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JAMA. 2015 Nov 3;314(17):1850-60. doi: 10.1001/jama.2015.13134.

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

Author information

  • 1Departments of Pediatrics (Hematology/Oncology) and Oncological Sciences, University of Utah School of Medicine, Salt Lake City.
  • 2Genomics and Computational Biology Program, University of Pennsylvania, Philadelphia.
  • 3Department of Human Genetics, University of Utah School of Medicine, Salt Lake City.
  • 4Ringling Bros Center for Elephant Conservation, Polk City, Florida.
  • 5Department of Statistical Genomics, Ronin Institute, West Lafayette, Indiana.
  • 6Departments of Radiation Oncology and Oncological Sciences, University of Utah School of Medicine, Salt Lake City7Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City.
  • 7Genomics and Computational Biology Program, University of Pennsylvania, Philadelphia8Department of Statistics, Wharton School, University of Pennsylvania, Philadelphia.
  • 8Biodesign Institute and School of Life Sciences, Arizona State University, Tempe10Center for Evolution and Cancer, University of California, San Francisco.
  • 9Departments of Pediatrics (Hematology/Oncology) and Oncological Sciences, University of Utah School of Medicine, Salt Lake City7Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City.

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.

PMID:
26447779
[PubMed - indexed for MEDLINE]
PMCID:
PMC4858328
Free PMC Article
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