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PubMed2005

High Mobility Group A1 (HMGA1) proteins interact with p53 and inhibit its apoptotic activity.

HMGA gene overexpression and rearrangements are frequent in several tumours, but their oncogenic function is still unclear. Here we report of a physical and functional interaction between High Mobility Group A1 (HMGA1) protein and p53 oncosuppressor. We found that HMGA1 binds p53 in vitro and in vivo, and both proteins are present in the same complexes bound to the Bax gene promoter. HMGA1 interferes with the p53-mediated transcription of p53 effectors Bax and p21(waf1) while cooperates with p53 in the transcriptional activation of the p53 inhibitor mdm2. This transcriptional modulation is associated with a reduced p53-dependent apoptosis in cells expressing exogenous HMGA1 and p53, or in cells expressing endogenously the proteins and in which p53 was activated by UV-irradiation. Furthermore, antisense inhibition of HMGA1b expression dramatically increases the UV-induced p53-mediated apoptosis. These data define a new physical and functional interaction between HMGA1 and p53 that modulates transcription of p53 target genes and inhibits apoptosis.

Apoptosis↗

PubMed2025

Genome-wide screening in human embryonic stem cells identifies genes and pathways involved in the p53 pathway.

BACKGROUND: The tumor suppressor protein, p53, which is mutated in half of human tumors, plays a critical role in cellular responses to DNA damage and maintenance of genome stability. Therefore, increasing our understanding of the p53 pathway is essential for improving cancer treatment and diagnosis. METHODS: This study, which aimed to identify genes and pathways that mediate resistance to p53 upregulation, used genome-wide CRISPR-Cas9 loss-of-function screening done with Nutlin-3a, which inhibits p53-MDM2 interaction, resulting in p53 accumulation and apoptotic cell death. We used bioinformatics analysis for the identification of genes and pathways that are involved in the p53 pathway and cell survival assays to validate specific genes. In addition, we used RNA-seq to identify differentially expressed p53 target genes in gene knockout (KO) cell lines. RESULTS: Our screen revealed three significantly enriched pathways: The heparan sulfate glycosaminoglycan biosynthesis, diphthamide biosynthesis and Hippo pathway. Notably, TRIP12 was significantly enriched in our screen. We found that TRIP12 is required for the p53-dependent transcription of several pro-apoptotic genes. CONCLUSION: Our study has identified two novel pathways that play a role in p53-mediated growth restriction. Moreover, we have highlighted the interaction between the Hippo and the p53 pathways. Interestingly, we have shown that TRIP12 plays an important function in the p53 pathway by selectively affecting its role as a transcription factor.

Humans↗

PubMed2025

Integrative multiomic approaches reveal ZMAT3 and p21 as conserved hubs in the p53 tumor suppression network.

TP53, the most frequently mutated gene in human cancer, encodes a transcriptional activator that induces myriad downstream target genes. Despite the importance of p53 in tumor suppression, the specific p53 target genes important for tumor suppression remain unclear. Recent studies have identified the p53-inducible gene Zmat3 as a critical effector of tumor suppression, but many questions remain regarding its p53-dependence, activity across contexts, and mechanism of tumor suppression alone and in cooperation with other p53-inducible genes. To address these questions, we used Tuba-seqUltra somatic genome editing and tumor barcoding in a mouse lung adenocarcinoma model, combinatorial in vivo CRISPR/Cas9 screens, meta-analyses of gene expression and Cancer Dependency Map data, and integrative RNA-sequencing and shotgun proteomic analyses. We established Zmat3 as a core component of p53-mediated tumor suppression and identified Cdkn1a as the most potent cooperating p53-induced gene in tumor suppression. We discovered that ZMAT3/CDKN1A serve as near-universal effectors of p53-mediated tumor suppression that regulate cell division, migration, and extracellular matrix organization. Accordingly, combined Zmat3-Cdkn1a inactivation dramatically enhanced cell proliferation and migration compared to controls, akin to p53 inactivation. Together, our findings place ZMAT3 and CDKN1A as hubs of a p53-induced gene program that opposes tumorigenesis across various cellular and genetic contexts.

Animals↗

PubMed2025

USP2 reversed cisplatin resistance through p53-mediated ferroptosis in NSCLC.

