Skip to main content
eScholarship
Open Access Publications from the University of California

UC Riverside

UC Riverside Electronic Theses and Dissertations bannerUC Riverside

Peto's Paradox and the Evolution of Cancer Suppression: Lessons From Flies, Humans, and Elephants

  • Author(s): Muir, Brian Michael
  • Advisor(s): Nunney, Leonard
  • et al.
Abstract

An unsuspected finding in cancer research is that different cancers result from mutations in different genes. If cancer is a problem of multicellularity, why is there not a single set of genes regulating all cancers of multicellular animals? Cancer risk is expected to be higher in larger, longer-lived species since the risk of cancer-initiating somatic mutations is expected to increase with the number of lifetime cell divisions. However, this expected relationship is not observed, and has been termed Peto’s Paradox. The evolution of additional mechanisms of cancer suppression in large, long-lived species can resolve the paradox and may explain the differences in the genetics of cancer between species and tissues. In a proof-of-concept experimental evolution study fruit flies with hereditary tumors were selected to evolve suppression of these tumors. A significant reduction in the incidence of tumors was observed in the final populations. The genetic changes involved in the evolution of additional mechanisms may come in two forms. First, a cancer-suppression mechanism acting may be recruited by its upregulation of gene expression in the target tissue. To address this, I compared the levels of gene expression of 15 tumor suppressor genes and 8 proto-oncogenes across dozens of non- diseased human tissues. I found that 15 of the 23 genes have their highest level of expression in the tissue types where they are implicated in hereditary cancer, relative to the tissue types where they are not. Second, additional mechanisms may arise by duplications of pre-existing tumor suppressor genes already acting in the target tissue. The recent finding of additional copies of the critical tumor suppressor gene, TP53, in the large-bodied African Elephant and the long-lived microbats has been suggested to explain the low-rates of cancers in these species. However, in a phylogenetic comparison of the coding regions of these retrogene copies relative to the normal TP53 copies in 24 mammals, I find that the additional copies in the elephant and bats are truncated early by stop codons, and are poorly conserved. In conclusion, incorporating evolutionary theory into cancer biology is critical for understanding the variation in cancer genetics across tissues and species.

Main Content
Current View