In March 2017 Science published a headline stating that “Random errors in DNA replication play a major role in cancer” referring to a new paper by Tomasetti et al. [1] which is a follow-up to their first paper in 2015. Headlines appeared on many media and social media outlets reading Most Cancer Cases Arise from “Bad Luck” (Scientific American/ STAT medicine) or “’Bad luck’ mutations increase cancer risk more than behavior, study says” (CNN). Such a message suggesting that cancers are largely due to bad luck is an incorrect interpretation of the authors’ results, and ultimately misleading. We are concerned about the adverse impact this message might have on public health policies to prevent cancers. Here we emphasize that mutations are a necessary but insufficient cause of cancer, and additional mechanisms (“hallmarks” of cancer) are at work, such as altered immune function.

Mala Suerte by AxelBoth Tomasetti et al’s  papers published in Science use mathematical modelling to analyse the probability of developing cancer based on the rate of stem cell divisions occurring in different organs. The authors’ analysis stops at the molecular level, and so should all ensuing conclusions. Random occurrences of mutations do not equate to random occurrence of cancers. This is partly because a whole other aspect of the carcinogenic process is missing: non-genotoxic alterations at the cellular level as expressed e.g. in the “hallmarks of cancer” paradigm [2]. Key among such alterations is immune function. A mutation at the cellular level must be followed by other non-genotoxic events, such as immune surveillance failure, for a cancer to occur.

Tomasetti et al. highlight that cell replication is a major factor determining the appearance of tumour cells. However, mutation is a necessary but not sufficient condition for developing a cancer. Cancers occur when several biological systems dysfunction, in particular the immune system. Immune surveillance must fail to identify and destroy a mutated cell, allowing it to replicate [3, 4] , and eventually form a tumour. However, the behaviour of the immune system has not been shown to be random. Indeed, immune system functioning and the failure of immune surveillance may be vulnerable to many exogenous factors [5]. Even when stem cell mutations occur at random, the initiation and development of a cancer cannot be considered a random process.

Conclusion

The idea that cancers are caused by “bad luck” is misleading and dangerous if policy makers and the public think that there is nothing to be done to prevent cancers. While tumour cell production may have an inherent stochastic nature, this is one component of an interaction between complex systems at the individual and population level, which are not eminently random. Medicine and public health need to persist in finding areas of cancer prevention moving above and beyond classic risk factors, taking whole systems, both social and biological, into account.

By

Michelle Kelly-Irving, Cyrille DelpierreInserm, UMR1027, F-31000 Toulouse, France; Université Toulouse III Paul-Sabatier, UMR1027, F-31000 Toulouse, France

and Paolo VineisFaculty of MedicineSchool of Public Health, Imperial College, London, UK

This is a pre-print version of a Commentary published in The Lancet Oncology

References

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  10. Mallath, M.K., D.G. Taylor, R.A. Badwe, G.K. Rath, V. Shanta, C.S. Pramesh, R. Digumarti, P. Sebastian, B.B. Borthakur, A. Kalwar, S. Kapoor, S. Kumar, J.L. Gill, M.A. Kuriakose, H. Malhotra, S.C. Sharma, S. Shukla, L. Viswanath, R.T. Chacko, J.L. Pautu, K.S. Reddy, K.S. Sharma, A.D. Purushotham, and R. Sullivan, The growing burden of cancer in India: epidemiology and social context. The Lancet Oncology, 2014. 15(6): p. e205-e212.
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