BACKGROUND: It has demonstrated the indispensable role of ferroptosis in conferring cisplatin resistance in non-small cell lung cancer (NSCLC), as well as the involvement of ubiquitin-specific protease (USP) in regulating ferroptosis. This paper aspired to the mechanism of USP2 and ferroptosis on NSCLC cisplatin resistance. METHODS: Ubiquitin-specific protease mRNA expression, was detected through RT-qPCR. In vitro functional assays assessed the effects of USP2 overexpression on DDP resistance, cell proliferation capability, and ferroptosis markers in A549/DDP and H1299/DDP cells. Ubiquitination assays evaluated the ubiquitination levels of p53 following USP2 overexpression. Co-immunoprecipitation (Co-IP) assays confirmed the binding relationship between USP2 and p53. In vivo experiments in mice explored the specific role of the USP2-p53 axis in a xenograft tumor model. RESULTS: USP2 expression was suppressed in cisplatin-resistant NSCLC cells. USP2 overexpression inhibited cell viability in cisplatin-resistant cells. Among the ferroptosis markers, the results showed that USP2 overexpression promoted LDH release, Fe2+ level, MDA and Lipid ROS, while inhibited GPX4 activity and GSH levels. The WB results revealed that USP2 overexpression inhibited GPX4, SLC7A11 and cytoplasm p53 protein expression, while promoted the nucleus p53 protein expression. Moreover, USP2 directly bound to p53 and USP2 overexpression stabilized p53 protein by suppressing its ubiquitination. In vivo experiments further suggest that the USP2-p53 pathway plays a crucial role in regulating cisplatin sensitivity in A549/DDP cells. CONCLUSION: USP2 acted on the K305R site of p53, which resulted in its deubiquitination. This cellular process could modulate cisplatin resistance through ferroptosis in NSCLC. This study could provide a potential therapeutic target to NSCLC.

Ferroptosis↗

PubMed2026

Association of HPV16 infection with p53 and survivin expression in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity and a major public health concern worldwide. This study aimed to investigate the relationship between p53 and survivin expression, clinicopathologic parameters and HPV16 infection in OSCC in order to elucidate the potential role of HPV16 in its pathogenesis.The study enrolled 45 patients who underwent surgical treatment for histologically confirmed OSCC. Tumor specimens were formalin-fixed and paraffin-embedded (FFPE) and histologically analyzed using hematoxylin/eosin staining. Immunohistochemistry for p53 and survivin was performed using the DAKO system. DNA extracted from FFPE tumor tissues was analyzed for HPV16 genome presence using polymerase chain reaction (PCR). All patients were followed for three years after primary treatment.No statistically significant associations were observed between p53 or survivin expression and clinicopathologic parameters including age, gender, tumor site, grade, stage, recurrence, metastasis or HPV16 status (P > 0.05). Among HPV16-positive patients (11/45, 24.4%), low survivin expression (<5%) was found in 8/11 (73%) patients, while high p53 expression (>10%) was observed in 7/11 (64%) patients. Disease-free interval did not differ significantly between patients with low vs. high p53 (P = 0.220) or survivin expression (P = 0.580). A significant correlation was detected between p53 and survivin expression (P = 0.04). HPV16 positivity was significantly associated with the absence of p53 immunoreactivity.These findings suggest that HPV16-independent oncogenic pathways are likely predominant in OSCC, while HPV16 infection may be associated with a distinct molecular subset characterized by absent p53 expression (p53-; survivin+/-; HPV16+). These results underscore the biological heterogeneity of OSCC and may have implications for future biomarker-based stratification of patients.

HPV16↗

PubMed2025

p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.

Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker γH2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of γH2A.X + CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.

Animals↗

PubMed2026

Hypertranscription caused by p53 deficiency triggers nucleotide insufficiency that induces replication stress and genomic instability.

p53 plays a central role in the DNA damage response, inducing repair, cell-cycle arrest or apoptosis. Its loss is associated with replication stress and genomic instability. While several underlying mechanisms were suggested, the primary triggers of catastrophic genomic events like chromothripsis, a known driver of tumorigenesis linked with p53 loss, are still unclear. Using p53-depleted epithelial cells and fibroblasts, as well as patient-derived fibroblasts with germline p53 variants that spontaneously undergo chromothripsis, we found that p53 loss causes hypertranscription and increased nucleotide consumption. The resulting nucleotide shortage induces replication stress, causing telomere dysfunction, micronuclei formation, and chromothripsis. These effects were rescued by nucleoside supplementation or normalization of transcription levels, demonstrating a causal link between transcriptional activity, nucleotide availability, and genome stability. Emerging chromothriptic clones displayed restored DNA replication, telomere stabilization, and extrachromosomal DNA, suggesting key features that support clonal selection. We identify nucleotide pool homeostasis as a critical p53 function that suppresses replication stress, prevents chromothripsis, and protects against early tumorigenesis.

