title: Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis.
abstract: Whales have 1000-fold more cells than humans and mice have 1000-fold fewer; however, cancer risk across species does not increase with the number of somatic cells and the lifespan of the organism. This observation is known as Peto's paradox. How much would evolution have to change the parameters of somatic evolution in order to equalize the cancer risk between species that differ by orders of magnitude in size? Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer risk to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. We surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, MAL in horses and FBXO31 in microbats, which might explain Peto's paradox in those species. Exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans.
authors.affiliation: Genomics and Computational Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19103, USA aleah.caulin@gmail.com.
authors.forename: Aleah F
authors.initials: AF
authors.lastname: Caulin
authors.affiliation: Evolution and Cancer Laboratory, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Graham
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19103, USA.
authors.forename: Li-San
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Biodesign Institute, School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA Center for Evolution and Cancer, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Carlo C
authors.initials: CC
authors.lastname: Maley
mesh_terms: D000818:Animals; D049628:Body Size; D019143:Evolution, Molecular; D018628:Gene Dosage; D016147:Genes, Tumor Suppressor; D006801:Humans; D008136:Longevity; D055641:Mathematical Concepts; D051379:Mice; D008957:Models, Genetic; D005810:Multigene Family; D009154:Mutation; D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D012307:Risk Factors; D013045:Species Specificity
keywords: Peto's paradox; Wright–Fisher model; algebraic model; cancer; evolution; tumour suppression