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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 kinds of cancer, often have an increased risk to develop cancers at early ages if they inherit p53 mutations.
Recent studies suggest that some people with inherited p53 mutations don’t have the early beginning or high frequency of cancers, suggesting that other genetic, environmental, immunological, epigenetic, or random factors play a role in the development of cancers.
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 corresponding and lead 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 research? Mutations in the p53 gene are the single most common spontaneous genetic alterations observed in human cancers. Approximately one in 20,000 people 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 when compared with the general population of developing adrenal cortical carcinoma, choroid plexus carcinoma, medullary blastoma, rhabdomyosarcoma and osteogenic sarcoma.
There’s 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 that they get and if they get it, therefore, it’s important to explore the influence of genetics and non-genetic factors on tumor formation and tumor type. These could include environment, immunological or arbitrary elements.
We made seven types of mice with different genetic backgrounds, all having the same p53 mutation. These mice are prone to developing many different tumor types because of the p53 mutation they harbor. The tumor types these mice develop are very much like human Li-Fraumeni patients. The mice from each genetic background are nearly genetically identical and the surroundings are controlled to be the same.
This allows us to compare the variability of these microbes 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 one mouse. The age at which a tumor occurs is connected with the tissue type of the tumor, although indistinguishable tumor tissue types can occur at very different ages. Sex of these mice also affect the risk for cancer in certain genetic backgrounds.
This helps to explain the wonderful diversity of cancers in different Li-Fraumeni patients over their lifetimes.
What are the implications of these findings? Even though 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 elements playing a part in the development of tumors. The most evident 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 could 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 choice of the tissue type of a tumor, and enhancement of tumor risk. Genome sequencing of these tumors can help identify the genes whose mutations behave with p53 mutations to influence benign and malignant tumors.
Rutgers Cancer Institute of New Jersey
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.