Genomic Instability↗

PubMed2026

Loss of BOK increases vulnerability of p53 deficient non-small cell lung cancer cells to ATR inhibition through its role in uridine metabolism.

BOK is a pro-apoptotic member of the BCL-2 family frequently repressed in cancer and with emerging roles beyond apoptosis. BOK interacts with and increases uridine monophosphate synthetase (UMPS) activity, thereby promoting uridine monophosphate (UMP) synthesis. We previously showed that BOK protein is downregulated in primary human lung cancer samples, correlating with poorer patient survival. Here, we demonstrate that BOK deficiency increases DNA damage, triggering p53 activation and cell cycle arrest in two independent non-small cell lung cancer (NSCLC) cell models that express either WT or defective p53. In a p53-deficient setting, BOK loss caused elevated baseline DNA damage rendering cells more dependent on alternative DNA repair pathways. We exploited this vulnerability by inhibiting the ATR-mediated DNA damage response pathway with the selective ATR inhibitor ceralasertib (AZD6738). ATR inhibition in BOK/p53 compound-deficient NSCLC cells exacerbated DNA damage and induced cell death, indicating a synthetic lethal interaction. The DNA damage in BOK-deficient cells was rescued by a cell permeable BOK-BH3-derived peptide, confirming the mechanistic link between BOK and UMPS. Taken together, our findings reveal a vulnerability in NSCLC, where combined loss of p53 and BOK sensitises cells to ATR inhibition. This synthetic interaction suggests that p53-deficient tumours with reduced BOK expression may be more reliant on ATR-mediated DNA repair, providing a mechanistic basis for their susceptibility to ATR inhibitors. Given the frequent inactivation of p53 in lung cancer, our study offers a rationale for clinical exploration of ATR inhibitors, in combination with standard chemotherapy, in the context of reduced BOK function. Future investigations into the broader role of BOK in genomic stability and nucleotide metabolism may uncover additional therapeutic strategies for cancers with repressed BOK.

Humans↗

PubMed2025

p53 Regulates Nuclear Architecture to Reduce Carcinogen Sensitivity and Mutagenic Potential.

The p53 tumor suppressor is an indispensable regulator of DNA damage responses that accelerates carcinogenesis when mutated. In this report, we uncover a new mechanism by which p53 maintains genomic integrity in the absence of canonical DNA damage response activation. Specifically, loss of p53 dramatically alters chromatin structure at the nuclear periphery, allowing increased transmission of an environmental carcinogen, ultraviolet (UV) radiation, into the nucleus. Genome-wide mapping of UV-induced DNA lesions in p53-deficient primary cells reveals elevated lesion abundance in regions corresponding to locations of high mutation burden in malignant melanomas. These findings uncover a novel role of p53 in the suppression of mutations that contribute to cancer and highlight the critical influence of nuclear architecture in regulating sensitivity to carcinogens.

Journal Article↗

PubMed2025

CCT8 drives colorectal cancer progression via the RPL4-MDM2-p53 axis and immune modulation.

