Multiple Copies of TP53 Tumor-Suppressor Gene Potentially Related to Lower-Than-Expected Cancer Rate in Elephants

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A lower-than-expected rate of cancer among elephants could be potentially related to multiple copies of TP53, “a crucial tumor suppressor gene mutated in the majority of human cancers,” according to a study published online by The Journal of the American Medical Association. “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 investigators concluded.

Joshua D. Schiffman, MD, of the University of Utah School of Medicine, Salt Lake City, and colleagues investigated the cancer rate in different mammals, including 644 elephants, identified potential molecular mechanisms of cancer resistance, and compared response to DNA damage in elephants with that in healthy human controls and patients with Li-Fraumeni syndrome (a genetic syndrome with a high lifetime risk of cancer).

Information on disease and cause of death was obtained for 36 mammalian species, from the striped grass mouse (weight, 51 g, with a maximum lifespan of 4.5 years) to the elephant (weight, 4,800 kg, with a maximum lifespan of 65 years). Cancer risk did not increase with body size and maximum lifespan among the 36 species analyzed. “No significant relationship was found with any combinations of mass, lifespan, and basal metabolic rate and cancer incidence,” the authors reported.

Shedding Light on Cancer Resistance

“Despite their large body size and long lifespan, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95% confidence interval [CI], 3.14%–6.49%), compared with humans, who have 11% to 25% cancer mortality,” the investigators stated.

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 Li-Fraumeni syndrome were tested in vitro in the laboratory for DNA-damage response. The study included African and Asian elephants (n = 8), patients with Li-Fraumeni syndrome (n = 10), and age-matched human controls (n = 11).

“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,” the researchers reported. “In response to DNA damage, elephant lymphocytes underwent p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53 status.”

After exposure to 2 Gy of ionizing radiation, the rates of apoptosis were 2.71% (95% CI, 1.93%–3.48%) for patients with Li-Fraumeni syndrome, vs 7.17% (95% CI, 5.91%–8.44%) for human controls and 14.64% (95% CI, 10.91%–18.37%) for elephants (P < .001). After doxorubicin exposure, the rates of apoptosis were 8.10% (95% CI, 6.55%–9.66%) for human controls vs 24.77% (95% CI, 23.0%–26.53%) for elephants (P < .001).

Further Commentary

“Perhaps the main message from this innovative investigation is to bring into focus the question of why humans appear to be so ill-adapted to cancer, given the average size and lifespan,”
Mel Greaves, PhD, and Luca Ermini, PhD, of the Institute of Cancer Research in London, wrote in an accompanying editorial. “The human genome is replete with footprints of positive selection in the not too distant historical past,” the editorialists noted. In other respects, however, “modern humans appear to be exceptionally vulnerable to cancer, especially in more developed societies.”

The risks of lifestyle behaviors, such as smoking and sun-soaking, “far exceed prior and otherwise effective cancer suppressor mechanisms that were inherited from primate ancestors. Contrariwise, humans have inadvertently become maladapted via mismatches between current lifestyles and inherent genetics that was adaptively forged in a very different ancestral environment.”  ■

Abegglen LM, et al: JAMA. Oct 8:1-11, 2015.

Greaves M, Ermini L: JAMA. Oct 8:1-3, 2015.