Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans.
Level 5 - mechanism / opinion, no new human data
Comparative genomic and in vitro laboratory assay with cross-species necropsy database review (bench/animal basic science).
PubMed 26447779 · doi:10.1001/jama.2015.13134
What was done
Necropsy records across 36 mammalian species (including n = 644 elephants) were analyzed to estimate cancer mortality relative to body mass and lifespan. African and Asian elephant genomes were evaluated for cancer-related genes, specifically TP53 copy number and transcriptional activity via reverse transcription polymerase chain reaction. In vitro cellular responses (p53-mediated apoptosis) to DNA damage induced by ionizing radiation and doxorubicin were compared in peripheral blood lymphocytes from elephants (n = 8), healthy human controls (n = 11), and cancer-prone patients with Li-Fraumeni syndrome (n = 10).
What was found
Mammalian cancer mortality did not correlate with body size or lifespan (e.g., rock hyrax: 1% [95% CI, 0%-5%]; African wild dog: 8% [95% CI, 0%-16%]; lion: 2% [95% CI, 0%-7%]). Elephants exhibited an estimated cancer mortality of 4.81% (95% CI, 3.14%-6.49%) compared to 11% to 25% in humans. African elephant genomes contained at least 20 copies (40 alleles) of TP53 (including 19 retrogenes), compared to 1 copy (2 alleles) in humans. Following ionizing radiation, elephant lymphocytes showed higher apoptotic rates (14.64% [95% CI, 10.91%-18.37%]) than human controls (7.17% [95% CI, 5.91%-8.44%]) and Li-Fraumeni syndrome patients (2.71% [95% CI, 1.93%-3.48%]; P < .001). Following doxorubicin exposure, elephant lymphocytes also exhibited significantly higher apoptosis than human controls (24.77% [95% CI, 23.0%-26.53%] vs 8.10% [95% CI, 6.55%-9.66%]; P < .001).
Why it matters
This study identifies a potential genetic and cellular mechanism for Peto's paradox, linking elephant cancer resistance to TP53 copy number amplification and heightened apoptotic sensitivity to DNA damage.
Limits
Cellular DNA-damage response experiments had small sample sizes (8 elephants, 11 human controls, 10 Li-Fraumeni syndrome patients) and tested only peripheral blood lymphocytes in vitro. Necropsy data across species were derived from retrospective surveys subject to ascertainment and reporting variability. In vivo causal links between specific TP53 retrogene transcription and lifetime cancer protection were not directly tested.
Cited by
- supports Elephants rarely get cancer because they have multiple copies of the p53 gene, which acts as a guardian of the genome preventing mutations.