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Substantial contribution of extrinsic risk factors to cancer development

Wu S, Powers S et al. Nature 2016;529: 43–47 (in response to the paper)

Variation in cancer risk among tissues can be explained by the number of stem cell divisions

Tomasetti C, Vogelstein B. Science 2015;347: 78–81

Last year a paper was published in Science (2014 Impact Factor 33.611), that received considerable exposure in the public domain. It concluded that '“bad luck” of random mutations plays predominant role in cancer'. The investigators showed that when considering R-tumours (that comprise the majority of tumours including pancreatic islet, osteosarcoma and head and neck cancer, but head and neck cancer only marginally), 'primary prevention measures (altered lifestyles or vaccines)...are not likely to be very effective'. However, primary prevention may have a major impact on D-tumours. Such are the minority of tumours and include HPV-16 head and neck cancer.

In contrast, the key conclusion made by S. Wu, S. Powers et al. in Nature (2014 Impact Factor 41.456), which contested the Science paper, is that 'intrinsic risk factors contribute only modestly (less than ∼10–30% of lifetime risk) to cancer development'. Intrinsic factors would be random and unavoidable DNA mutations. How can leading scientists who have had their research published in such high impact journals have such diametrically opposed views?

In PubMed Commons, a forum for encouraging 'constructive criticism and high quality discussions of scientific issues', Miguel Lopez-Lazaro argues 'the bad luck of cancer' theory is flawed; there is a distinction between 'stem cell divisions' and 'DNA replication mutations'. The division of stem cells is not a random process whereas the mutations arising during DNA replication are random and unavoidable. But then Lopez-Lazaro also challenges the modelling used by the investigators in the Nature paper; most cancer is not avoidable. Ageing gives rise to random and unavoidable DNA mutations, and is the most important risk factor for the majority of cancers. For example, the risk of lung cancer is over 600 times higher in people over 60 years of age than in those under 30 years of age, yet smoking, an extrinsic factor, only increases lung cancer risk by approximately 20 times.

Lopez-Lazaro makes the following point, albeit subtle: 'Preventing a small percentage of cancer risk may be sufficient to prevent a high percentage of cancer cases.' Put more simply, 'avoiding smoking prevents a high percentage of lung cancer cases' as smoking maybe the 'the straw that breaks the camel's back'.