Uncommon, Low Penetrance TP53 Mutation Linked to Certain Familial Cancers in Ashkenazi Jews

by Danielle Bradshaw from In The Cloud Copy

Research into the common but rare TP53 mutation – which can be found in many Ashkenazi Jewish people – revealed that it could increase the risk of many kinds of cancers. Further genetic analysis of the TP53 gene has revealed that some of those cancers are early-onset, while others have been found to develop much later in life.

The Reuters Health Interview with Dr. Kara Maxwell

Dr. Kara Maxwell, from the University of Pennsylvania, says that one such early-onset illness is classic Li-Fraumeni syndrome (LFS), which can be described as a “cancer syndrome” which essentially means that it makes it that much more likely for many kinds of cancers to develop in a patient’s childhood. Dr. Maxwell goes on to say that this is caused by fully non-functioning, mutated TP53 genes.

She mentions that the p53 protein has also been found to be half-functional as well and that this is what’s known as a hypomorphic mutation – meaning that it is only partially damaged. This half-working protein results in “low-risk LFS”; this is what happens when p53 sensitive tissues show early cancer development. Dr. Maxwell says that the adrenal gland is one such “sensitive tissue” and that the half-working p53 can also cause certain cancers to develop much later in other tissues. She does note, however, that cancer can develop due to other factors, as well.

The TP53 Study

When asked about the study that she and her team did on the TP53 gene, Dr. Kara Maxwell says that TP53 p.G334R is a hypomorphic mutation. The p53 still has its “classical” functions, but there are other functions that are broken. The team’s report in Cancer Research specifies that they’d sequenced multiple members from eight different families of cell lines. They then combined this data with that of carriers from two other genetic cohort tests.

Maxwell says that the mutation is shown to result in an unstable p53 that seems to gather inside of the cells and it’s mostly (though rarely) found in Ashkenazi Jewish people. There are families with people that have early-onset adrenal cancers. In these cases, however, patients are typically older if and when they develop cancers. These cancers were also mostly breast cancers.

Exome sequencing helped the team discover that TP53p.G334R was paired together among third-degree relatives in a family that had multiple LFS-component cancers that began to develop between the fourth and ninth decades and five other members of the family that had a plethora of primary malignancies.

A group of seven families that carried the mutation was able to be identified by clinical genetics practices. There was one family that had a separation of LFS-component cancers to third-degree familial relations. The majority of the patients had early-onset cancers (most of which were variations of breast cancer), but Dr. Maxwells states that there were six people from four other families that had pediatric adrenocortical tumors (ATCs) and one family that had ATCs in two of its siblings.

Altogether, eight people in four separate families had multiple primary tumors. Each proband (a member of the family first tested for the genetic disorder, illness, etc.) tested negative for mutated genes that would leave them likely to develop cancer.

Study Summary

Dr. Maxwell summarizes the study by saying that patients that come from families predisposed to developing cancer should consider being evaluated by a genetics provider to look over their family history and any previously performed testing to see if any new testing should be performed.

The doctor says that there are no extensively studied guidelines that can be used for proper screening of patients with this or any other kind of hypomorphic TP53 mutations. They start screening for classic LFS as babies and keep performing the procedure every year along with other types of screenings.

And Now, Someone Else

Dr. Margaret Hill, of Roswell Park’s Comprehensive Cancer Center in Buffalo, New York, also spoke to Reuters Health. She said that people that have a harmful TP53 mutation – regardless of what the mutation actually is – should abide by NCCN (National Comprehensive Cancer Network) guidelines for LFS. She says that following these guidelines should also take into account whatever the patient’s family’s history with cancer is.

Dr. Hill advises both clinicians and families identified as having the TP53 mutation to keep abreast of any changes in screening methods and policies.

Continue reading about this here.

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