NEW YORK (GenomeWeb) – Multiple copies of the tumor suppressor gene TP53 appear to play a role in lower rates of cancer development in elephants, according to a new study led by Joshua Schiffman of the University of Utah School of Medicine.
The results, published today in the Journal of the American Medical Association, may also have potential to provide a better understanding of the suppression (or promotion) of cancer in humans, according to Schiffman and his colleagues.
In the study, investigators initially looked for potential molecular mechanisms of cancer resistance in both Asian and African elephants, after a broader study of necropsy data in over 30 mammalian species to validate an observed cancer resistance in large, long-lived animals.
After noting the presence of multiple copies of TP53 in existing and newly sequenced elephant genome data — up to 20 copies of the gene compared to human's single copy — the researchers then set out to compare the response of elephant versus human white blood cells to DNA damage in order to shed light on the biological impact of this difference in gene copy number.
According to the study authors, it has been long observed that large mammals like elephants seem to get cancer much less frequently than would be expected based on their lifespans and the large number of cells in their bodies.
To investigate this paradox, Schiffman set out first to comprehensively investigate cancer mortality across a range of animal sizes and lifespans by analyzing existing necropsy data for a large number of individuals including 644 elephants. While it's generally understood that elephants and other large mammals can have unexpectedly low cancer rates, the authors wrote that theirs is some of the first empirical data backing this up.
The researchers found that cancer mortality did not appear to increase with body size or maximum life span across mammals. Elephants in particular had a cancer mortality of only 4.8 percent, compared to 11 percent to 25 percent among humans, the study authors wrote.
The team then went on to analyze the genomes of African and Asian elephants for potential mechanisms of cancer resistance. Researchers first analyzed genomic sequence data from the publicly available scaffolds of the African elephant genome in the Ensembl and NCBI Gene databases, looking specifically at oncogenes and tumor suppressors. They then went on to perform whole-genome sequencing of an African elephant, as well as additional functional molecular studies to further refine their findings.
Interestingly, while humans have a single copy of the tumor suppressor TP53, the study found that the African elephant appeared to have 20 copies — one original copy, and 19 copies known as retrogenes.
To investigate the biologic influence of this observed difference in TP53 copy number on cancer predisposition — essentially whether these extra retrogene copies actually result in functioning proteins that affect downstream biology — Schiffman and his team decided to look at peripheral blood lymphocytes from one African elephant (tested in triplicate), 11 healthy human controls, and 10 human subjects with the familial cancer predisposition disorder Li-Fraumeni syndrome, testing these cells in vitro for their response DNA damage by radiation.
Patients with Li-Fraumeni inherit only one functioning TP53 allele rather than the normal two, and this aberration is linked to an elevated lifetime risk of cancer.
When the group looked at the response of the isolated white blood cells from elephants and humans, they found that the elephant lymphocytes underwent p53-mediated apoptosis, or cell death, at higher rates than human lymphocytes — about twice the rate of the healthy controls' cells, and a bit more than five times the rate of the cells from Li-Fraumeni subjects.
As a secondary analysis, the group repeated the same radiation experiment in samples from six Asian elephants of different ages, which also all showed an increased rate of apoptosis in response to DNA damage relative to the human cells.
"These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression," the authors wrote.
However, they stressed that the study was limited in its ability to precisely compare the rate of cancer mortality in elephants and other animals with that of humans, since sufficient sample sizes of animals are difficult to find for comparison.
Moreover, they wrote, "neither the African nor Asian elephant genome has been formally assembled [so] … studying the p53 pathway require[d] certain assumptions" on their part.
"With further assembly of the elephant genome, future experiments with genomic technologies like RNA sequencing will prove helpful in understanding the functional differences reflected in the increased apoptosis found in elephants," they concluded.