The mechanisms for cancer resistance in elephants has baffled scientists for decades, but a new study in the Journal of the American Medical Association may have identified a genetic explanation for their lower-than-expected rate of cancer.

Sir Richard Peto was the inspiration for “Peto’s Paradox,” after he highlighted that greater cell division in larger animals and a longer lifespan should in theory also increase the mutational and malignancy risk proportionally. However, he and his colleagues observed that cancer rates do not actually appear to increase with animal size and cell numbers. Joshua D. Schiffman, MD, of the University of Utah School of Medicine in Salt Lake City, and colleagues conducted a comprehensive survey of necropsy data across 36 mammalian species to identify cancer resistance in large and long-lived organisms, including elephants. In particular, the African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance and compared to those from healthy human controls and cancer-prone patients with Li-Fraumeni syndrome (LFS).

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Cancer mortality did not increase with body size and/or maximum lifespan; elephants had an estimated cancer mortality of 4.8% vs. 11–25% in humans. Humans have 1 copy of TP53 (a tumor suppressor gene that is mutated in the majority of human cancers), but African elephants have at least 20 copies. Patients with LFS have only 1 functioning TP53 allele and may have a 90–100% cancer risk over their lifetime. They also discovered that elephant lymphocytes go through p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53. The multiple copies of TP53 and the enhanced p53-mediated apoptosis may have evolved to offer such cancer protection in elephants.

In an accompanying editorial, Mel Greaves, PhD, and Luca Ermini, PhD added that because modern humans appear to be particularly vulnerable to cancer as aging occurs, other factors may increase cancer risk in humans such as smoking, reproductive, dietary, and sun-exposure habits.

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