Resolving Peto's paradox: Modeling the potential effects of size‐related metabolic changes, and of the evolution of immune policing and cancer suppression. (4th June 2020)

• Record Type: Journal Article
• Authors: Nunney, Leonard
• Other Names: Thomas Frédéric guestEditor.; Giraudeau Mathieu guestEditor.; Hamede Rodrigo guestEditor.; Roche Benjamin guestEditor.; Ujvari Beata guestEditor.
• Is Part Of: Evolutionary applications. Volume 13:Number 7(2020)
• Page Start: 1581
• Page End: 1592
• Publication Date: 2020-06-04
• Subjects: blue whale -- body size -- cancer -- cancer suppression -- elephant -- evolution -- immune policing -- multistage carcinogenesis -- somatic mutation; Evolution (Biology) -- Periodicals; Genetics -- Periodicals; Natural selection -- Periodicals; Ecology -- Periodicals; 576.8
• DOI: 10.1111/eva.12993
• Languages: English
• ISSNs: 1752-4571

Abstract

Abstract: The intrinsic risk of cancer increases with body size and longevity; however, big long‐lived species do not exhibit this increase, a contradiction named Peto's paradox. Five hypotheses potentially resolving this paradox were modeled using the multistage model of carcinogenesis. The five hypotheses were based on (1) intrinsic changes in metabolic rate with body size; adaptive increase in immune policing of (2) cancer cells or (3) cells with driver mutations; or adaptive increase in cancer suppression via (4) decreased somatic mutation rate, or (5) increased genetic control. Parameter changes needed to stabilize cancer risk in three types of cancer were estimated for tissues scaled from mouse size and longevity to human and blue whale levels. The metabolic rate hypothesis alone was rejected due to a conflict between the required interspecific effect with the observed intraspecific effect of size on cancer risk, but some metabolic change was optionally incorporated in the other models. Necessary parameter changes in immune policing and somatic mutation rate far exceeded values observed; however, natural selection increasing the genetic suppression of cancer was generally consistent with data. Such adaptive increases in genetic control of cancers in large and/or long‐lived animals raise the possibility that nonmodel animals will reveal novel anticancer mechanisms.