Cancer is a scary topic, in part because people usually only hear about it after they (or someone they know) has developed it. But that doesn’t always have to be the case. With advances in DNA sequencing, efforts are being made to help people identify if they are at risk of developing cancer long before it starts. Identification of cancer predispositions can help people take steps to decrease the impact of such a disease. For this reason, genes like TP53 have been added to the ACMG 59 list.

TP53 is one of the most well-studied genes in the entirety of scientific literature [1]. This is because it codes for the p53 protein, which plays a major role in preventing cancer. At its core, cancer is a disease where cells in a person’s body act abnormally by duplicating themselves over and over again. Typically, this doesn’t happen because cell duplication is a tightly regulated process. Only when the body really needs new cells—like when it needs to heal a scratch, grow new blood vessels, or make new immune cells—will it prompt cells to duplicate. Even then, the cells that are supposed to duplicate are only able to do so if their DNA is stable and unbroken. But sometimes, changes in the DNA of a person can help it bypass these checkpoints, and that’s when it’s able to become cancerous. One of the big hurdles preventing a cell from becoming cancerous is the TP53 gene.

TP53 and elephants

TP53 has gained public attention in the last few years after researchers found that elephants rarely develop cancer, which may be due to their numerous copies of the TP53 gene. Elephants are large animals which means they have many cells and many more opportunities for one of those cells to become cancerous—yet they seem to rarely ever get it. The researchers from this study suggest that having multiple copies of TP53 helps them guard their genome, but more research is needed before solid conclusions can be made [2].

The p53 protein plays a big role in coordinating the safety mechanisms that prevent cancer. For example, broken DNA during cell duplication is a liability because it can cause mutations and lead to cancer. If a cell detects DNA damage when duplicating itself, p53 triggers a stop to the duplication process and may even help coordinate proteins to repair the DNA in that cell. If necessary, p53 may also participate in the process of killing a cell that is beyond repair. In this way, p53 is like a guardian of the genome. For this reason, variants in the TP53 gene that decrease its ability to function can leave someone vulnerable to cancer development.

Variants in the TP53 gene are relatively rare, with some research indicating that 1 in 5,000 to 20,000 people will inherit a variant associated with Li-Fraumeni syndrome. These variants affect p53’s ability to respond to DNA damage and uncontrolled cell duplication—meaning individuals with Li-Fraumeni syndrome are at an increased likelihood of developing various types of cancer such as breast cancer, osteosarcoma, colon cancer, leukemia, and soft tissue sarcomas. Research indicates that this syndrome is inherited in an autosomal dominant pattern, which means there is a 50% chance that someone with Li-Fraumeni syndrome will pass it on to their offspring. P53 has been incorporated into the ACMG 59 list due to the high penetrance of variants in this gene, the significant risk of mortality related to those variants, and the fact that many of the cancers associated with Li-Fraumeni are at least somewhat preventable. If someone tests positive for a TP53 variant, they may be able to decrease their risks with increased screening and prevention. Prevention and surveillance may include things like annual breast MRIs and potential preemptive mastectomy to decrease chances of breast cancer development, regular colonoscopies to monitor for colon cancer, and yearly comprehensive physical examinations. In some situations, surveillance may also include organ-specific monitoring depending on a person’s health history. Together, these steps have the potential to decrease the spread of cancer and possibly even prevent it.

Knowing if a person has Li-Fraumeni syndrome is also important because these variants are heritable, meaning the family members of people with Li-Fraumeni syndrome may have also inherited these variants. Genetic counseling can be a helpful resource when learning about Li-Fraumeni syndrome and the risks associated with it.

Fortunately, you can analyze your DNA for variants in genes in the ACMG 59 list, including TP53, and Helix will soon be launching such a test in partnership with PerkinElmer Genomics. Sign up below to learn when this test becomes available.

References

1. Dolgin, Elie. “The Most Popular Genes in the Human Genome.” Nature News, Nature Publishing Group, 22 Nov. 2017, www.nature.com/articles/d41586-017-07291-9.

2. Sulak, Michael et al. “TP53 Copy Number Expansion Is Associated with the Evolution of Increased Body Size and an Enhanced DNA Damage Response in Elephants.” Ed. Joaquín M Espinosa. eLife 5 (2016): e11994. PMC. Web. 14 June 2018.