Rare genetic mutation leaves people at higher risk for multiple cancers

Rare inherited mutations in the body’s master regulator of the DNA repair system—the TP53 gene—can leave people at a higher risk of developing multiple types of cancer over the course of their lives. Now, for the first time, a team led by researchers in the Basser Center for BRCA at the Abramson Cancer Center details the potential implications of a lower risk TP53 mutation, including an association with a specific type of Li-Fraumeni syndrome (LFS), an inherited predisposition to a wide range of cancers. The findings raise questions about how to appropriately screen patients for this mutation and whether the standard process of full-body scans for LFS patients should be modified for this group, since their risk profile is different than those with classic LFS. The researchers published their findings in Cancer Research, a journal of the American Association for Cancer Research.

illustration of a microscopic gene and the isolated protein with the mutation.

Mutations in the TP53 gene are the most commonly acquired mutations in cancer. The p53 protein, made by the TP53 gene, normally acts as the supervisor in the cell as the body tries to repair damaged DNA. Different mutations can determine how well or how poorly that supervisor is able to direct the response. The more defective the mutation, the greater the risk. When TP53 mutations are inherited, they cause LFS, a disease that leaves people with a 90 percent chance of developing cancer in their lifetime. There are currently no therapies that target the p53 pathway.

Researchers determined that there is an inherited set of genetic material shared among people who have this mutation, suggesting it’s what’s called a founder mutation—a mutation that tracks within one ethnicity. In this case, that ethnicity is the Ashkenazi Jewish population.

“Due to the wide variety of disease types associated with inherited TP53 mutations and the early age of cancer diagnoses, cancer screening is exceptionally aggressive. However, we do not yet know if all mutations require the same high level of screening,” says the study’s senior author Kara N. Maxwell, an assistant professor of hematology-oncology and Genetics in the Perelman School of Medicine and a member of the Abramson Cancer Center and the Basser Center for BRCA. “It is therefore critical to study the specifics of individual TP53 mutations so we can understand how best to screen people who carry lower risk mutations.”

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