Towards a unified theory of cancer risk

Martin Nowak and Bartlomiej Waclaw conclude their recent commentary [1] on the “bad luck and cancer” debate with a look to the future:

“The earlier analysis by Tomasetti and Vogelstein has already stimulated much discussion… It will take many years to answer in detail the interesting and exciting questions that have been raised.”

I agree. When a couple of journalists [2, 3] contacted me for comments on the latest follow-up paper from Christian Tomasetti, Bert Vogelstein and Lu Li, I emphasized what can be gained from rekindling the decades-old debate about the contribution of extrinsic (or environmental, or preventable) factors to cancer risk. In particular, the diverse scientific critiques of Tomasetti and Vogelstein’s analysis suggest important avenues for further inquiry.

My own take is summarized in the figure below. This diagram (inspired by Tinnbergen) reframes the question in terms of proximate mechanisms and ultimate causes. It also provides a way of categorizing cancer etiology research.

Causes of cancer

Tomasetti and Vogelstein’s 2015 paper [4] demonstrated that the lifetime number of stem cell divisions is correlated with cancer risk across human tissues (part A in the figure). Colleagues and I have argued [5, 6] that, although characterizing this association is important, it cannot be used to infer what proportion of cancer risk is due to intrinsic versus extrinsic factors. This is because cancer initiation depends not only on mutated cells, but also on the fitness landscape that governs their fate, which is determined by a microenvironment that differs between tissues (figure part B).

Moreover, the supply of mutated cells and the microenvironment are both shaped by an interaction of nature and nurture (figure part C). In a recently published paper [7], Michael Hochberg and I draw attention to the relationship between cancer incidence and environmental changes that alter organism body size and/or life span, disrupt processes within the organism, or affect the germline (figure part D). We posit that “most modern-day cancer in animals – and humans in particular – are due to environments deviating from central tendencies of distributions that have prevailed during cancer resistance evolution”. We support this claim in our paper with a literature survey of cancer across the tree of life, and with an estimate of cancer incidence in ancient humans based on mathematical modelling [7].

To understand why cancer persists at a certain baseline level even in stable environments, we must further examine the role of organismal evolution (figure part E). If cancer lowers organismal fitness then we might expect selection for traits that reduce risk. But continual improvement in cancer prevention is expected to come at a cost, and the net effect on fitness will depend on life history. For example, more stringent control of cell proliferation might reduce cancer risk and so lower the mortality rate at older ages, while also increasing deaths in juveniles and young adults due to impaired wound healing. We can predict outcomes of such trade-offs by calculating selection gradients, which is what I’ve been doing in a research project that I presented at an especially stimulating MBE conference in the UK last week.

The quest to understand cancer risk must then encompass not only cell biology, but also ecology and evolution at both tissue and organismal levels. One of my goals is to make connections between these currently disparate lines of research in pursuit of a more unified theory.


  1. Nowak, M. A., & Waclaw, B. (2017). Genes, environment, and “bad luck”. Science, 355(6331), 1266–1267.
  2. Ledford, H. (2017) DNA typos to blame for most cancer mutationsNature News.
  3. Chivers, T. (2017) Here’s Why The “Cancer Is Caused By Bad Luck” Study Isn’t All It Seems. Buzzfeed.
  4. Tomasetti, C., & Vogelstein, B. (2015). Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science, 346(6217), 78–81.
  5. Noble, R., Kaltz, O., & Hochberg, M. E. (2015). Peto’s paradox and human cancers. Philosophical Transactions of the Royal Society B: Biological Sciences, 370(1673), 20150104–20150104.
  6. Noble, R., Kaltz, O., Nunney, L., & Hochberg, M. E. (2016). Overestimating the Role of Environment in Cancers. Cancer Prevention Research, 9(10), 773–776.
  7. Hochberg, M. E., & Noble, R. J. (2017). A framework for how environment contributes to cancer risk. Ecology Letters20(2), 117–134.

Author: Rob Noble

I use mathematical and computational models to investigate evolutionary and ecological systems. I am currently working, in close collaboration with laboratory scientists, on models of cancer evolution and the development of drug resistance. My methods include game theory, analysis of dynamical systems, spatially structured models, and Bayesian inference. During my PhD at the University of Oxford (2009-2013) I used mathematical models, informed by statistical analysis of laboratory data, to understand the immune evasion mechanisms of the malaria parasite Plasmodium falciparum.

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