Understanding p53: Cancer Risks, Genetic Mutations, and Emerging Therapies

Written by: Drita Ferati

Edited by: Shivani Verma, Ava Hargrave, Hiuyi Cheng

Illustrated by: Toni Chavez

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Introduction to the p53 Gene

The p53 gene, otherwise known as the "guardian of the genome,” is a tumor suppressor gene that may help prevent cancer by regulating the cell cycle and ensuring that cells with damaged DNA can either repair themselves or go through apoptosis, a form of programmed cell death. It is important to know that there are two different types of the p53 gene: wild type and mutant type. When the wild type functions properly, it is capable of stopping cells with errors from dividing, preventing tumors associated with cancer from developing. However, when the p53 gene mutates (mutant-type p53), it loses its ability to control cell division, allowing cells with damaged DNA to multiply uncontrollably and ultimately lead to cancer. 

Common Cancers Associated with p53 Gene Mutations

Mutations within this gene are specifically found in diseases like breast, pancreatic, colorectal, liver, lung, and ovarian cancers. In lung cancer, p53 mutations have been detected in 56% of tissue samples; in colorectal, esophageal, ovarian, pancreatic, and skin cancers, the prevalence ranges from 44% to 50% [2]. Studies also show that each cancer type has distinct mutation, or more frequently referred to as "hotspots," with some codons being more commonly mutated in specific types of cancers [2]. For example, codon 249 is a major hotspot in liver cancer, while codon 273 is more frequently mutated in lung cancer. A codon is a sequence of three nucleotides in DNA or RNA that corresponds to a specific amino acid or a stop signal during protein synthesis. The numbers that follow  (e.g., codon 249, codon 273) refer to the position of that codon in the gene's sequence. Interestingly, even at shared hotspots, such as codon 273, different patterns of base pair changes were observed: C→T mutations were common in liver cancer, while G→T mutations were more frequent in lung cancer. Nonetheless, there is a need to rethink the definition of 'hotspot' mutations since some cancers may not have clear hotspots. Even in DNA regions that frequently mutate in cancer, some spots rarely change. This is because not all parts of DNA mutate at the same rate, as some are more stable, while others are more prone to damage. Factors like DNA folding, how often the cell copies its DNA, and how well repairs are made, affect which spots mutate more. Thus, even in a "hotspot" where mutations are common, certain positions might stay mostly unchanged [2]. 

Causes of p53 Gene Mutations

Mutations within the p53 gene are caused by environmental and/or external factors, including radiation, chemicals, viruses, and pollutants. When a cell experiences stress (endogenous or exogenous), or DNA damage (usually caused by UV light, chemicals, or radiation) the p53 gene is activated [3]. Endogenous stressors are internal challenges that cells face during normal biological processes, which can disrupt their function. This includes replication stress, which happens when DNA replication is slowed down or damaged; hypoxia, where cells are deprived of oxygen; and oncogenic activation, where mutations cause genes to trigger uncontrolled cell growth. Exogenous stress refers to external factors that can negatively impact a cell's normal function. This includes nutrient deprivation, where the lack of essential nutrients forces cells to adapt or face damage, irradiation(which refers to damage caused by radiation exposure that can lead to mutations or cell death) and cytotoxic agents, which are harmful substances often used in cancer treatments that can kill or damage cells [3]. To avoid nutrient deprivation, it is important to eat a balanced diet that provides all the essential vitamins and minerals. To protect against irradiation, one should limit exposure to harmful radiation by using sunscreen, avoiding unnecessary medical scans, and staying away from high-radiation areas. Cytotoxic agents should only be used under medical supervision, as they can harm healthy cells along with targeting the disease. Mutations can also be inherited, causing diseases such as Li-Fraumeni syndrome (LFS), a condition that gives individuals a 90% lifetime risk of developing cancer. 

Discovering Gene Therapies for p53 Mutations

As previously stated, the p53 gene is an important component of the cell cycle as it acts as a tumor suppressor gene. The p53 gene helps prevent the production of damaged DNA by causing DNA repair or initiating apoptosis. In many cancers, p53 mutations lead to the damaging of DNA, promoting cancer progression. In terms of discovering different pathways to target the different types of cancer caused by these mutations, there are many different ways, one being the restoration of p53 gene function through gene therapy or small molecule activators [4]. Gene therapy works by adding new copies of a gene that is broken or by replacing a defective gene with a healthier version. However, it is important to mention that gene therapy is not always successful. Sometimes the new gene doesn't work as expected, or the body may reject it. It can also be hard to insert the gene into the right cells, and in some cases, the treatment may cause side effects or only have a short-term impact [4]. In cancers with mutant p53, one is able to restore the normal p53 function by introducing a wild-type (normal) copy of the p53 gene into the cancer cells, either via viral vectors or other gene delivery methods [5]. Some small molecules, such as PRIMA 1 and RITA [6], are designed to specifically bind to mutant p53 proteins, restoring the function and conformation of the wild-type gene. This helps regulate cell division, DNA repair, and initiate apoptosis. It is important to note that many scientists currently consider the development of p53-targeted genes difficult because one must specifically target the mutant type p53 in cancer cells while having no effect on the cells holding the wild-type p53. 

