Study Finds New Mutation in Ashkenazi Jews

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Maureen Murphy, far left, holding results in her lab | Courtesy of The Wistar Institute

A team led by researchers in the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania has published a study detailing the implications of a rare genetic mutation most commonly found in people of Ashkenazi Jewish descent.

This mutation occurs in the TP53 gene and makes carriers highly susceptible to different forms of cancer throughout their lives.

The study’s senior author is Kara Maxwell, assistant professor of genetics and medicine at Penn. The co-first authors are Jacquelyn Powers, a genetic counselor in the Basser Center, and Emilia Modolo Pinto, associate scientist at St. Jude Children’s Research Hospital. 


They published their findings July 16 in Cancer Research, a journal of the American Association for Cancer Research.

Initially, the study did not intentionally focus on Ashkenazi Jews. Maxwell wanted answers for patients who had extensive family histories of breast cancer but did not test positive for mutations in the BRCA1 or BRCA2 genes, the most common cause of hereditary breast cancer. 

“It’s not like they’re depressed they don’t have a mutation, but they want an answer to what’s going on in their family,” she said.

Maxwell and her team identified the TP53 mutation in patients and their family members, but more research was needed to understand the implication of the finding.

“Ultimately, what vexes us in clinical cancer genetics are findings known as variants of uncertain significance,” Powers said. “Is it a harmless difference or is it a mutation that impacts the function of the gene and leads to increased risk?”

Maureen Murphy, program leader of the Molecular & Cellular Oncogenesis Program of the Wistar Institute Cancer Center, studied the mutation’s consequences. 

The TP53 gene makes the p53 protein, which helps cells repair damaged DNA and kills cancerous cells. Mutations in the gene can reduce the protein’s ability to fight cancer.

“It is your cell’s best defense against cancer and also a protein absolutely necessary for chemotherapy to work,”  Murphy said. “People with a mutation can get cancer as early as age 2 and don’t respond to chemotherapy, and it’s devastating.” 

The mutation that Maxwell and her team identified does not guarantee that carriers will develop cancer, but it can cause Li-Fraumeni syndrome. The disorder leaves people with an extremely high chance of developing cancer in their lifetimes. Those commonly include soft tissue and bone sarcomas, breast and brain cancer, adrenocortical tumors and leukemia. LFS patients can develop these cancers in early childhood.

The TP53 mutation in this study causes a milder form of LFS, which gives patients a 40% chance of developing cancer rather than the 90% chance in classic LFS cases. It also makes patients less vulnerable to developing cancer in childhood but leaves them high risk later in life. 

As they identified more families across the country with the TP53 mutation, Maxwell and her colleagues noticed a pattern.

“We were struck by the fact that all these families were Jewish,” she said.

Researchers at St. Jude determined that there is an inherited set of genetic material shared among people with this mutation, suggesting it is a founder mutation — a mutation that tracks within one ethnicity. 

“This mutation was originated in a person a long time ago — the founder — and passed down to new generations,” Pinto said.

“Because it was found in individuals from Ashkenazi Jewish descent, the impact of this finding will be of interest for this community,” she explained.

The study’s findings raise questions about how to screen patients with mild LFS versus classic LFS and can be useful to oncologists and genetic counselors.

“Once you know where the mutation is it’s pretty easy to screen,” Murphy said. “People who are carriers then should get enhanced MRI screening basically every year to look for tumors as they develop. That’s what’s done now for people with LFS.”

Maxwell emphasized that the TP53 mutation is not as common as mutations in BRCA1 and BRCA2, which are found in one of 40 people of Ashkenazi Jewish descent.

“It does appear to be quite rare and found in less than one in 1,000 individuals,” she said. “That said, it’s important to add it to the group of genetic changes that we think about in highly cancer-prone families of [Ashkenazi] Jewish descent.”

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