title: Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  METHODS
  Ionizing radiation and doxorubicin.
  
  
  METHODS
  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
  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.
authors.affiliation: Departments of Pediatrics (Hematology/Oncology) and Oncological Sciences, University of Utah School of Medicine, Salt Lake City.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Abegglen
authors.affiliation: Genomics and Computational Biology Program, University of Pennsylvania, Philadelphia.
authors.forename: Aleah F
authors.initials: AF
authors.lastname: Caulin
authors.affiliation: Departments of Pediatrics (Hematology/Oncology) and Oncological Sciences, University of Utah School of Medicine, Salt Lake City.
authors.forename: Ashley
authors.initials: A
authors.lastname: Chan
authors.affiliation: Departments of Pediatrics (Hematology/Oncology) and Oncological Sciences, University of Utah School of Medicine, Salt Lake City.
authors.forename: Kristy
authors.initials: K
authors.lastname: Lee
authors.affiliation: Departments of Pediatrics (Hematology/Oncology) and Oncological Sciences, University of Utah School of Medicine, Salt Lake City.
authors.forename: Rosann
authors.initials: R
authors.lastname: Robinson
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Campbell
authors.affiliation: Ringling Bros Center for Elephant Conservation, Polk City, Florida.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Kiso
authors.affiliation: Ringling Bros Center for Elephant Conservation, Polk City, Florida.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Schmitt
authors.affiliation: Department of Statistical Genomics, Ronin Institute, West Lafayette, Indiana.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Waddell
authors.affiliation: Departments 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.
authors.forename: Srividya
authors.initials: S
authors.lastname: Bhaskara
authors.affiliation: Genomics and Computational Biology Program, University of Pennsylvania, Philadelphia8Department of Statistics, Wharton School, University of Pennsylvania, Philadelphia.
authors.forename: Shane T
authors.initials: ST
authors.lastname: Jensen
authors.affiliation: Biodesign Institute and School of Life Sciences, Arizona State University, Tempe10Center for Evolution and Cancer, University of California, San Francisco.
authors.forename: Carlo C
authors.initials: CC
authors.lastname: Maley
authors.affiliation: Departments 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.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Schiffman
mesh_terms: D000818:Animals; D017209:Apoptosis; D005075:Biological Evolution; D016022:Case-Control Studies; D004249:DNA Damage; D004260:DNA Repair; D060467:Disease Resistance / Q000235:genetics*; D004317:Doxorubicin; D004606:Elephants / Q000235:genetics*; D016158:Genes, p53; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics; D008214:Lymphocytes; D008322:Mammals / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000401:mortality; D011839:Radiation, Ionizing
chemical_list: D004317:Doxorubicin