Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention
http://science.sciencemag.org/content/355/6331/1330.full
Cancer and the unavoidable R factor
Most
textbooks attribute cancer-causing mutations to two major sources:
inherited and environmental factors. A recent study highlighted the
prominent role in cancer of replicative (R) mutations that arise from a
third source: unavoidable errors associated with DNA replication.
Tomasetti et al. developed a method for determining the
proportions of cancer-causing mutations that result from inherited,
environmental, and replicative factors (see the Perspective by Nowak and
Waclaw). They found that a substantial fraction of cancer driver gene
mutations are indeed due to replicative factors. The results are
consistent with epidemiological estimates of the fraction of preventable
cancers.
Abstract
Cancers
are caused by mutations that may be inherited, induced by environmental
factors, or result from DNA replication errors (R). We studied the
relationship between the number of normal stem cell divisions and the
risk of 17 cancer types in 69 countries throughout the world. The data
revealed a strong correlation (median = 0.80) between cancer incidence
and normal stem cell divisions in all countries, regardless of their
environment. The major role of R mutations in cancer etiology was
supported by an independent approach, based solely on cancer genome
sequencing and epidemiological data, which suggested that R mutations
are responsible for two-thirds of the mutations in human cancers. All of
these results are consistent with epidemiological estimates of the
fraction of cancers that can be prevented by changes in the environment.
Moreover, they accentuate the importance of early detection and
intervention to reduce deaths from the many cancers arising from
unavoidable R mutations.
It is now widely accepted
that cancer is the result of the gradual accumulation of driver gene
mutations that successively increase cell proliferation (1–3).
But what causes these mutations? The role of environmental factors (E)
in cancer development has long been evident from epidemiological
studies, and this has fundamental implications for primary prevention.
The role of heredity (H) has been conclusively demonstrated from both
twin studies (4) and the identification of the genes responsible for cancer predisposition syndromes (3, 5).
We recently hypothesized that a third source—mutations due to the
random mistakes made during normal DNA replication (R)—can explain why
cancers occur much more commonly in some tissues than others (6).
This hypothesis was based on our observation that, in the United
States, the lifetime risks of cancer among 25 different tissues were
strongly correlated with the total number of divisions of the normal
stem cells in those tissues (6, 7). It has been extensively documented that approximately three mutations occur every time a normal human stem cell divides (8, 9).
We therefore inferred that the root causes of the correlation between
stem cell divisions and cancer incidence were the driver gene mutations
that randomly result from these divisions. Recent evidence from mouse
models supports the notion that the number of normal cell divisions
dictates cancer risk in many organs (10).
This
hypothesis has generated much scientific and public debate and
confusion, in part because our analysis was confined to explaining the
relative risk of cancer among tissues rather than the contribution of
each of the three potential sources of mutations (E, H, and R) to any
single cancer type or cancer case. Determination of the contributions of
E, H, and R to a cancer type or cancer case is challenging. In some
patients, the contribution of H or R factors might be high enough to
cause all the mutations required for that patient’s cancer, whereas in
others, some of the mutations could be due to H, some to R, and the
remainder to E. Here we perform a critical evaluation of the hypothesis
that R mutations play a major role in cancer. Our evaluation is
predicated on the expectation that the number of endogenous mutations
(R) resulting from stem cell divisions in a tissue, unlike those caused
by environmental exposures, would be similarly distributed at a given
age across human populations. Though the number of stem cell divisions
may vary with genetic constitution (e.g., taller individuals may have
more stem cells), these divisions are programmed into our species’
developmental patterns. In contrast, deleterious environmental and
inherited factors, either of which can directly increase the mutation
rate or the number of stem cell divisions, vary widely among individuals
and across populations.
Our previous analyses were
confined to the U.S. population, which could be considered to be exposed
to relatively uniform environmental conditions (6).
