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.

Peto's paradox and the hallmarks of cancer: constructing an evolutionary framework for understanding the incidence of cancer

“…For example, 'resisting cell death' involves cells overcoming the machinery of apoptosis, which often means disabling TP53. It is therefore notable that there is evidence of multiple TP53 duplications in the large-bodied, long-lived elephant [17], a response that is consistent with the evolutionary expectation.…”

Peto's paradox and the promise of comparative oncology

“…Telomerase suppression is another possibility and has been found to correlate with body size in rodents [31]. Caulin & Maley [32] provided an in-depth review of the range of additional hypotheses that could potentially resolve Peto's paradox. One filter through which to view these hypotheses is that, given the magnitude of the differences in cancer susceptibility originally outlined by Peto [23], any hypotheses proposed must be consistent with an evolutionary model.…”

Comparative oncology: what dogs and other species can teach us about humans with cancer

“…ERCC1 and PCNA) [167]. Elephants represent another large mammal that appears to be protected from cancer [168,169], and various studies are underway to explain the molecular basis for this phenomenon known as Peto's paradox (large and long-lived animals that appear to be cancer resistant) [170][171][172][173][174][175].…”