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A personalized therapeutic approach for cancer containing the African-centric P47S variant of TP53

ABSTRACT: We performed RNA-sequencing comparing WT and P47S HepG2 tumor cells (P47S clone is 5B4). We previously performed a drug screen in WT and P47S HepG2, and we found that Lexibulin (an anti-mitotic compound) preferentially decreases cell viability in the P47S mutant compared to WT. Our preliminary data show that Lexibulin induces p53 target gene expression but no apparent differences in cell death between WT and P47S HepG2. We performed RNA-seq to capture the whole transcriptional profile, comparing our vehicle controls to Lexibulin-treated cells, and comparing Lexibulin-treated WT to Lexibulin-treated P47S cells to identify key genes that contribute to preferential targeting of P47S HepG2 in an unbiased manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311354 | GEO | 2026/03/10

REPOSITORIES: GEO

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Tailoring Chemotherapy for the African-Centric S47 Variant of TP53.

Project description:The tumor suppressor TP53 is the most frequently mutated gene in human cancer and serves to restrict tumor initiation and progression. Single-nucleotide polymorphisms (SNP) in TP53 and p53 pathway genes can have a marked impact on p53 tumor suppressor function, and some have been associated with increased cancer risk and impaired response to therapy. Approximately 6% of Africans and 1% of African Americans express a p53 allele with a serine instead of proline at position 47 (Pro47Ser). This SNP impairs p53-mediated apoptosis in response to radiation and genotoxic agents and is associated with increased cancer risk in humans and in a mouse model. In this study, we compared the ability of wild-type (WT) and S47 p53 to suppress tumor development and respond to therapy. Our goal was to find therapeutic compounds that are more, not less, efficacious in S47 tumors. We identified the superior efficacy of two agents, cisplatin and BET inhibitors, on S47 tumors compared with WT. Cisplatin caused dramatic decreases in the progression of S47 tumors by activating the p53/PIN1 axis to drive the mitochondrial cell death program. These findings serve as important proof of principle that chemotherapy can be tailored to p53 genotype.Significance: A rare African-derived radioresistant p53 SNP provides proof of principle that chemotherapy can be tailored to TP53 genotype. Cancer Res; 78(19); 5694-705. ©2018 AACR.

| S-EPMC6168343 | biostudies-literature

Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53.

Project description:Subtelomeric transcription and chromatin can have a significant impact on telomere repeat maintenance and chromosome stability. We have previously found that tumor suppressor protein p53 (TP53) can bind to retrotransposon-like elements in a majority of human subtelomeres to regulate TERRA transcription and telomeric histone acetylation in response to DNA damage. TP53 also prevents the accumulation of γH2AX DNA-damage signaling at telomeres. We now show that the inherited TP53 polymorphism Pro47Ser (hereafter S47), which is enriched in populations of African descent, is associated with elevated marks of telomere dysfunction. We found that human and mouse cells carrying the S47 variant show increased γH2AX DNA-damage signals at telomeres, as well as reduced TERRA transcription and subtelomeric histone acetylation in response to DNA damage stress. Cell-lines containing inducible genes for P47 or S47 versions of p53, as well mouse embryo fibroblasts (MEFs) reconstituted with human p53, showed elevated telomere-induced DNA damage foci and metaphase telomere signal loss in cells with S47. Human lymphoblastoid cell lines (LCLs) derived from individuals homozygous for S47, show increased accumulation of subtelomeric γH2AX and unstable telomere repeats in response to DNA damage relative to age matched LCLs homozygous for P47. Furthermore, LCLs with S47 had reduced replicative lifespan. These studies indicate that the naturally occurring S47 variant of p53 can affect telomeric chromatin, telomere repeat stability, and replicative capacity. We discuss the potential evolutionary significance of the S47 variant to African populations with respect to telomere regulation and the implications for inherited health disparities.

| S-EPMC6557208 | biostudies-literature

A personalized therapeutic approach for cancer containing the African-centric P47S variant of TP53

Project description:A personalized therapeutic approach for cancer containing the African-centric P47S variant of TP53

| PRJNA1369191 | ENA

African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin.

Project description:A variant at amino acid 47 in human TP53 exists predominantly in individuals of African descent. P47S human and mouse cells show increased cancer risk due to defective ferroptosis. Here, we show that this ferroptotic defect causes iron accumulation in P47S macrophages. This high iron content alters macrophage cytokine profiles, leads to higher arginase level and activity, and decreased nitric oxide synthase activity. This leads to more productive intracellular bacterial infections but is protective against malarial toxin hemozoin. Proteomics of macrophages reveal decreased liver X receptor (LXR) activation, inflammation and antibacterial defense in P47S macrophages. Both iron chelators and LXR agonists improve the response of P47S mice to bacterial infection. African Americans with elevated saturated transferrin and serum ferritin show higher prevalence of the P47S variant (OR = 1.68 (95%CI 1.07-2.65) p = 0.023), suggestive of its role in iron accumulation in humans. This altered macrophage phenotype may confer an advantage in malaria-endemic sub-Saharan Africa.

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Tumor cells containing the African-Centric S47 variant of <i>TP53</i> show increased Warburg metabolism.