In this study, we have evaluated cancer incidence in 69 countries,
representing a variety of environments distributed throughout the world
and representing 4.8 billion people (two-thirds of the world’s
population). Cancer incidences were determined from analysis of 423
cancer registries that were made available by the International Agency
for Research on Cancer (IARC) (http://ci5.iarc.fr/CI5-X/Pages/download.aspx).
All 17 different cancer types recorded in the IARC database for which
stem cell data are available were used for this analysis (see
supplementary materials). The Pearson’s correlation coefficients of the
lifetime risk of cancer in a given tissue with that tissue’s lifetime
number of stem cell divisions are shown in Fig. 1. Strong, statistically significant correlations were observed in all countries examined (median P value = 1.3 × 10−4; full range: 2.2 × 10−5 to 6.7 × 10−3).
The median correlation was 0.80 (95% range: 0.67 to 0.84), with 89% of
the countries having correlations >0.70 in the 0 to 85+ age interval (Table 1).
This correlation of 0.80 is nearly identical to that observed for a
somewhat different set of tissues, which did not include those of the
breast or prostate, in the U.S. population (6). Details of the incidence data and correlations for each evaluated country and registry are provided in tables S1 to S4.
Fig. 1 Correlations between stem cell divisions and cancer incidence in different countries.
For
each country, the correlation between the number of stem cell divisions
in 17 different tissues and the lifetime incidence of cancer in those
tissues was calculated. This resulted in 69 correlation coefficients,
which were grouped and plotted into a histogram. In this histogram, the x axis represents the correlation coefficients and the y
axis represents the number of countries with the corresponding
correlation coefficient. For example, there were seven countries in
which the correlation between the number of stem cell divisions and
cancer incidence was between 0.82 and 0.83; these seven countries are
represented by the tallest green bar in the histogram. The median
correlation coefficient over all countries was 0.8. The black line
represents the density for the observed distribution of the correlation
coefficient among different countries.
Table 1 Correlations between the lifetime risk of cancers in 17 tissues and the lifetime number of stem cell divisions in those tissues.
The
median Pearson’s correlation coefficients and 95% range in various
geographic regions are listed. The values in columns CR 0–85+, CR 0–85,
CR 0–80, and CR 0–75 represent the correlations when the lifetime risk
of each cancer (cumulative risk, CR) could be determined from birth to
age 85+, birth to age 85, birth to age 80, and birth to age 75,
respectively. No cancer incidence data were available for individuals
older than 80 years in African countries (tables S1 to S4). NA, not
applicable.
View this table:
The correlations in Fig. 1 were derived for the largest age interval available (0 to 85+ in Table 1).
Data on individuals from the same countries at younger ages indicate
that the larger the age range considered, the higher the correlation.
Note that cancer incidence increases exponentially with age (11),
but stem cell divisions do not increase proportionally with age in
tissues with low or no cell turnover, such as bone and brain. An
increase in the evaluated age range would therefore be expected to be
associated with an increase in the correlation between the lifetime
number of stem cell divisions and cancer incidence, as was observed (Table 1).
The universally high correlations between normal stem cell divisions and cancer incidences shown in Table 1
are surprising given the voluminous data indicating large differences
in exposures to environmental factors and associated cancer incidences
across the world (12–16).
