copying errors during stem cell division are a significant cause of cancer, they
are not as important as mutations caused by factors such as radiation and
chemical carcinogens; being careful about the environment and our lifestyle are
effective ways of reducing our chances of developing cancer Prof Peter Saunders
Cancer is a
disease, or a group of diseases, in which cells in the body grow and multiply uncontrollably;
they can invade and destroy the surrounding healthy tissue and they can spread to other parts of the body. Cells become malignant,
i.e. cancerous, through mutations that occur either as damage caused by
radiation or by various (mostly chemical) carcinogens, or else through copying
errors when the cells are dividing and the DNA is being replicated  (but see  Cancer an
Epigenetic Disease, SiS 54). It is now widely believed that the mutations
that matter are in the stem cells, undifferentiated cells that can either
differentiate into the specialised cells that make up a tissue or divide to
produce more stem cells .
is far more common in some tissues than in others. In the UK, one in eight
women will be diagnosed with breast cancer at some
time in their lives, one in 18 with lung cancer and one in 214 with liver
cancer . The incidence of cancer also varies from country to country: for
women the age standardised rate per 100 000 is 325 in France, 318 in the US,
273 in the UK and 217 in Japan. The rates for men are generally higher . (Because
older people are more likely to develop cancer, for international comparisons the
rates have to be ‘age adjusted’ to what they would be if all countries
had the same age distribution.)
These variations give us clues about the causes of cancer and how
to prevent it. The best known example is the discovery that lung cancer is far
more common among smokers than among non-smokers. This implied that
discouraging smoking would be an effective and inexpensive way of reducing the
number of cases of lung cancer. Experience has shown this to be correct,
despite determined opposition from the tobacco industry and dragging of feet by
Just plain bad luck
Why are the rates
so different for different tissues? Let’s concentrate on copying errors for a
moment. The chance that an error will occur in any division is about the same
for all cells but the number of stem cell divisions over a lifetime varies
considerably from tissue to tissue. So if copying errors in stem cells were
the only causes of cancer, the lifetime risk of cancer in any tissue would be
proportional to the total number of stem cell divisions. If we plotted the
lifetime risk of cancer in different tissues against the number of cell divisions,
the points would all lie on a straight line.
course copying errors on division are not the only causes of cancer and the
points do not all lie on a straight line. But in a recent study, Cristian Tomasetti and Bert Vogelstein  at Johns
Hopkins University in Baltimore found that they lie reasonably close to a
straight line (the solid black line in Figure 1). The correlation coefficient
is 0.81, which is generally accepted to indicate a strong linear correlation.
Copying errors are not, however, the only cause of cancer. We know
that radiation and a large number of carcinogens are also implicated. What we
need to know is how significant the other causes are. There may not
be very much we can do about stem cell divisions and copying errors, and if
that’s how most harmful mutations occur, getting
cancer is largely a matter of bad luck. Avoiding carcinogens may improve our
chances a bit, but not by much. The more important carcinogens are as a cause, however,
the more important it is to do all we can to avoid them, both as individuals
(e.g. by not smoking) and as a society (e.g. by banning the use of known
A standard statistical method for dealing with this sort of
question (but see below) is to suppose that the variation in the incidence of cancer
is the sum of two causes: intrinsic (e.g. stem cell divisions) and extrinsic
(e.g. radiation and carcinogens). The proportion that is due to stem cell
divisions can be shown to be equal to the square of the correlation coefficient,
which for the data in Fig 1 is about 0.81. This suggests that 65 % of cancer is
just bad luck and at most 35 % is due to things we can do something about.
and Vogelstein argue on the basis of their results that for a majority of
cancers (lung cancer in smokers and colorectal cancers are among the exceptions)
primary prevention such as changes in our lifestyles or in the environment is
unlikely to make a major impact. We should be concentrating instead on early
detection and treatment.
were true, it would be good news for the manufacturers of chemicals known to be
carcinogens and governments reluctant to spend money to cut down on pollution.
