Rare TP53 Mutation Confers Risk of Several Cancers in Ashkenazi Jewish Population | OncLive

Rare TP53 Mutation Confers Risk of Several Cancers in Ashkenazi Jewish Population

July 28, 2020

A lower-risk TP53 mutation has been linked with a specific kind of Li Fraumeni Syndrome which predisposes individuals to a wide range of cancers, and this newly described variant of p53 is most commonly found in the Ashkenazi Jewish population.

A lower-risk TP53 mutation has been linked with a specific kind of Li Fraumeni Syndrome (LFS) which predisposes individuals to a wide range of cancers, and this newly described variant of p53 is most commonly found in the Ashkenazi Jewish (AJ) population, according to results from a study recently published in Cancer Research.1

“We identified a rare TP53 tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers,” the authors wrote. “Twenty additional c.1000G>C probands and one c.1000G>A probrand were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited Chromosome 17p13.1 haplotype.”

Mutations in the TP53 are the most commonly acquired mutations in cancer; when these mutations are inherited, they can lead to LFS, which is a syndrome that puts individuals at a 90% likelihood of developing cancers, such as soft tissue and bone sarcomas, breast and brain cancers, adrenocortical tumors, and leukemia, at some point in their lifetime.2

In the study, investigators performed whole exome sequencing on several members of 8 different families. Results revealed TP53 c.1000G>C;p.G334R in a pair of third-degree relatives of a family with several LFS-component cancers which were mostly identified in the fourth to ninth decades, in addition to 5 family members with several primary malignancies.

Seven additional independent families with c.1000G>C were discovered via clinical genetics practices, according to the study authors. One such family demonstrated segregation of LFS-component cancers to third-degree relatives. Although the majority of affected individuals were found to have adult-onset cancers, 6 individuals from 4 different families were noted to have adrenocortical tumors (ACTs). A total of 8 individuals from 4 families were found to have multiple primary tumors.

Two genetic testing laboratory cohorts and literature review identified 13 additional TP53 c.1000G>C;p.G334R carriers. Among 309,922 patients undergoing testing at Ambry Genetics Laboratories, 8 probands were identified; 3 probands were identified among 21,729 patients who underwent tumor genomic profiling at Memorial Sloan Kettering Cancer Center. A total of 3 probands were found to be unaffected although they came from multicancer families. Eleven probands were found to have several tumor types in the fifth to eighth decades; 2 of these had multiple primary tumors.

For 16 probands with TP53 c.1000G>C, p.G334R, ancestry data were available. Results showed that all 8 families in the clinical cohort and 7 of 8 families from the 2 genetic testing cohorts, had AJ ancestry. “The mutation was found at an approximately ten-fold enrichment in AJ versus non-AJ individuals in both genetic testing cohorts (0.023% AJ vs 0.001% of Caucasian non-AJ and 0.07% AJ vs 0.005% of non-AJ,” the study authors wrote. Additional analyses revealed that 9 individuals from 4 families all had the chromosome 17p13.1 haplotype.

When combining all the data collected, investigators found that the newly identified mutation presents a risk of childhood cancer in certain families, but later onset cancers in other families, with a lifetime risk lower than 90%, according to the press release. After investigators from St. Jude Children’s Research Hospital modeled the TP53 mutation to determine its impact on the protein’s structure, investigators revealed an “inherited set of genetic material” that was present in all individuals harboring the mutation. These finding suggested that the newly discovered mutation was predominantly observed in 1 ethnicity: the AJ population.

Subsequently, an investigational team from The Wistar Institute found that the mutation impacted the p53 protein in cells and affected the expression of p53 target genes, suggesting that the mutation may be a key player in transformation and cancer formation. As no therapies targeting the p53 pathway are currently available, investigators are currently examining how this condition might be targeted and treated.

“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,” Kara N. Maxwell, MD, PhD, a senior researcher on the study, an assistant professor of Hematology-Oncology and Genetics in the Perelman School of Medicine at the University of Pennsylvania, and a member of the Abramson Cancer Center and the Basser Center for BRCA, stated in a press release. “However, we do not yet know if all mutations require the same high level of screening. 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.”

As this population of patients seem to have a different risk profile compared with patients with classic LFS, investigators have begun to question whether the standard approach utilizing full-body scans should be modified. To this end, investigators are developing liquid biopsy techniques that may help to improve detection within this patient population.

“By identifying and understanding this Ashkenazi variant of p53, our goal is to help people who have genetic variants of this critical gene to better understand their cancer risk, and eventually to assist the development of new specific treatments that will reduce the burden of cancer on this population,” Maureen E. Murphy, PhD, Ira Brind professor and program leader of the Molecular and Cellular Oncogenesis Program of the Wistar Cancer Center stated in the press release.

References

  1. Powers J, Pinto EM, Barnoud T, et al. A rare TP53 mutation predominant in Ashkenazi Jews confers risk of multiple cancers. Cancer Res. Published online July 16, 2020. doi:10.1158/0008-5472.CAN-20-1390
  2. Rare mutation of TP53 gene leaves people at higher risk for multiple cancers. News release. Penn Medicine. July 16, 2020. Accessed July 28, 2020. https://bit.ly/30V7IAX.

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