To explore the basis for this apparent discrepancy, we sought to
determine what fractions of cancer-causing mutations result from E, H,
or R. As these fractions have not been estimated for any cancer type, we
developed an approach to achieve this goal. A theoretical example that
illustrates the underlying conceptual basis of this approach is as
follows. Imagine that a population of humans in which all inherited
mutations have been corrected move to Planet B, where the environment is
perfect. On this planet, E and H are zero, and the only somatic
mutations are caused by R. Note that the number of R mutations in all
tissues is >0, regardless of the environment, because perfect,
error-free replication is incompatible with basic biologic principles of
evolution. Suppose that a powerful mutagen, E, was then introduced into
the environment of Planet B, and all inhabitants of Planet B were
equally exposed to it throughout their lifetimes. Assume that this
mutagen substantially increased the somatic mutation rate in normal stem
cells, causing a 10-fold increase in cancer risk, i.e., 90% of all
cancer cases on this planet were now attributable to E. Therefore, 90%
of all cancer cases on Planet B would be preventable by avoiding
exposure to E. But even in this environment, it can be shown that 40% of
the driver gene mutations are attributable to R (Fig. 2A
and supplementary materials). This extreme example demonstrates that
even if the vast majority of cancer cases were preventable by reducing
exposure to environmental factors, a large fraction of the driver gene
mutations required for those cancers can still be due to R—as long as
the number of mutations contributed by normal stem cell divisions is not
zero. In other words, the preventability of cancers and the etiology of
the driver gene mutations that cause those cancers are related but have
different metrics (see supplementary materials for their mathematical
relationship).
Fig. 2 Mutation etiology and cancer prevention in a hypothetical scenario and in real life.
Patients
exposed to environmental factors, such as cigarette smoke, are
surrounded by a cloud. The driver gene mutations calculated to be
attributable to environmental (E), hereditary (H), and replicative (R)
factors are depicted as gray, blue (containing an “H”), and yellow
circles, respectively. For simplicity, each cancer patient is shown as
having three driver gene mutations, but the calculations are based on
percentages. Thus, if there are three driver gene mutations in a cancer
and R accounts for 33% of them, then one mutation is assigned to R. (A)
A hypothetical scenario consisting of an imaginary place, Planet B,
where all inherited mutations have been corrected and where the
environment is perfect. A powerful mutagen is then introduced that
increases cancer risk 10-fold, so that 90% of cancers on this planet are
preventable. In some individuals on this planet, all mutations are due
to E, whereas in the two individuals in the bottom right corner, all are
due to R. In the other patients, only some of the somatic mutations in
their tumors result from E. Even though 90% of the cancers are
preventable by eliminating the newly introduced mutagen, 40% of the
total driver gene mutations are due to R. (B to D)
Real-life examples of mutation etiology and cancer prevention. (B) The
approximate proportion of driver gene mutations in lung adenocarcinomas
that are due to environmental versus nonenvironmental factors are shown
as gray and yellow circles, respectively. Even though 89% of lung
adenocarcinomas are preventable (17)
by eliminating E factors, we calculate that 35% (95% CI: 30 to 40%) of
total driver gene mutations are due to factors unrelated to E or H and
presumably are due to R. (C) The approximate proportion of driver gene
mutations in pancreatic ductal adenocarcinomas, in which hereditary
factors are known to play a role. It has been estimated that ~37% (17)
of pancreatic ductal adenocarcinomas are preventable, but at most 18%
and 5% of the driver gene mutations in these cancers are estimated to be
due to E and H, respectively. The remaining 77% (95% CI: 82 to 94%) of
the total driver gene mutations are due to factors other than E or H,
presumably R. (D) The approximate proportion of driver gene mutations in
prostate cancers, in which environmental factors are thought to play
essentially no role (17)
and hereditary factors account for 5 to 9% of cases (see supplementary
materials). None of these cancers are preventable, and less than 5% of
the driver mutations in these cancers are due to E or H. The remaining
95% of the total driver gene mutations are due to factors other than E
or H, presumably R. [Image: The Johns Hopkins University]
This theoretical example is not very different
from what occurs on Earth with respect to the etiology of the most
common form of lung cancer, adenocarcinoma. Epidemiologic studies have
estimated that nearly 90% of adenocarcinomas of the lung are preventable
and that tobacco smoke is by far the major component of E. Secondhand
smoking, occupational exposures, ionizing radiation, air pollution, and
diet play important but smaller roles (17, 18). Moreover, no hereditary factors have been implicated in lung adenocarcinomas (19).
