Computational molecular modeling of p53-G334R substitution was performed by a team at St. Jude’s Children’s Hospital, and results indicated decreased thermal stability of the G334R tetramer relative to wild-type p53.2 Efficient tetrameter formation in wild-type p53 is essential in normal promoter binding and transcriptional activation in nonpathogenic p53. A team at the Wistar Cancer Center further validated the impact of the G334R substitution on gene expression and cellular function by performing in-vitro assays with DNA-damaging agents such as cisplatin on immortalized lymphoblastoid cell lines from family members carrying the G334R mutation, followed by RNA-sequencing to compare the effects of G334R p53 on target gene expression.
The transcriptomic analysis indicated significantly impaired gene expression induction of p53 target genes such as PCLO, PLTP, PLXNB3 and LCN15 relative to wild-type p53 lymphoblastoid cell lines.2
“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,” said Maureen E. Murphy, PhD, program leader of the Molecular & Cellular Oncogenesis Program of the Wistar Cancer Center, in a press release.5
Given the authors’ comprehensive analysis and validation of the rare TP53 G334R variant, the work of the multidisciplinary teams has the potential to benefit all family members of carriers of the rare variant, and increases the overall understanding of one of the most important genes in mammalian DNA repair and cancer cell biology. In conclusion, the researchers wrote that “TP53 c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish–predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.”2
- Leroy B, Ballinger ML, Baran-Marszak F, et al. Recommended guidelines for validation, quality control, and reporting of TP53 variants in clinical practice. Cancer Res. 2017;77(6):1250-1260. doi:10.1158/0008-5472.CAN-16-2179
- Powers J, Pinto EM, Barnoud T, et al. A rare TP53 mutation predominant in Ashkenazi Jews confers risk of multiple cancers. Cancer Res. 2020;80(17):3732-3744. doi:10.1158/0008-5472.CAN-20-1390
- Achatz MI, Zambetti GP. The inherited p53 mutation in the Brazilian population. Cold Spring Harb Perspect Med. 2016;6(12):a026195. doi:10.1101/cshperspect.a026195
- Maxwell KN, Wubbenhorst B, D’Andrea K, et al. Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. 2015;17(8):630-638. doi:10.1038/gim.2014.176
- University of Pennsylvania School of Medicine. Rare mutation of TP53 gene leaves people at higher risk for multiple cancers: Newly-described mutation is most common in Ashkenazi Jewish population [press release]. Published July 16, 2020. Accessed August 20, 2020.