference:
C. Tomasetti, B. Vogelstein. Variation in cancer risk among
tissues can be explained by the number of stem cell divisions. Science,
2015; 347 (6217): 78 DOI: 10.1126/science.1260825
Cite This Page:
Johns Hopkins Medicine. "'Bad luck' of random mutations
plays predominant role in cancer, study shows." Science Daily,
1 January 2015. <www.sciencedaily.com/releases/2015/01/150101142318.htm>.