To determine the fraction of mutations attributable to nonenvironmental
and nonhereditary causes in lung adenocarcinomas, we developed an
approach based on the integration of genome-wide sequencing and
epidemiological data. The key insight is the recognition of a
relationship between mutation rates in a cancer type and the etiology of
the somatic mutations that are detected in that cancer. Specifically,
if an environmental factor causes the normal somatic mutation rate to
increase by a factor x, then (x–1)/x of the
somatic mutations found in a cancer can be attributed to that
environmental factor (see supplementary materials). For example, if
patients exposed to a factor E have a mutation rate that is three times
higher than that of patients not exposed to it, then two-thirds of the
mutations in the exposed patients can be attributed to factor E. This
method is completely independent of any data or knowledge about normal
stem cell divisions. We applied this approach to representative patients
with lung adenocarcinomas as depicted in Fig. 2B.
In 8 of the 20 depicted patients, all of the driver gene mutations can
be attributed to E. In 10 of the 20 depicted patients, a portion of the
driver gene mutations are attributable to E. And in the two patients
depicted on the bottom right of Fig. 2B,
none of the driver gene mutations are attributable to E. We calculate
that 35% [95% confidence interval (CI): 30 to 40%] of the total driver
gene mutations are due to factors that, according to current exhaustive
epidemiologic studies, are unrelated to H or E and thus are presumably
due to R. These data are based on conservative assumptions about the
risk contributed by factors other than smoking. For example, we assumed
that the increase in mutations resulting from poor diet is identical to
the increase resulting from smoking cigarettes. Thus, Cancer Research UK
estimates that the great majority (89%) of lung adenocarcinoma cases
are preventable (17), but even so, more than a third (35%) of the driver gene mutations in lung cancers can be attributed to R.
This
same analytic approach can be applied to cancer types for which
epidemiologic studies have indicated a less pronounced role of
environmental factors. Figure 2C
depicts pancreatic ductal adenocarcinomas. About 37% of these cancers
are thought to be preventable (versus 89% for lung adenocarcinomas) (17).
Using exome sequencing data and extremely conservative assumptions
about the influence of environmental factors, we calculated that 18% of
the driver gene mutations were due to environmental factors, at most 5%
were due to hereditary factors, and the remaining 77% (95% CI: 67 to
84%) were due to nonenvironmental and nonhereditary factors, presumably R
(see supplementary materials). As with lung adenocarcinomas, these
results are independent of any assumptions about, or measurements of,
stem cell divisions.
A third class of cancers comprise those in which only a very small effect of E or H has been demonstrated (17),
such as those of the brain, bone, or prostate. For example, a very high
fraction of the driver gene mutations in prostate cancers can be
attributed to R (95%; Fig. 2D
and supplementary materials). In the past, the causes of cancer types
like these were obscure, as there was no evidence that the two most
well-recognized causes of cancer—environment and heredity—play a
substantial role. The recognition that a third source of mutations,
i.e., those due to R, are omnipresent helps explain the pathogenesis of
these malignancies. Even if future epidemiological or genetic studies
identify previously unknown E or H factors that permit 90% of cancers of
the prostate to be prevented, the percentage of mutations due to R will
still be very high, as illustrated by the Planet B analogy in Fig. 2A.
We
next calculated the proportion of driver gene mutations caused by E or H
in 32 cancer types (see supplementary materials and tables S5 and S6).
