Considering the Origins of Peto's Paradox

If cancer results from mutation, then why don't species with more cells have more cancer? That is clearly not the case. Whales, for example, have a lower rate of cancer than humans despite having something like a thousand times as many cells as we do. Mice have a much higher rate of cancer than we do. This is Peto's paradox in a nutshell, and the observation is the basis for a range of fundamental research that seeks to understand large variations in cancer rates across mammalian species, and then perhaps do something with that understanding. This paper looks at the evolutionary origins of this variation between species of differing sizes:

Multicellularity is risky. Every cell could, in principle, escape the checks and balances of healthy organisms that keep individual cells from proliferating in an uncontrolled manner and cause cancer. If having many cells is risky, then having even more cells should be even riskier. If the hazard rate increases with age, then a longer life should progressively increase cancer risk. Hence, large, long-lived organisms are expected to suffer a higher lifetime cancer risk than small, short-lived organisms. This does not seem to be the case; an apparent contradiction known as Peto's paradox. There is significant recent interest in Peto's paradox and the related problem of the evolution of large, long-lived organisms in terms of cancer robustness. Peto's paradox, however, is circular. The paradox relies on assuming a certain lifespan, after which the cancer risk during that lifetime is evaluated. This seems the wrong procedure. Lifespan is a function, among others, of cancer robustness: organisms are long-lived because they are cancer robust. If not, then they would be short-lived. One cannot next expect that they are not cancer robust and should therefore have a higher lifetime cancer risk, based on the very same lifespan that derives from high cancer robustness. Similarly, large organisms exist because they are cancer robust; one cannot next expect that they are not.

Because no set of competing risks is generally prevalent, it is instructive to temporarily dispose of competing risks and investigate the pure age dynamics of cancer. In addition to augmenting earlier results, I show that in terms of cancer-free lifespan large organisms reap greater benefits from an increase in cellular cancer robustness than smaller organisms. Conversely, a higher cellular cancer robustness renders cancer-free lifespan more resilient to an increase in size. This interaction may be an important driver of the evolution of large, cancer-robust organisms. Large, long-lived animals can exist if and only if they are cancer robust; one cannot next expect them to have a higher lifetime cancer risk because they are not cancer robust. The observation that (cells of) large, long-lived organisms must be more cancer robust than (those of) small, short-lived organisms is shrewd and of great importance, but should have been the endpoint. The expectation that large, long-lived animals should have a higher lifetime cancer risk than small, short-lived organisms is an unnecessary and faulty extra step, as is the resulting paradox when that prediction remains unconfirmed. Given that whales live up to 200 years and weigh up to 200,000 kg, their cancer dynamics differ from those of humans, and the "promise of comparative oncology" stands.



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