The most frequently mutated gene in human cancers is called p53. Patients with Li-Fraumeni syndrome, which is a rare disorder that increases the risk of developing several types of cancer, often have an increased risk to develop cancers at early ages if they inherit p53 mutations.
Recent studies suggest that some individuals with inherited p53 mutations do not have the early onset or high frequency of cancers, suggesting that other genetic, environmental, immunological, epigenetic, or random factors play a part in the development of cancers.
A recent study from Rutgers Cancer Institute of New Jersey tested this possibility by analyzing tumor formation and p53 mutations in mice from different genetic backgrounds.
Observations from this work may further elucidate the diversity of cancers in different Li-Fraumeni patients. Senior and corresponding author of the work Wenwei Hu, PhD, researcher at Rutgers Cancer Institute and professor of radiation oncology at Rutgers Robert Wood Johnson Medical School, along with lead and corresponding author Chang S. Chan, PhD, researcher at Rutgers Cancer Institute and associate professor of medicine at Rutgers Robert Wood Johnson Medical School, share more about the findings published in Life Science Alliance.
Why is this topic important to explore?
Mutations in the p53 gene are the single most common spontaneous genetic alterations observed in human cancers. Approximately one in 20,000 individuals inherit heterozygous p53 mutations, resulting in early onset and high frequency of cancers in each patient over a lifetime. Individuals with an inherited p53 mutation have a much higher risk compared to the general population of developing adrenal cortical carcinoma, choroid plexus carcinoma, medullary blastoma, rhabdomyosarcoma and osteogenic sarcoma.
There is also a high relative risk of developing breast cancer, lipomas and liposarcomas, and leiomyosarcomas. However, even within family members who share the same p53 mutation, there is great variability in what cancer types they get and when they get it, thus, it is important to explore the influence of genetics and non-genetic factors on tumor formation and tumor type. These may include environment, immunological or random factors.
Describe the work and tell us what the team discovered.
We created seven sets of mice with different genetic backgrounds, all having the same p53 mutation. These mice are prone to developing a variety of tumor types because of the p53 mutation they harbor. The tumor types these mice develop are very similar to human Li-Fraumeni patients. The mice from each genetic background are almost genetically identical and the environments are controlled to be the same.
This allows us to compare the variability of the tumors within genetically identical mice to mice with different genetic backgrounds, and thus tease apart the contribution of genetics and randomness to tumor formation.
We discovered that certain genetic backgrounds greatly increase the chance of developing specific tumor types and the number of tumors in a single mouse. The age at which a tumor occurs is correlated with the tissue type of that tumor, although identical tumor tissue types can occur at very different ages. Sex of the mice also impact the risk for cancer in certain genetic backgrounds.
These observations present evidence for both genetic and random effects upon tumor formation in diverse groups of mice. This helps to explain the great diversity of cancers in different Li-Fraumeni patients over their lifetimes.
What are the implications of these findings?
Although the results are consistent with a series of genetic modifiers that influence the age of onset of a tumor and the tumor tissue type, the results also support random factors playing a role in the development of tumors. The most obvious random event is a spontaneous mutation in one of the many different tissue specific stem cells of the body that increase cancer risk. Other random factors may include different microbiomes from mouse to mouse, random errors in development and the adaptive immune system which is different between identical strains of mice or identical twins.
The approach in this work can lead to the identification of the gene or genes that predispose individuals to early onset tumors, the selection of the tissue type of a tumor, and enhancement of tumor risk. Genome sequencing of these tumors will help identify the genes whose mutations act with p53 mutations to influence benign and malignant tumors.
Chan, C. S., et al. (2020) Genetic and stochastic influences upon tumor formation and tumor types in Li-Fraumeni mouse models. Life Science Alliance. doi.org/10.26508/lsa.202000952.