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


CONCLUSIONS
Here 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.


CONCLUSIONS
The 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.
MIVEGEC, UMR IRD/CNRS/UM 5290, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France. hugo.ducasse@ird.fr.|CREEC, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France. hugo.ducasse@ird.fr.|Université Montpellier, 163 rue Auguste Broussonnet, 34090, Montpellier, France. hugo.ducasse@ird.fr.
Hugo
H
Ducasse
Centre for Integrative Ecology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Vic, Australia.
Beata
B
Ujvari
INSERM U1009, Université Paris-Sud, Gustave Roussy, Villejuif, France.
Eric
E
Solary
MIVEGEC, UMR IRD/CNRS/UM 5290, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.|CREEC, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.|Centre de Recherche de la Tour du Valat, Le Sambuc, 13200, Arles, France.
Marion
M
Vittecoq
MIVEGEC, UMR IRD/CNRS/UM 5290, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.|CREEC, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.
Audrey
A
Arnal
CREEC, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.|Université Montpellier, 163 rue Auguste Broussonnet, 34090, Montpellier, France.|RHEM, Réseau d'Histologie Expérimentale de Montpellier, IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM, U1194 Montpellier France, Montpellier, France.|ICM, 208 Avenue des Apothicaires, Montpellier, 34298, France.
Florence
F
Bernex
CREEC, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.|Université Montpellier, 163 rue Auguste Broussonnet, 34090, Montpellier, France.|RHEM, Réseau d'Histologie Expérimentale de Montpellier, IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM, U1194 Montpellier France, Montpellier, France.|ICM, 208 Avenue des Apothicaires, Montpellier, 34298, France.
Nelly
N
Pirot
MIVEGEC, UMR IRD/CNRS/UM 5290, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.|CREEC, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.
Dorothée
D
Misse
ISEM, UMR CNRS/IRD/EPHE/UM 5554, Place Eugène Bataillon, Montpellier Cedex 5, 34095, France.
François
F
Bonhomme
MIVEGEC, UMR IRD/CNRS/UM 5290, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.|CREEC, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.
François
F
Renaud
MIVEGEC, UMR IRD/CNRS/UM 5290, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.|CREEC, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.
Frédéric
F
Thomas
MIVEGEC, UMR IRD/CNRS/UM 5290, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.|CREEC, 911 Avenue Agropolis, BP 64501, 34394, Montpellier Cedex 5, France.|UMMISCO, UMI IRD/UPMC, 32 Avenue Henri Varagnat, 93143, Bondy Cedex, France.
Benjamin
B
Roche
D000818:Animals; D005075:Biological Evolution; D063646:Carcinogenesis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D013045:Species Specificity