PURPOSE: Colorectal cancer (CRC) ranks high in global mortality, emphasizing the need for effective interventions. The aim of the research is to elucidate the oncogenic role of CCT8 in CRC and its interaction with RPL4 in the RPL4-MDM2-p53 axis. METHODS: TIMER 2.0, TCGA, and GTEx databases were used to analyze CCT8 expression patterns in CRC. Immunohistochemistry was performed to examine CCT8 distribution in CRC tissues and adjacent non-tumor tissues. Functional assays, including CCK-8, transwell, wound-healing, and flow cytometry, were conducted using DLD-1 and HCT116 cell lines to assess the effects of CCT8 on cell proliferation, migration, invasion, and apoptosis. Gene set enrichment analysis, protein-protein interaction network analysis, and co-immunoprecipitation were performed to explore the interaction between CCT8 and RPL4 and their role in the RPL4-MDM2-p53 pathway. Additionally, gene set variation analysis was applied to investigate the relationship between CCT8/RPL4 expression and immune infiltration patterns in CRC. RESULTS: CCT8 was significantly upregulated in CRC and associated with tumor progression. Mechanistically, CCT8 potentially synergizes with RPL4 concluded from their positive correlation and similar immune infiltration patterns, influencing the RPL4-MDM2-p53 axis and contributing to p53 ubiquitination and degradation. CONCLUSION: These findings underscore the oncogenic significance of CCT8 in CRC and shed light on its molecular mechanisms, paving the way for potential therapeutic applications.

Humans↗

PubMed2025

Divergent PTEN-p53 interaction upon DNA damage in a human thyroid organoid model with germline PTEN mutations.

Germline mutations in the tumor suppressor phosphatase and tensin homolog (PTEN) cause PTEN hamartoma tumor syndrome (PHTS). PHTS is characterized by an elevated lifetime risk of differentiated thyroid cancer (DTC), 30 times higher than the general population. However, only 1 in 3 PHTS patients develop DTC, and it remains unknown whether specific PTEN variants are associated with an increased risk of DTC. PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway, a frequently affected pathway in sporadic DTC. PTEN also acts as a guardian of the genome by interacting with other tumor suppressors. Here, we report how ionizing radiation, an environmental tumorigenic contributor, modifies the DNA damage response based on the type of germline PTEN variants. We hypothesized that certain PTEN variants associated with DTC create a pro-oncogenic molecular signature upon radiation-induced DNA damage. DTC-associated (PTEN M134R ) or DTC-non-associated (PTEN G132D ) germline PTEN mutant alleles were introduced into a human induced pluripotent cell (hiPSC) line derived from a healthy donor utilizing CRISPR-Cas9 gene editing technology. We determined radiation-induced transcriptomic changes in functional thyroid organoids induced from wild-type and both heterozygous PTEN mutant hiPSCs. Both bulk and single-cell RNA sequencing data indicated that radiation upregulated the p53 network more potently in the thyroid organoids with PTEN WT/G132D than those with PTEN WT/M134R , which could be mediated by AKT-dependent MDM2 inactivation and PTEN-p53 physical interaction. Our data suggest that the lack of p53 pathway activation through PTEN-p53 network interactions explains why PTEN M134R is a DTC-susceptible variant.

Humans↗

PubMed2024

Inactivation of the SLC25A1 gene during embryogenesis induces a unique senescence program controlled by p53.

Germline inactivating mutations of the SLC25A1 gene contribute to various human disorders, including Velocardiofacial (VCFS), DiGeorge (DGS) syndromes and combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a severe systemic disease characterized by the accumulation of 2-hydroxyglutaric acid (2HG). The mechanisms by which SLC25A1 loss leads to these syndromes remain largely unclear. Here, we describe a mouse model of SLC25A1 deficiency that mimics human VCFS/DGS and D/L-2HGA. Surprisingly, inactivation of both Slc25a1 alleles results in alterations in the development of multiple organs, and in a severe proliferation defect by activating two senescence programs, oncogene-induced senescence (OIS) and mitochondrial dysfunction-induced senescence (MiDAS), which converge upon the induction of the p53 tumor suppressor. Mechanistically, cells and tissues with dysfunctional SLC25A1 protein undergo metabolic and transcriptional rewiring leading to the accumulation of 2HG via a non-canonical pathway and to the depletion of nicotinamide adenine dinucleotide, NAD+, which trigger senescence. Replenishing the pool of NAD+ or promoting the clearance of 2HG rescues the proliferation defect of cells with dysfunctional SLC25A1 in a cooperative fashion. Further, removal of p53 activity via RNA interference restores proliferation, indicating that p53 acts as a critical barrier to the expansion of cells lacking functional SLC25A1. These findings reveal unexpected pathogenic roles of senescence and of p53 in D/L-2HGA and identify potential therapeutic strategies to correct salient molecular alterations driving this disease.

Animals↗

PubMed2025

MYC and p53 Alterations Cooperate through VEGF Signaling to Repress Cytotoxic T-cell and Immunotherapy Responses in Prostate Cancer.

