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Title: Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis

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. Also, 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. Lastly, 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:
 [1] ;  [2] ;  [3] ;  [4]
  1. Univ. of Pennsylvania, Philadelphia, PA (United States). Genomics and Computational Biology Graduate Program
  2. Queen Mary University of London, London (United Kingdom). Evolution and Cancer Laboratory, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry
  3. Univ. of Pennsylvania, Philadelphia, PA (United States). Department of Pathology and Laboratory Medicine
  4. Arizona State Univ., Tempe, AZ (United States). Biodesign Institute, School of Life Sciences; Univ. of California, San Francisco, CA (United States). Center for Evolution and Cancer
Publication Date:
Grant/Contract Number:
FG02-97ER25308
Type:
Accepted Manuscript
Journal Name:
Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences
Additional Journal Information:
Journal Volume: 370; Journal Issue: 1673; Journal ID: ISSN 0962-8436
Publisher:
The Royal Society Publishing
Research Org:
Univ. of Pennsylvania, Philadelphia, PA (United States)
Sponsoring Org:
USDOE; National Institutes of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Peto’s paradox; evolution; cancer; tumour suppression; algebraic model; Wright–Fisher model
OSTI Identifier:
1343568