Editors' ChoiceCancer

What the elephant knew

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Science Translational Medicine  21 Oct 2015:
Vol. 7, Issue 310, pp. 310ec182
DOI: 10.1126/scitranslmed.aad4452

Four decades ago, Richard Peto, a statistical epidemiologist from Oxford, made the observation that at the species level, the incidence of cancer does not appear to correlate with the number of cells or the life span of an organism. This became known as “Peto’s paradox.” However, the mechanism underlying this relative resistance to cancer was not understood. Now, Abegglen et al. show that multiple copies of TP53 found in the elephant genome may lie at the basis of this resistance. TP53 is a crucial tumor suppression gene that is mutated in the majority of human cancers. The human genome contains two alleles of the gene, and the absence of one functional allele causes Li-Fraumeni syndrome (LFS), a cancer predisposition with more than a 90% lifetime risk for cancer.

In their study, the investigators examined 14 years of zoo necropsy data for 36 mammalian species and found no significant relationship between mass, life span, basal metabolic rate, and cancer incidence. Elephants have a 100-fold greater cellular mass compared with humans. However, among 644 elephants, the lifetime cancer mortality rate was only 3.11%, as compared with 11 to 25% in humans. Whole-genome sequencing of the African and Asian elephant genome revealed that it contains up to 20 copies of TP53. One of these is considered to be the ancestral copy, and the rest appear to be retrogenes because they lack true introns. Expression, transfection, and coimmunoprecipitation experiments provided evidence of protein expression from the extra copies of TP53 in response to DNA damage. At the functional level, the investigators showed that elephant peripheral blood lymphocytes (PBLs) were approximately 2 to 3 and 6 times more likely to undergo apoptosis in response to DNA damage, compared with PBLs from healthy human controls or patients with LFS, respectively. This increase in apoptosis was associated with increased expression of p21, the downstream effector of p53. Staining for double-stranded DNA breaks confirmed that the cause was not a relative increase in DNA damage incurred in elephant cells. These results were replicated in fibroblasts.

This study has several limitations, including the relatively small number of captive animals studied, the reduced life span of captive animals potentially resulting in under representation of cancer, which is more frequent at older ages, and an incomplete explanation of how TP53 retrogenes confer cancer resistance (for example, by increasing the amount of active protein or providing a degradation decoy). Nevertheless, this study offers a compelling example of how evolutionary medicine can provide insights into mechanisms of cancer suppression.

L. M. Abegglen et al., Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans. JAMA 10.1001/jama.2015.13134 (2015). [Abstract]

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