Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans

Abstract

IMPORTANCE Evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology. OBJECTIVE To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS). DESIGN, SETTING, AND PARTICIPANTS A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11). Human samples were collected at the University of Utah between June 2014 and July 2015. EXPOSURES Ionizing radiation and doxorubicin. MAIN OUTCOMES AND MEASURES Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes. RESULTS Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95%CI, 0%–5%]; African wild dog, 8%[95%CI, 0%–16%]; lion, 2%[95%CI, 0% –7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95%CI, 3.14%–6.49%), compared with humans, who have 11% to 25%cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain reaction. In response to DNA damage, elephant lymphocytes underwent p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53 status (ionizing radiation exposure: patients with LFS, 2.71% [95%CI, 1.93%–3.48%] vs human controls, 7.17%[95%CI, 5.91%–8.44%] vs elephants, 14.64%[95%CI, 10.91%–18.37%]; P < .001; doxorubicin exposure: human controls, 8.10% [95%CI, 6.55%–9.66%] vs elephants, 24.77%[95%CI, 23.0%–26.53%]; P < .001). CONCLUSIONS AND RELEVANCE Compared with other mammalian species, elephants appeared to have a lower-than-expected rate of cancer, potentially related to multiple copies of TP53. Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage. These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression.

The p53–Mdm2 interaction and the E3 ligase activity of Mdm2/Mdm4 are conserved from lampreys to humans

“…The p53 response is activated in part through increased protein levels and decreased degradation when the p53/Mdm2/4 complex is disrupted; for example, in response to oncogene activation, nuclear stress, and DNA damage (Vousden and Lu 2002;Reinhardt and Schumacher 2012;Hock and Vousden 2014;Khoo et al 2014;Meek 2015). The significant role of p53 in response to DNA damage is highlighted by the recent discovery of multiple functional copies of the Tp53 gene in elephants (Abegglen et al 2015). The Tp63 gene also shows a response to DNA damage, acting as a major regulator of the response in female germ cells (Suh et al 2006;Gonfloni et al 2009;Levine et al 2011).…”

Leveraging Naked Mole Rat (Heterocephalus glaber) Comparative Genomics to Identify Canine Genes Modulating Susceptibility to Tumorigenesis and Cancer Phenotypes

“…A more recent example of a comparative genomics approach to identify anti-cancer mechanisms leveraged the genome of the African elephant to investigate the genomic basis of reduced tumorigenesis within this species [14]. The results of this comparative study identified approximately 20 duplications of the p53 tumor-suppressor gene in the African elephant genome, which likely contribute to a decreased rate of tumorigenesis in the elephant.…”

The evolution of p53 network behavior

“…It was found that elephant cells have 20 copies of the T P 53 gene as compared to the single copy observed in human cells. Elephant cells were also found to carry out p53-dependent apoptosis at a much higher rate than human cells for the same amount of DNA damage [29].To test the effect of increasing the number of copies of the T P 53 gene, we took the full vertebrate network Nv described above and increased the basal and kinase-dependent rates of production of p53, while keeping all other parameters constant. We found that this would cause the level of threshold T2, shown in Fig.…”