We considered those mutations not attributable to either E or H to be
due to R. These cancers have been studied in depth through sophisticated
epidemiological investigations and are reported in the Cancer Research
UK database [see (17, 20–22)
and references therein]. For the U.K. female population, mutations
attributable to E (right), R (center), and H (left) are depicted in Fig. 3
(see fig. S2 for equivalent representations of males and table S6 for
the numerical values for both sexes). The median proportion of driver
gene mutations attributable to E was 23% among all cancer types. The
estimate varied considerably: It was greater than 60% in cancers such as
those of the lung, esophagus, and skin and 15% or less in cancers such
as those of the prostate, brain, and breast. When these data are
normalized for the incidence of each of these 32 cancer types in the
population, we calculate that 29% of the mutations in cancers occurring
in the United Kingdom were attributable to E, 5% of the mutations were
attributable to H, and 66% were attributable to R. Cancer Research UK
estimates that 42% of these cancer cases are preventable. Given the
mathematical relationship between cancer etiology and cancer
preventability (see supplementary materials), the proportion of
mutations caused by environmental factors is always less than the
proportion of cancers preventable by avoidance of these factors. Thus,
our estimate that a maximum of 29% of the mutations in these cancers are
due to E is compatible with the estimate that 42% of these cancers are
preventable by avoiding known risk factors.
For
each of 18 representative cancer types, the schematic depicts the
proportion of mutations that are inherited, due to environmental
factors, or due to errors in DNA replication (i.e., not attributable to
either heredity or environment). The sum of these three proportions is
100%. The color codes for hereditary, replicative, and environmental
factors are identical and span white (0%) to brightest red (100%). The
numerical values used to construct this figure, as well as the values
for 14 other cancer types not shown in the figure, are provided in table
S6. B, brain; Bl, bladder; Br, breast; C, cervical; CR, colorectal; E,
esophagus; HN, head and neck; K, kidney; Li, liver; Lk, leukemia; Lu,
lung; M, melanoma; NHL, non-Hodgkin lymphoma; O, ovarian; P, pancreas;
S, stomach; Th, thyroid; U, uterus. [Image: The Johns Hopkins
University]
The results described above have important
ramifications for understanding the root causes of cancer as well as for
minimizing deaths from this disease. Uniformly high correlations
between the number of stem cell divisions and cancer risk among tissues
were observed in countries with widely different environments. This
strongly supports the idea that R mutations make major contributions to
cancer (see also fig. S1). However, the actual contribution of R
mutations to any particular cancer type cannot be reliably estimated
from such correlations. The approaches described here—a combination of
cancer sequencing data and conservative analyses of environmental and
hereditary risk factors—provide such estimates. They indicated that even
in lung adenocarcinomas, R contributes a third of the total mutations,
with tobacco smoke (including secondhand smoke), diet, radiation, and
occupational exposures contributing the remainder. In cancers that are
less strongly associated with environmental factors, such as those of
the pancreas, brain, bone, or prostate, the majority of the mutations
are attributable to R.
These data and analyses should help clarify prior confusion about the relationship between replicative mutations and cancer (23–28).
First, the data demonstrate that the correlation between cancer
incidence and the number of stem cell divisions in various tissues
cannot be explained by peculiarities of the U.S. population or its
environment. This correlation is observed worldwide, as would be
expected for a fundamental biological process such as stem cell
divisions. Second, these results explicitly and quantitatively address
the difference between cancer etiology and cancer preventability. As
illustrated in Figs. 2 and 3,
these concepts are not equivalent. A cancer in which 50% of the
mutations are due to R can still be preventable. The reason for this is
that it generally requires more than one mutation to develop the
disease. A cancer that required two mutations is still preventable if
one of the mutations was due to R and the other due to an avoidable
environmental factor.
Our results are fully consistent
with epidemiological evidence on the fraction of cancers in developed
countries that are potentially preventable through improvements in
environment and lifestyle. Cancer Research UK estimates that 42% of
cancer cases are preventable (17); the U.S. Centers for Disease
Control and Prevention estimates that 21% of annual cancer deaths in
individuals <80 a="" be="" class="xref-bibr" could="" href="http://science.sciencemag.org/content/355/6331/1330.full#ref-29" id="xref-ref-29-1" old="" prevented="" years="">29
Of
equal importance, these studies provide a well-defined, molecular
explanation for the large and apparently unpreventable component of
cancer risk that has long puzzled epidemiologists. It is, of course,
possible that virtually all mutations in all cancers are due to
environmental factors, most of which have simply not yet been
discovered. However, such a possibility seems inconsistent with the
exhaustively documented fact that about three mutations occur every time
a normal cell divides and that normal stem cells often divide
throughout life.
