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expert reaction to study investigating extrinsic and intrinsic risk factors in cancer development

The relative contribution of intrinsic (e.g. genetic) and extrinsic (e.g. environmental) risk factors in cancer development is the subject of a paper published in the journal Nature, which reports that external risk factors have a greater influence on cancer risk compared to intrinsic risk factors which only contribute modestly.


Prof. Paul Pharoah, Professor of Cancer Epidemiology, University of Cambridge, said:

“The analyses presented in this paper have been carried out primarily in response to a controversial paper published in Science about a year ago (citation number 5 in this paper). The Tomasetti and Vogelstein paper had made the claim that the majority of cancers were the results of “intrinsic” factors that simply reflected the way that the cells that make up any given tissue divide as the tissue grows.

“This paper uses a variety of different data modelling approaches to demonstrate that the majority of cancer risk comes from external factors. While each of the methods used has different assumptions, any of which might be challenged, all of them result in the same conclusion, suggesting that in general term the conclusion is robust. The results are also broadly in line with other published data.

“The estimates of 10-30% of the variation in risk being intrinsic is not cancer specific and the data for any one cancer are not accurate enough to be able to state with any certainty what the contribution of intrinsic and extrinsic factors are to any one cancer. Nor do the data tell us about specific external risk factors other than those we already know about.

“It is important to realise that these results do not tell us anything about the absolute risks of any given cancer.

“These findings do not have any implications for cancer treatment, but they do tell us that most cancers would be preventable if we knew all of the extrinsic risk factors that cause disease. This is not really novel in itself, and we already know for many cancers some major avoidable risk factors.”


Prof. Kevin McConway, Professor of Applied Statistics, The Open University, said:

“I think it’s important to mention that this study is in a sense a reply to the paper by Cristian Tomasetti and Bert Vogelstein, which was published in Science in January 2015. The Tomasetti and Vogelstein paper was very heavily reported and created considerable controversy. Its authors calculated that about 65% of the variation in cancer risk between different body tissues could be explained in terms of the pattern of divisions in the cells in the tissues. This 65% was reported and explained in many different ways, some of them misleading. It does have a particular statistical meaning. But a real difficulty was that it is not the sort of percentage that would spring to most people’s minds if they were thinking about the extent to which cancers might be caused by external factors such as tobacco, alcohol, sun exposure, and some viruses.

“The new study deals with this question in a very different way. The authors’ aim is to calculate what percentage of cancers would not arise, if we could wave a magic wand and get rid of all possible external risk factors. There would still be cancers, because of the way that cells divide in the body. But there would be fewer of them.

“This percentage is not easy to estimate. But the researchers do make relevant estimates, by four different methods. I’m impressed with what they have achieved. But they cannot answer everything. The numerical results of their different methods do not agree exactly, but that is to be expected given the considerable uncertainty in some of the data. In broad terms, though, the results do agree with one another. For many common types of cancer, this study concludes that at least 70% to 90% of the cancers are due to external risk factors – roughly speaking, that 70% to 90% would not occur if we could magic away all the risk factors. But this percentage varies between different types of cancer, and in some cancers, it is much smaller, so that in those cases, the external risk factors seem much less important.

“So I don’t think these authors are really claiming that 70% to 90% of all cancers are caused by external risk factors. But they do provide pretty convincing evidence that external factors play a major role in many cancers, including some of the most common. Even if someone is exposed to important external risk factors, of course it isn’t certain that they will develop a cancer – chance is always involved. But this study demonstrates again that we have to look well beyond pure chance and luck to understand and protect against cancers.”


Substantial contribution of extrinsic risk factors to cancer development’ by Wu et al. published in Nature on Wednesday 16th December. 


Declared interests

Prof. Paul Pharoah: I have no conflicts of interest

Prof. Kevin McConway: I have no relevant interests to declare.

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