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Rare TP53 Mutation Implicated in Familial Cancers in Ashkenazi Jews, but With Low Penetrance

Rare TP53 Mutation Implicated in Familial Cancers in Ashkenazi Jews, but With Low Penetrance

NEW YORK (Reuters Health) – A rare TP53 mutation common in Ashkenazi Jews confers risk of multiple cancers, but while some are early-onset, others may occur later, a genetic analysis reveals.

“Fully non-functional TP53 mutations cause classic Li Fraumeni Syndrome (LFS), a rare cancer syndrome that predisposes to childhood- and other early-onset adult cancers,” Dr. Kara Maxwell of the University of Pennsylvania in Philadelphia told Reuters Health by email. “However, the p53 protein can also be partially dysfunctional – a so-called hypomorphic mutation – where it catches some damage, but not all. This appears to lead to what we refer to as ‘low-risk LFS,’ where cancer development can be early in tissues that are very sensitive to dysfunctional p53, like the adrenal gland, or later in other tissues. Cancer development is also likely more influenced by other factors.”

“Our study shows that TP53 p.G334R is a hypomorphic mutation, where classic p53 functions remain intact, but other functions are still defective,” she said.

As reported in Cancer Research, the team sequenced cell lines from multiple members of eight families, then combined those data with data from carriers from two genetic testing cohorts.

“We show that the mutation causes a less stable p53 that appears to accumulate in the cells (and) that this p53 mutation is mostly found in Ashkenazi Jewish individuals, although it is very rare,” Dr. Maxwell said. “Families with the mutation have some patients with early-onset adrenal cancers, but most patients are older when and if cancer develops. Cancers were most predominantly breast cancers.”

Specifically, whole exome sequencing identified TP53p.G334R in a pair of third-degree relatives from a family with multiple LFS-component cancers mostly occurring in the fourth to ninth decades, as well as five family members with multiple primary malignancies.

Seven other families with the mutation were identified from clinical genetics practices. One family showed segregation of LFS-component cancers to third-degree relatives. While most affected individuals had adult-onset cancers – mainly breast cancers, as Dr. Maxwell indicated – six individuals from four families had pediatric adrenocortical tumors (ACTs), including one family with pediatric ACTs in a sibling pair.

In total, eight individuals from four families had multiple primary tumors. All probands were negative for other cancer predisposition gene mutations when tested.

“We feel that patients from families with cancer benefit from evaluation with a genetics provider to review their cancer family history and prior genetic testing and determine if updated testing is warranted,” Dr. Maxwell said. “Genetics changes frequently and patients from cancer-prone families will likely benefit from re-evaluation in the future as well.”

“In patients found to carry this and other hypomorphic TP53 mutations, we currently do not have well-studied guidelines for cancer screening,” she added. “Patients with classic LFS begin full body screening as infants, and continue this yearly along with a variety of other screenings and the potential for prophylactic surgeries.”

Dr. Margaret Hill, a genetics counselor at Roswell Park Comprehensive Cancer Center in Buffalo, New York, commented in an email to Reuters Health, “For individuals with a deleterious TP53 mutation, usually regardless of what the exact mutation is, recommendations are to follow the current NCCN screening guidelines for LFS, with consideration of an individual’s family history of cancer. While this variant could warrant unique screening recommendations related to its potentially lower penetrance cancer risks in the future, there is currently limited data to support such at this time.”

“Clinicians should continue to be aware that our understanding of genetic variants, as well as screening and medical management guidelines related to such, changes over time,” she said. “We always encourage clinicians and identified families who have a genetic variant to stay up to date with the information available.”

SOURCE: Cancer Research, online July 16, 2020.

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