Our studies complement, rather than
oppose, those of classic epidemiology. For example, the recognition of a
third, major factor (R) underlying cancer risk can inform epidemiologic
studies by pointing to cancers that cannot yet be explained by R (i.e.,
those with too few stem cell divisions to account for cancer
incidence). Such cancer types seem particularly well suited for further
epidemiologic investigation. Additionally, R mutations appear
unavoidable now, but it is conceivable that they will become avoidable
in the future. There are at least four sources of R mutations in normal
cells: quantum effects on base pairing (30), mistakes made by polymerases (31), hydrolytic deamination of bases (32), and damage by endogenously produced reactive oxygen species or other metabolites (33). The last of these could theoretically be reduced by the administration of antioxidant drugs (34).
The effects of all four could, in principle, be reduced by introducing
more efficient repair genes into the nuclei of somatic cells or through
other creative means.
As a result of the aging of the human population, cancer is today the most common cause of death in the world (12).
Primary prevention is the best way to reduce cancer deaths. Recognition
of a third contributor to cancer—R mutations—does not diminish the
importance of primary prevention but emphasizes that not all cancers can
be prevented by avoiding environmental risk factors (Figs. 2 and 3).
Fortunately, primary prevention is not the only type of prevention that
exists or can be improved in the future. Secondary prevention, i.e.,
early detection and intervention, can also be lifesaving. For cancers in
which all mutations are the result of R, secondary prevention is the
only option.
Supplementary Materials
Supplementary Materials
Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention
Cristian Tomasetti, Lu Li, Bert VogelsteinMaterials/Methods, Supplementary Text, Tables, Figures, and/or References
- Materials and Methods
- Figs. S1 and S2
- Captions for tables S1 to S6
- References
- Cumulative risk and correlation data for age interval zero to75.
- Cumulative risk and correlation data for age interval zero to 80.
- Cumulative risk and correlation data for age interval zero to 85.
- Cumulative risk and correlation data for the age interval zero to 85+.
- Epidemiological cancer data.
- Proportion of driver gene mutations attributable to E, H, and R.
Materials and Methods
Figs. S1 and S2
Tables S1 to S6
References and Notes
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- Acknowledgments: We thank W. F. Anderson [Biostatistics branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI)], N. Chatterjee [Johns Hopkins University (JHU)], K. W. Kinzler (JHU), B. Mensh [Howard Hughes Medical Institute (HHMI)], and J. T. Vogelstein (JHU) for their comments. We thank A. Blackford (JHU) and R. H. Hruban (JHU) for providing the pancreatic cancer data set. This work was made possible through the support of grants from the John Templeton Foundation, the Virginia and D. K. Ludwig Fund for Cancer Research, the Lustgarten Foundation for Pancreatic Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, and NIH grants P30-CA006973, R37-CA43460, and P50-CA62924. The opinions expressed in this publication are those of the authors and do not necessarily reflect the views of the John Templeton Foundation. C.T. conceived the ideas for determining the proportions of drivers and developed the mathematical methods and their application. C.T. and B.V. designed and performed the research. C.T. performed the world data analysis. L.L. obtained the estimates in tables S5 and S6. C.T. and B.V. wrote the paper. C.T. and L.L. have nothing to disclose. B.V. is on the scientific advisory boards of Morphotek, Exelixis GP, and Sysmex Inostics, and is a founder of PapGene and Personal Genome Diagnostics. Morphotek, Sysmex Inostics, PapGene, and Personal Genome Diagnostics, as well as other companies, have licensed technologies from JHU on which B.V. is an inventor. These licenses and relationships are associated with equity or royalty payments to B.V. The terms of these arrangements are being managed by JHU in accordance with its conflict of interest policies.
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