Vulnerability of the Ashkenazi Jewish Population to p53 Gene Mutations

While p53 mutations are found across many different populations and cancer types, certain inherited variants can disproportionately affect specific ethnic groups. One notable example is the Ashkenazi Jewish population, a minority group that is more commonly affected by mutations in the P53 gene (particularly the G334R variant) [7]. This mutation has been found to run in families within the Ashkenazi Jewish population and has been passed down through generations. In one study, 43 people, across 14 different families, carried the TP53 mutation, many of whom were of Ashkenazi Jewish descent. The TP53 is responsible for producing the p53 protein, and a mutation disrupts this process, allowing cells with genetic damage to survive and multiply, which significantly increases the risk of developing cancer. As a result, individuals with this mutation have a higher risk of developing Li-Fraumeni syndrome; a rare genetic disorder that increases one's risk to develop cancer [9]. Research shows that this TP53 mutation appears on a shared genetic background, suggesting it may have originated from a common ancestor [7].  Because of this, Ashkenazi Jews face a greater genetic risk for cancers linked to p53 dysfunction, making regular cancer screening and preventive care especially important for those who are more likely to carry the mutation. 

Conclusion 

The p53 gene plays a crucial role in preventing cancer by regulating cell division and repairing damaged DNA. When mutated, it loses this ability, leading to uncontrolled cell growth and tumor formation. Understanding how p53 mutations contribute to cancer helps researchers develop targeted treatments, such as gene therapy and small-molecule drugs. Ongoing research continues to explore ways to restore p53 function, offering hope for more effective cancer treatments in the future [4]. 

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References

[1] Rivlin, N., Brosh, R., Oren, M., & Rotter, V. (2011). Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis. Genes & Cancer, 2(4), 466–474. https://doi.org/10.1177/1947601911408889

[2] Frawley, R., White, K., Brown, R., Musgrove, D., Walker, N., & Germolec, D. (2011). Gene Expression Alterations in Immune System Pathways in the Thymus after Exposure to Immunosuppressive Chemicals. Environmental Health Perspectives, 119(3), 371–376. https://doi.org/10.1289/ehp.1002358

[3] Lonetto, G., Koifman, G., Silberman, A., Ayush Attery, Solomon, H., Smadar Levin-Zaidman, Goldfinger, N., Porat, Z., Erez, A., & Rotter, V. (2018). Mutant p53-dependent mitochondrial metabolic alterations in a mesenchymal stem cell-based model of progressive malignancy. Cell Death and Differentiation, 26(9), 1566–1581. https://doi.org/10.1038/s41418-018-0227-z

[4] Zhang, S., Carlsen, L., Hernandez Borrero, L., Seyhan, A. A., Tian, X., & El-Deiry, W. S. (2022). Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer. Biomolecules, 12(4), 548. https://doi.org/10.3390/biom12040548

[5] Martinez, J. D. (2010). Restoring p53 tumor suppressor activity as an anticancer therapeutic strategy. Future Oncology, 6(12), 1857–1862. https://doi.org/10.2217/fon.10.132

[6] Mandinova, A., & Lee, S. W. (2011). The p53 Pathway as a Target in Cancer Therapeutics: Obstacles and Promise. Science Translational Medicine, 3(64), 64rv1–64rv1. https://doi.org/10.1126/scitranslmed.3001366

[7] Powers, J., Pinto, E. M., Barnoud, T., Leung, J. C., Martynyuk, T., Kossenkov, A. V., Philips, A. H., Desai, H., Hausler, R., Kelly, G., Le, A. N., Li, M. M., MacFarland, S. P., Pyle, L. C., Zelley, K., 

[8] Nathanson, K. L., Domchek, S. M., Slavin, T. P., Weitzel, J. N., & Stopfer, J. E. (2020). A Rare TP53 Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers. Cancer Research, 80(17), 3732–3744. https://doi.org/10.1158/0008-5472.can-20-1390

[9] Cleveland Clinic. (2022). Li-Fraumeni Syndrome. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/22073-li-fraumeni-syndrome