p53 and Li-Fraumeni Syndrome
p53: Guardian of the Genome
p53 is the protein encoded by the TP53 tumor suppressor gene. p53, referred to as the “guardian of the genome,” plays an essential role in cancer prevention. The loss of proper p53 function leads to the suppression of cell death (suppression of apoptosis), increased cell proliferation, and genomic instability. These are considered hallmarks of cancer cells, mainly cells that never die, grow forever, and are full of mutations.
Each of the cells in our body contains two functional TP53 alleles. Even with these two functioning TP53 alleles, 50% of all men and 33% of all women will develop cancer in their lifetime. However, the absence of one functional TP53 allele leads to the cancer predisposition syndrome known as Li-Fraumeni Syndrome (LFS).
LFS presents with nearly 100% lifetime cancer risk, multiple primary tumors, and early childhood cancers. Even in the absence of LFS, 50% of all tumors harbor a mutation in the TP53 gene, indicating that p53 plays a critical role in protecting our bodies from cancer. The goal of our research in the Schiffman Lab is to enhance and restore p53 function to help children and families with Li-Fraumeni Syndrome, as well as the general cancer patient population.
In the Schiffman Lab, we use comparative oncology to explore cancer in animals, which informs our studies about cancer in humans.
Peto’s Paradox is the observation that cancer incidence does NOT increase as expected with the size and lifespan of an animal.
Statistically, one would expect an organism comprised of more cells to have a higher chance of developing cancer. Since it only takes one cell to mutate and become a cancer cell, the presence of each additional cell increases the potential for a cancer-causing mutation to occur. However, the observation of Peto’s Paradox shows us that is not always the case in the animal kingdom, indicating that the difference in cancer incidence across species may be due to the evolution of specific cancer resistance strategies.
In a 2015 article published in the Journal of the American Medical Association (JAMA), together with our colleagues (including Dr. Carlo Maley at Arizona State University), we conducted a survey of zoo necropsy data from 36 mammalian species and confirmed Peto’s Paradox by showing that cancer incidence across species is not associated with increasing mass and life span.
Despite elephants having a 100 times increase in cellular mass compared to humans, our calculated estimate for the elephant cancer mortality rate (4.81%) was much lower than the human cancer mortality rate (11%-25%). This supported the hypothesis that underlying evolutionary mechanisms may explain higher cancer resistance in elephants than in humans.
Elephant Cancer Resistance
Upon examining cancer-related genes in the African elephant genome, again, with our colleagues, we found 40 copies of the TP53 gene. Since each copy amounts to two alleles, this means that African elephants have 20 times the number of TP53 alleles compared to humans!
Furthermore, when we compared peripheral blood cells from patients with Li-Fraumeni Syndrome (1 allele), healthy humans (2 alleles), and elephants (40 alleles), we found that the degree of apoptotic response to DNA damage in each cell type was correlated with the number of TP53 alleles. These results suggested that cancer resistance in elephants may be related to increased TP53 copies. Additional experiments in our JAMA paper also indicate that elephant cells undergoing cell death (apoptosis) are utilizing the p53-signaling pathway.
We are currently working to understand how elephant p53 function is enhanced compared to human p53. In addition, we hope to apply these mechanisms of cancer resistance to develop and test effective treatments for cancer.
Elephant P53 and Dogs
In the US, dogs are diagnosed with cancer over 10 times more than humans. Interestingly, the types of cancer present in dogs are associated with specific breeds, which indicates a strong genetic basis for cancer predisposition. Moreover, humans and dogs show a remarkable similarity in the types of cancer that they get, which include:
- Brain cancer
- Breast cancer
- Bladder cancer
- Cutaneous cancer
- Oral melanoma
- Prostate cancer
The Schiffman Lab loves dogs! Our lab has studied cancer that develops naturally in pet dogs as part of our comparative oncology approach. We have previously worked with Dr. Matthew Breen at North Carolina State University to identify genes responsible for causing cancer in both dogs and humans. Just like for our human patients, the Schiffman Lab is always thinking about novel genomic methods to help prevent or treat cancer in pet dogs. What we learn from our pet dogs may also be helpful to our human friends and loved ones with cancer.