Can Peto’s paradox be used as the null hypothesis to identify the role of evolution in natural resistance to cancer? A critical review

Abstract

BackgroundCarcinogenesis affects not only humans but almost all metazoan species. Understanding the rules driving the occurrence of cancers in the wild is currently expected to provide crucial insights into identifying how some species may have evolved efficient cancer resistance mechanisms. Recently the absence of correlation across species between cancer prevalence and body size (coined as Peto’s paradox) has attracted a lot of attention. Indeed, the disparity between this null hypothesis, where every cell is assumed to have an identical probability to undergo malignant transformation, and empirical observations is particularly important to understand, due to the fact that it could facilitate the identification of animal species that are more resistant to carcinogenesis than expected. Moreover it would open up ways to identify the selective pressures that may be involved in cancer resistance. However, Peto’s paradox relies on several questionable assumptions, complicating the interpretation of the divergence between expected and observed cancer incidences.DiscussionsHere we review and challenge the different hypotheses on which this paradox relies on with the aim of identifying how this null hypothesis could be better estimated in order to provide a standard protocol to study the deviation between theoretical/theoretically predicted and observed cancer incidence. We show that due to the disproportion and restricted nature of available data on animal cancers, applying Peto’s hypotheses at species level could result in erroneous conclusions, and actually assume the existence of a paradox. Instead of using species level comparisons, we propose an organ level approach to be a more accurate test of Peto’s assumptions.SummaryThe accuracy of Peto’s paradox assumptions are rarely valid and/or quantifiable, suggesting the need to reconsider the use of Peto’s paradox as a null hypothesis in identifying the influence of natural selection on cancer resistance mechanisms.

Life history, immunity, Peto's paradox and tumours in birds

“…However, no such relationship has so far been found at the interspecific level (hence Peto's, paradox). The lack of such a relationship between incidence of tumours and body size bears testimony to the evolution of mechanisms that protect against cancer (Leroi et al ., ; Caulin & Maley, ; Nunney, ; Aktipis et al ., ; Brown et al ., ; Ducasse et al ., ; Noble et al ., ). The two previous points suggest that these mechanisms are likely related to life‐history characteristics and their trade‐offs (Jacqueline et al ., ), and, thus, we tested whether there is a positive relationship between incidence of cancers and body size in birds after controlling for interspecific covariation with developmental rates and immune responses.…”

Importance of metabolic rate to the relationship between the number of genes in a functional category and body size in Peto's paradox for cancer

“…In addition to this, factors like lifespan, generation time and mutation rate are also different across species; however, because it is believed that these biological parameters are related to metabolic rate, a correction based on mass-specific metabolic rate may be the most useful one to remove most of the effects of these biological parameters [ 11 , 13 , 16 , 56 ]. A critical review [ 57 ] claims that Peto's paradox relies on several questionable assumptions, and it emphasizes the importance of organ-level comparisons rather than species-level comparisons in addressing the variation in cancer risk across tissues [ 58 ]. The differences in risk may be explained in terms of differences in the number of tissue cell divisions [ 58 ] as well as differences in the robustness of cancer signalling networks [ 59 , 60 ].…”

The ecological and evolutionary meaning of cancer

“…In fact, there are even those who question it through arguments as logical as those that seek to explain it. 34 The problem is that each theory seeks, separately, to satisfy from its perspectives the immense amount of variables involved in the dynamics of multicellular organisms and their mechanisms to reduce the risk of mismatching multicellular cooperation. It is almost certain that all have their part of reason.…”