Identification and functional characterization of new missense SNPs in the coding region of the TP53 gene

Abstract

Infrequent and rare genetic variants in the human population vastly outnumber common ones. Although they may contribute significantly to the genetic basis of a disease, these seldom-encountered variants may also be miss-identified as pathogenic if no correct references are available. Somatic and germline TP53 variants are associated with multiple neoplastic diseases, and thus have come to serve as a paradigm for genetic analyses in this setting. We searched 14 independent, globally distributed datasets and recovered TP53 SNPs from 202,767 cancer-free individuals. In our analyses, 19 new missense TP53 SNPs, including five novel variants specific to the Asian population, were recurrently identified in multiple datasets. Using a combination of in silico, functional, structural, and genetic approaches, we showed that none of these variants displayed loss of function compared to the normal TP53 gene. In addition, classification using ACMG criteria suggested that they are all benign. Considered together, our data reveal that the TP53 coding region shows far more polymorphism than previously thought and present high ethnic diversity. They furthermore underline the importance of correctly assessing novel variants in all variant-calling pipelines associated with genetic diagnoses for cancer.

Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman–Diamond Syndrome Subjects

“…Our results show that the p53 content in SDS-OBs was significantly higher (p < 0.05) compared to that in H-OBs (Figure 5b). This increase could not be ascribed to activating mutations of the Tp53 gene, as the sequencing of the coding region of Tp53 performed on RNA from SDS-OBs (n = 11) and H-OBs (n = 4) only showed the presence of the missense SNP rs1042522 in all the subjects, which occurs in the worldwide population [33]. To find the possible link between p53 and collagen and ALP, we treated SDS-OBs with a small interference RNA (siRNA, 5nM) targeting Tp53.…”

Three optimized assays for the evaluation of compounds that can rescue p53 mutants

“…Over ten assays for the determination of p53 activity at different levels have been used to evaluate compounds that can rescue p53 mutants. These include the differential scanning fluorimetry (DSF) assay ( Zhang et al., 2018 ), PAb1620 immunoprecipitation (IP) assay ( Xirodimas and Lane, 1999 ), luciferase reporter assay ( Doffe et al., 2020 ), PAb1620 ELISA assay, PAb1620 immunostaining assay, electrophoretic mobility-shift assay, biotin-DNA pull-down assay for assessing DNA-binding ability, various p53 target expression assays, etc. Some assays such as PAb1620 immunostaining assay are not highly sensitive in our hands, presumably due to the challenge in maintaining structural PAb1620 epitope during paraformaldehyde fixation.…”

Frequencies of TP53 Germline Variations and Identification of Two Novel 3’UTR Variants in a Series of Head and Neck Cancer Cases

“…An earlier study found that Arg/Arg homozygotes induce apoptosis more efficiently as compared to Pro/Pro homozygotes through the arrest of cell cycle in G1 phase (Pim and Banks, 2004), however, this observation is not supported by a recent study where wild-type p53 was indistinguishable from the variant forms in its apoptotic function (Doffe et al, 2021).…”

“…It presents in the PRD of p53. This domain regulates apoptosis and growth suppression of cell (Doffe et al, 2021;Almutairi et al, 2021). The SNP results in the missense substitution of proline (Pro) by arginine (Arg) (dbSNP, 2021).…”

“…It presents in the PRD of p53. This domain regulates apoptosis and growth suppression of cell (Doffe et al, 2021;Almutairi et al, 2021). The SNP results in the missense substitution of proline (Pro) by arginine (Arg) (dbSNP, 2021).An earlier study found that Arg/Arg homozygotes induce apoptosis more efficiently as compared to Pro/Pro homozygotes through the arrest of cell cycle in G1 phase (Pim and Banks, 2004), however, this observation is not supported by a recent study where wild-type p53 was indistinguishable from the variant forms in its apoptotic function (Doffe et al, 2021).…”