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There has been a lot of media attention over the last few days about whether cancer is caused mainly by "intrinsic factors" (i.e. "bad luck" - i.e. mutations that just happen when stem cells replicate which lead to cancer) or "extrinsic factors" (colloquially, "bad behaviors" - i.e. our lifestyle choices, like smoking, diet, exercise, etc.). The controversy stems from two recent papers, [1] and [2], both of which seem to come to conflicting conclusions. 

 

In [1], the authors looked at different organs and compared the cancer rates in those organs with the number of stem cell divisions that occur in those organs. They found a high correlation - i.e. the more stem cells have to divide to maintain an organ over a person's or animal's lifetime, the more likely it is that cancer will occur in that organ. The authors of [1] (and especially the media covering the study when it first came out earlier this year) appear to interpret this to mean that most incidents of cancer can be chalked up to 'bad luck', rather than bad lifestyle choices or other environmental factors. To quote from the abstract of [1]:

 

These results suggest that only a third of the variation in cancer risk among tissues
is attributable to environmental factors or inherited predispositions. The
majority is due to "bad luck," that is, random mutations arising during DNA
replication in normal, noncancerous stem cells.

 

In what appears to be a direct response to [1], the authors of [2] did a somewhat different analysis, using epidemiological data to show that the relatively simple model to predict various cancer rates from the number of stem cell divisions doesn''t fit the data well at all. They conclude instead that 70-90% of cancer rates are a result of extrinsic factors, like exposure to carcinogens from smoking, foods, environment etc. It isn't from this paper, but here is a very interesting table from this popular press article (originally from the American Cancer Society) estimating the percentage of risk coming from extrinsic factors, and what those specific extrinsic factors are, for various types of cancer:

 

MW-EB543_cancer_20151217110902_NS.jpg

So how to reconcile the seemingly conflicting studies? One of the authors of [2] had what I thought was a good analogy in this interview to explain the apparent discrepancy.

 

He likened cancer to playing Russian roulette. Some organs have a high rate of stem cell division, correspond to spinning the chamber and pulling the trigger many times, while other organs require you to "take a chance" with stem cell division much less often. This represents the intrinsic difference between various organs. In this analogy, extrinsic factors (e.g. smoking, diet, lifestyle, etc.) determine the number of bullets in the gun's chamber. With more bullets in the chamber, there is a greater chance that on any one round (i.e. stem cell division), you'll get unlucky and the division will go badly, resulting in cancer.

 

Take home message - since we can't really change the number of stem cell divisions our organs require to function and maintain themselves, it is important for cancer prevention to minimize our exposure to extrinsic factors that increase the risk of bad stem cell divisions that result in cancer, by following a healthy diet and lifestyle.

 

--Dean

 

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[1] Science. 2015 Jan 2;347(6217):78-81. doi: 10.1126/science.1260825.

 
Cancer etiology. Variation in cancer risk among tissues can be explained by the
number of stem cell divisions.
 
Tomasetti C(1), Vogelstein B(2).
 
 
Some tissue types give rise to human cancers millions of times more often than
other tissue types. Although this has been recognized for more than a century, it
has never been explained. Here, we show that the lifetime risk of cancers of many
different types is strongly correlated (0.81) with the total number of divisions 
of the normal self-renewing cells maintaining that tissue's homeostasis. These
results suggest that only a third of the variation in cancer risk among tissues
is attributable to environmental factors or inherited predispositions. The
majority is due to "bad luck," that is, random mutations arising during DNA
replication in normal, noncancerous stem cells. This is important not only for
understanding the disease but also for designing strategies to limit the
mortality it causes.
 
PMID: 25554788
 
--------
[2] Nature. 2015 Dec 16. doi: 10.1038/nature16166. [Epub ahead of print]
 
Substantial contribution of extrinsic risk factors to cancer development.
 
Wu S(1,)(2), Powers S(1,)(2,)(3), Zhu W(1,)(2), Hannun YA(2,)(3,)(4,)(5).
 
 
Recent research has highlighted a strong correlation between tissue-specific
cancer risk and the lifetime number of tissue-specific stem-cell divisions.
Whether such correlation implies a high unavoidable intrinsic cancer risk has
become a key public health debate with the dissemination of the 'bad luck'
hypothesis. Here we provide evidence that intrinsic risk factors contribute only 
modestly (less than ~10-30% of lifetime risk) to cancer development. First, we
demonstrate that the correlation between stem-cell division and cancer risk does 
not distinguish between the effects of intrinsic and extrinsic factors. We then
show that intrinsic risk is better estimated by the lower bound risk controlling 
for total stem-cell divisions. Finally, we show that the rates of endogenous
mutation accumulation by intrinsic processes are not sufficient to account for
the observed cancer risks. Collectively, we conclude that cancer risk is heavily 
influenced by extrinsic factors. These results are important for strategizing
cancer prevention, research and public health.
 
PMID: 26675728

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