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Cited by 485Veterinary Oncology ResearchGenetics, Aging, and Longevity in Model OrganismsCancer-related Molecular Pathways

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

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Abegglen, Lisa M., Caulin, Aleah F., Chan, Ashley, Lee, Kristy, Robinson, Rosann, Campbell, Michael S., Kiso, Wendy K., Schmitt, Dennis L. +5 more·2015·JAMA
DOI 10.1001/jama.2015.13134PMC PMC4858328
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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.

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  • Elephants possess at least 20 copies of the gene TP5, which prevents apoptosis, or cell death, and protects elephants from cancer.

    “elephants possess at least 20 copies of the gene TP5, which prevents apoptosis, or cell death, and protects elephants from cancer (Abegglen et al., 2015; Chusyd et al., 2021; Padariya et al., 2022; Sulak et al., 2016).”

    From Do elephants really never forget? What we know about elephant memory and a call for further investigation (2025) · cites this paper as Abegglen et al., 2015

    The Results (African Elephant Genome Analysis) report 20 total copies of TP53, not TP5. More importantly, the Discussion says the additional TP53 copies may protect against cancer by increasing apoptosis after DNA damage—the opposite of preventing cell death. (LLM, conf=0.92)

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  • Humans possess only one copy of the gene TP5.

    “In comparison, humans possess only one copy (Abegglen et al., 2015; Chusyd et al., 2021; Padariya et al., 2022; Sulak et al., 2016).”

    From Do elephants really never forget? What we know about elephant memory and a call for further investigation (2025) · cites this paper as Abegglen et al., 2015

    The Results (African Elephant Genome Analysis; page not provided) state that the human haploid genome contains one copy of TP53. The claim names TP5 instead; our copy does not establish a copy count for that gene. (LLM, conf=0.83)

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Authors
Abegglen, L. M., Caulin, A. F., Chan, A., Lee, K., Robinson, R., Campbell, M. S., Kiso, W. K., Schmitt, D. L., Waddell, P. J., Bhaskara, S., Jensen, S. T., Maley, C. C., & Schiffman, J. D.
Affiliations
  • University of Utah (US)
  • University of Pennsylvania (US)
  • Ringling Bros Center for Elephant Conservation, Polk City, Florida
  • Ronin Institute (US)
  • University of California, San Francisco (US)
Corresponding author
Schiffman, Joshua D.
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2015-11-03
Volume
314
Issue
17
Pages
1850
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2015.13134
PMC
PMC4858328
OpenAlex
W2097260622
Cited by
485
References
4
Citations by year
2026: 34 · 2025: 42 · 2024: 42 · 2023: 51 · 2022: 57 · 2021: 47 · 2020: 47 · 2019: 49 · 2018: 32 · 2017: 36 · 2016: 40 · 2015: 7
FWCI
30.36
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • ScholarlyCommons (University of Pennsylvania) (submittedVersion)
Funders
  • U.S. Department of Energy (DEFG0297ER25308, DE‐FG02‐, FG02-97ER25308)
  • Intermountain Healthcare
  • Huntsman Cancer Institute (CA24014)
  • National Institutes of Health (BC132057)
  • National Cancer Institute (CA24014, CA91955, CA140657, CA185138, CA170595, R01CA149566, P01CA091955, R01CA185138, R01CA170595, P01CA91955, R01CA140657)
  • U.S. National Library of Medicine (R01LM008626)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Veterinary Oncology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
DNA damage response, apoptosis, DNA repair, peripheral blood lymphocytes, Li-Fraumeni syndrome, ionizing radiation, doxorubicin, evolutionary medicine, elephants, human, rock hyrax, Lycaon pictus, lion, Columba livia
MeSH terms
Animals, DNA Damage, DNA Repair, Doxorubicin, Elephants, Biological Evolution, Humans, Lymphocytes, Mammals, Neoplasms, Radiation, Ionizing, Case-Control Studies, Genes, p53, Li-Fraumeni Syndrome, Apoptosis, Disease Resistance

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