In a recent paper,
however, Song Wu and colleagues at Stony Brook
University in New York State refute this argument . They deal with Tomasetti
and Vogelstein’s analysis but also draw on a number of different kinds of
evidence. They point out that there is a great deal of variation among
countries in the rates of many cancers, including breast cancer (almost 5 times
as high in Europe as in Eastern Asia), and prostate cancer (almost 25 times
higher in Australia and New Zealand than in South-Central Asia). What is more,
when immigrants move from a country with a lower rate to one with a higher
rate, they soon acquire the higher risk of their new country. This points very
strongly to environmental factors; the genetic makeup of migrants cannot change
in a couple of generations.
cancers, the environmental risk factors are known to be large. The best known
is of course lung cancer; about 85 % of cases are due to long term exposure to
tobacco smoke . An estimated 75 % of the risk of colorectal cancer is
attributable to diet, and for melanoma the risk ascribed to sun exposure is
around 75 % .
have also been studies of what are called mutational signatures in cancers,
traces in the genome of cancer cells left by different mutagenic processes.
There are about 30 distinct signatures, and only two are strongly correlated
with the age of the patient. That suggests that these two are acquired at a
more or less constant rate over the patient’s lifetime, and are probably the
results of intrinsic processes. The others seem to be acquired at different
rates in life and are probably caused by extrinsic factors; indeed several have
been linked to factors such as ultra-violet radiation and smoking. Wu and
colleagues point out that only a few cancers have large proportions of
intrinsic mutations; most have large proportions of extrinsic mutations: almost
100% for myeloma, lung and thyroid cancers and 80-90% for bladder, colorectal
and uterine cancers.
about the correlation that Tomasetti and Vogelstein found? Even if their
analysis is correct, the most it can tell us is that the number of stem cell
divisions accounts for 65 % of the variation in cancer rates among
tissues. That’s not the same as saying that it is 65 % of the cause of
the distinction, imagine a large class of Asian students. All of them were born
with black hair, but some have hair of a different colour because they have
dyed it. The variability in hair colour is entirely due to the
environment and not at all due to heredity. But we would be quite wrong to
infer from this that heredity is not the reason almost all Asians have black
hair. In the same way, Tomasetti and Vogelstein
cannot infer from their analysis that errors in stem cell divisions are 65 % of
the cause of cancer.
Wu and colleagues adopt a different approach. They argue that we
would expect all tissues with the same number of cell divisions to have the
same intrinsic risk of cancer. We do not know what that is, but it cannot be
less than the smallest lifetime risk in any tissue with that number of
divisions. We can therefore take this smallest risk as an estimate of the
intrinsic risk, with the higher risks observed in other tissues reflecting
factors that are additional and almost certainly extrinsic.
Wu and colleagues therefore drew the regression line (the dashed
red line labelled ‘“intrinsic” risk line’ in Fig. 1) that best fits not all the
data but only the points corresponding to these minimal risk tissues. This,
they argue, gives a good estimate of the intrinsic risk for a tissue with a
given number of stem cell divisions. It follows that variations from the line
give good estimates of the extrinsic risks.
Figure 1 Estimate of intrinsic and extrinsic risks
(see text for details)
Most cancer risks lie well above the “intrinsic” regression line,
and Wu and colleagues estimate that the proportion of risk that is not
accounted for by intrinsic factors is typically larger than 90 %.
Of course even the values on the intrinsic risk line may also
include extrinsic factors. If that is the case, however, it means that Wu and
colleagues have overestimated the intrinsic risk. As their claim is that the
intrinsic risk is much smaller than that claimed by Tomasetti and Vogelstein,
this strengthens rather than weakens their argument.
and Vogelstein, Wu and colleagues assume that it is errors in stem cell
divisions that largely account for the intrinsic risk. To check that their analysis
does not depend crucially on this assumption,
they carry out a similar calculation using total tissue cell divisions, i.e.
