Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA Damage in Humans

Lisa M. Abegglen, Aleah F. Caulin, Ashley Chan, Kristy Lee, Rosann Robinson, Michael S. Campbell, Wendy K. Kiso, Dennis L. Schmitt, Peter J. Waddell, Srividya Bhaskara, Shane T. Jensen, Carlo Maley, Joshua D. Schiffman

Research output: Contribution to journalArticle

118 Citations (Scopus)

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 datawas 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 specieswas 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

Original languageEnglish (US)
Pages (from-to)1850-1860
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume314
Issue number17
DOIs
StatePublished - Nov 3 2015

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DNA Damage
Li-Fraumeni Syndrome
Neoplasms
Body Size
Lymphocytes
Mortality
Alleles
Ionizing Radiation
Hyraxes
Genome
Lions
Apoptosis
Neoplasm Genes
DNA Repair
Doxorubicin
Reverse Transcription
Mammals
Medicine
Dogs
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Abegglen, L. M., Caulin, A. F., Chan, A., Lee, K., Robinson, R., Campbell, M. S., ... Schiffman, J. D. (2015). Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA Damage in Humans. JAMA - Journal of the American Medical Association, 314(17), 1850-1860. https://doi.org/10.1001/jama.2015.13134

Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA Damage in Humans. / Abegglen, Lisa M.; Caulin, Aleah F.; Chan, Ashley; Lee, Kristy; Robinson, Rosann; Campbell, Michael S.; Kiso, Wendy K.; Schmitt, Dennis L.; Waddell, Peter J.; Bhaskara, Srividya; Jensen, Shane T.; Maley, Carlo; Schiffman, Joshua D.

In: JAMA - Journal of the American Medical Association, Vol. 314, No. 17, 03.11.2015, p. 1850-1860.

Research output: Contribution to journalArticle

Abegglen, LM, Caulin, AF, Chan, A, Lee, K, Robinson, R, Campbell, MS, Kiso, WK, Schmitt, DL, Waddell, PJ, Bhaskara, S, Jensen, ST, Maley, C & Schiffman, JD 2015, 'Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA Damage in Humans', JAMA - Journal of the American Medical Association, vol. 314, no. 17, pp. 1850-1860. https://doi.org/10.1001/jama.2015.13134
Abegglen, Lisa M. ; Caulin, Aleah F. ; Chan, Ashley ; Lee, Kristy ; Robinson, Rosann ; Campbell, Michael S. ; Kiso, Wendy K. ; Schmitt, Dennis L. ; Waddell, Peter J. ; Bhaskara, Srividya ; Jensen, Shane T. ; Maley, Carlo ; Schiffman, Joshua D. / Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA Damage in Humans. In: JAMA - Journal of the American Medical Association. 2015 ; Vol. 314, No. 17. pp. 1850-1860.
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