Project description:Mutations in the TP53 tumor suppressor gene remain a hallmark of human cancer. In addition to mutation of TP53, single nucleotide polymorphisms (SNPs) in this gene can have a profound impact on p53 function, and can affect cancer risk as well as other p53 functions. Wild type (WT) p53 contains a proline at amino acid 47, but approximately 1% of African-Americans express a p53 allele with a serine at amino acid 47 (Pro47Ser, hereafter S47). In a mouse model for this variant, mice expressing S47 are predisposed to spontaneous cancers. The S47 variant also is associated with increased pre-menopausal breast cancer risk in African American women. We recently reported that S47 tumor cells are resistant to the majority of cytotoxic chemotherapeutic agents, but show increased sensitivity to a subset of anti-cancer agents, compared to tumors with WT p53. In this work, we report on another potentially promising therapeutic vulnerability of S47 tumors. We find that S47 tumors show decreased mitochondrial metabolism, along with increased dependency on glycolysis. S47 tumor cells also show increased sensitivity to the glycolytic poison 2-deoxy-glucose. We propose that the altered metabolism in S47 tumor cells may be yet another potentially-actionable therapeutic vulnerability to exploit in cancer-prone individuals with this genotype.

| S-EPMC6383823 | biostudies-literature

The African-centric P47S Variant of <i>TP53</i> Confers Immune Dysregulation and Impaired Response to Immune Checkpoint Inhibition.

Project description:The tumor suppressor TP53 is the most frequently mutated gene in cancer and is mutationally inactivated in 50% of sporadic tumors. Inactivating mutations in TP53 also occur in Li Fraumeni syndrome (LFS). In addition to germline mutations in TP53 in LFS that completely inactivate this protein, there are many more germline mutant forms of TP53 in human populations that partially inactivate this protein: we call these partially inactivating mutations "hypomorphs." One of these hypomorphs is a SNP that exists in 6%-10% of Africans and 1%-2% of African Americans, which changes proline at amino acid 47 to serine (Pro47Ser; P47S). We previously showed that the P47S variant of p53 is intrinsically impaired for tumor suppressor function, and that this SNP is associated with increased cancer risk in mice and humans. Here we show that this SNP also influences the tumor microenvironment, and the immune microenvironment profile in P47S mice is more protumorigenic. At basal levels, P47S mice show impaired memory T-cell formation and function, along with increased anti-inflammatory (so-called "M2") macrophages. We show that in tumor-bearing P47S mice, there is an increase in immunosuppressive myeloid-derived suppressor cells and decreased numbers of activated dendritic cells, macrophages, and B cells, along with evidence for increased T-cell exhaustion in the tumor microenvironment. Finally, we show that P47S mice demonstrate an incomplete response to anti-PD-L1 therapy. Our combined data suggest that the African-centric P47S variant leads to both intrinsic and extrinsic defects in tumor suppression.SignificanceFindings presented here show that the P47S variant of TP53 influences the immune microenvironment, and the immune response to cancer. This is the first time that a naturally occurring genetic variant of TP53 has been shown to negatively impact the immune microenvironment and the response to immunotherapy.

| S-EPMC10335007 | biostudies-literature

Human HepG2 cells: control DMSO vs. K7174-treated

Project description:Transcriptional profiling of human HepG2 cells comparing control DMSO-treated cells with K7174-treated cell Two-condition experiment, DMSO-HepG2 vs. K7174-HepG2 cells. Biological replicates: 1 control, 1 treated, independently grown and harvested. One replicate per array.

2014-08-01 | E-GEOD-48618 | biostudies-arrayexpress

Next Generation Sequencing Analysis of control and DEHP exposure HepG2 cell Transcriptomes

Project description:we treated the HepG2 cells with low concentration or control solvent for a long time. Then we extracted the RNAs and performed the next generation sequencing. By comparing sequcing data from control and DEHP treated samples, we profiled the gene expression regulated by low concentration exposure.

2016-08-30 | GSE83321 | GEO

Human HepG2 cells: control DMSO vs. K7174-treated

Project description:Transcriptional profiling of human HepG2 cells comparing control DMSO-treated cells with K7174-treated cell

2014-08-01 | GSE48618 | GEO

Neither the African-Centric S47 Nor P72 Variant of TP53 Is Associated With Reduced Risk of Febrile Malaria in a Malian Cohort Study.

Project description:BackgroundTP53 has been shown to play a role in inflammatory processes, including malaria. We previously found that p53 attenuates parasite-induced inflammation and predicts clinical protection to Plasmodium falciparum infection in Malian children. Here, we investigated whether p53 codon 47 and 72 polymorphisms are associated with differential risk of P. falciparum infection and uncomplicated malaria in a prospective cohort study of malaria immunity.Methodsp53 codon 47 and 72 polymorphisms were determined by sequencing TP53 exon 4 in 631 Malian children and adults enrolled in the Kalifabougou cohort study. The effects of these polymorphisms on the prospective risk of febrile malaria, incident parasitemia, and time to fever after incident parasitemia over 6 months of intense malaria transmission were assessed using Cox proportional hazards models.ResultsConfounders of malaria risk, including age and hemoglobin S or C, were similar between individuals with or without p53 S47 and R72 polymorphisms. Relative to their respective common variants, neither S47 nor R72 was associated with differences in prospective risk of febrile malaria, incident parasitemia, or febrile malaria after parasitemia.ConclusionsThese findings indicate that p53 codon 47 and 72 polymorphisms are not associated with protection against incident P. falciparum parasitemia or uncomplicated febrile malaria.

| S-EPMC10345479 | biostudies-literature

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