assuming that every dividing cell has the potential to initiate cancer. They find much the same result: the proportion of the risk
that cannot be attributed to intrinsic factors is still mostly greater than 90
Wu and colleagues modelled the potential lifetime cancer risk due to intrinsic
stem cell mutation, varying the number of driver gene mutations needed for
cancer to develop. They found that if one or two mutations were enough, the lifetime
risk for most cancers would be much higher than is actually observed. If three
or more are required, the intrinsic risks are even less than those predicted
from their analysis of Tomasetti and Vogelstein’s data, and of course much less
than the 65 % claimed by the authors themselves. This is further support for
the conclusion that the contribution of extrinsic factors to the lifetime risk
of cancer is greater than 70-90 % for most
The chief causes of
cancer are almost certainly extrinsic: radiation, chemical carcinogens, etc.
This is a very important finding, because if Tomasetti and Vogelstein were
right and most cancers were due to copying errors, and bearing in mind that
whatever we do we cannot avoid all extrinsic causes, then it might seem that
the scope for preventing cancer by reducing our exposure to all but the most
obvious carcinogens would be comparatively small.
would of course suit the manufacturers of known carcinogens. It would also suit
governments, who find it very difficult to regulate or ban harmful products in
the face of determined and well-funded obstruction from industry. Remember how
long it took to get action on asbestos and tobacco. And the tobacco industry is
still fighting hard against measures to discourage smoking.
were an estimated 14.1 million cases of cancer in the world in 2012 . Even
if extrinsic factors played only a minor role in most of these, we would still
want to do all we can to reduce their effect. A small fraction of 14.1 million
is still a lot of human beings. When, however, we realise that they are far and
away the most important contributors to cancer, it becomes a matter of urgency.
susie greaves Comment left 3rd February 2016 16:04:15 Very timely article.There are so many implications to the subject.
The appalling procrastination about compiling a list of the endocrine disruptors at the European Commission that has held up legislation for more than a decade. See the film of Stephane Horel, in English called Endocrination.
https://www.youtube.com/watch?v=6ks5OSVDl00, in which it becomes clear that it is pressure from the chemical industries lobby that is preventing the correct labelling (or banning) of these products.
For anyone who wants to understand the process by which industry prevents legislation to protect us against toxic products, read the book by David Michaels "Doubt is their product". Finally, try to see the Canadian film "Pink Ribbon Inc." or read the book by Samantha King "Pink Ribbons, Inc: Breast Cancer and the Politics of Philanthropy" which is an astonishing study of the breast cancer "industry" in which the same people who give you breast cancer, sell you the cure. I am being slightly facetious here, but please see the film or read the book, and listen to what breast cancer sufferers say about the cancer charities, who are completely uninterested in the cause of cancer but very interested in the next pharmacological money spinner.
Finally, it goes without saying that the rate of childhood thyroid cancer in Fukushima prefecture is now 230 times normal. Still, the nuclear industry and the Japanese government claim there is no "provable"link to radiation.
Aquifer Comment left 3rd February 2016 16:04:10 Great piece! Should be widely publicized and read ..
Adrian Hepworth Comment left 3rd February 2016 17:05:32 I had understood that copying errors occured in everyone every day but under normal circumstances the immune system would spot these faulty cells and destroy them so they are removed from the body. Only if the immune system is under performing can these faulty cells continue to replicate and a possible cancer grow. The cause of faulty copies may be chance but in the same way that road systems and vehicles can be made safer, it is impossible to prevent accidents. I can understand the importance of early diagnosis but surely prevention is even more important so educating the masses on how to maintain a healthy immune system would be paramount.
Deanna Johnston Clark Comment left 11th February 2016 14:02:46 Thank you for this excellent report...it should go viral. More correlations need to be made public...birth control pills, breast feeding both for mother and child, root canals, cosmetics and hair dyes, all herbecides and on and on.
We are living in an ocean of chemical poisons...yet with some education and immune system support our amazing bodies can serve us better even today.
Too many working women skim through the day with horrible snacks...they need to do better...they deserve better!!