UNLABELLED: Patients with castration-resistant prostate cancer (CRPC) are generally unresponsive to tumor-targeted treatments and immunotherapies. Genetic alterations acquired during the evolution of CRPC may affect antitumor immunity and immunotherapy responses, which could inform personalized therapeutic strategies. Using our innovative electroporation-based mouse models, we generated distinct genetic subtypes of CRPC found in patients and uncovered unique immune microenvironments. Specifically, mouse and human prostate tumors with MYC amplification and p53 disruption had weak cytotoxic lymphocyte infiltration and an overall dismal prognosis. MYC and p53 cooperated to induce tumor-intrinsic secretion of VEGF, which signaled through VEGFR2 expressed on CD8+ T cells to directly inhibit T-cell migration and effector functions. Targeting VEGF-VEGFR2 signaling in vivo remodeled the immunosuppressive prostate tumor microenvironment, leading to CD8+ T-cell-mediated primary tumor and metastasis growth suppression and significantly increased overall survival in MYC- and p53-altered CRPC. VEGFR2 blockade also led to the induction of PD-L1 in tumors and produced antitumor efficacy in combination with PD-L1 immune checkpoint blockade in multiple preclinical CRPC mouse models. Thus, these results identify a genetic mechanism of immunosuppression through VEGF signaling in prostate cancer that can be targeted to reactivate immune and immunotherapy responses in an aggressive subtype of CRPC. SIGNIFICANCE: VEGFR2 blockade inhibits VEGF-mediated T-cell suppression and potentiates the effects of PD-L1 immune checkpoint blockade to treat castration-resistant prostate cancer driven by MYC and p53 alterations.

Male↗

PubMed2026

Characteristics of p53 and Smad4 immunohistochemistry in pancreatic ductal adenocarcinoma and validation by next-generation sequencing.

BACKGROUND: Mutations in four major driver genes -KRAS, CDKN2A, TP53, and SMAD4- are central to the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) and critically inform diagnosis, therapeutic decision-making, and prognostic assessment. Although next-generation sequencing (NGS) is widely regarded as the gold standard for detecting these mutations, its clinical application is often limited by suboptimal analytical efficiency and substantial economic cost. Among these genes, immunohistochemical (IHC) staining for the proteins encoded by TP53 and SMAD4 has been extensively adopted in routine pathology practice. However, standardized IHC pattern classification schemes and rigorous validation of their predictive accuracy for underlying genomic alterations remain lacking in PDAC. METHODS: We retrospectively enrolled 63 PDAC patients and systematically characterized the typical IHC expression patterns of p53 and Smad4. Targeted NGS was subsequently performed on all available tumor specimens, and the resulting mutational profiles were correlated with corresponding IHC findings. Diagnostic performance including sensitivity, specificity and accuracy of p53 IHC for predicting TP53 mutations and of Smad4 IHC for predicting SMAD4 mutations was rigorously evaluated. RESULTS: Among the four canonical driver genes, co-occurring double- or triple-gene mutations were prevalent; within TP53 and SMAD4, missense mutations constituted the most frequent variant type. Using NGS as the reference standard, we validated the diagnostic utility of a three-tiered p53 IHC classification system, particularly in fine-needle biopsy (FNB) specimens. Furthermore, we proposed a novel, refined Smad4 IHC pattern classification that incorporates an "intermediate" category, thereby expanding upon conventional binary interpretation. This new scheme achieved markedly improved mutation prediction accuracy (0.76) compared with traditional approaches (0.57). CONCLUSION: Our study highlights the complementary diagnostic value of p53 and Smad4 IHC relative to molecular testing in PDAC, especially when tissue is limited, as commonly encountered in FNB specimens. The newly established Smad4 IHC classification system, which integrates an intermediate expression category into the conventional two-tier framework, demonstrates superior clinical utility and enhances predictive accuracy for SMAD4 genomic alterations.

Humans↗

PubMed2026

SLC25A45 as a prognostic biomarker promotes malignant progression via mutant p53 in hepatocellular carcinoma.

BACKGROUND: SLC25A45 belongs to the mitochondrial trimethyllysine carrier protein family. To date, its role in tumor development has not been fully elucidated. Previous studies have demonstrated its pro-tumor function in ovarian cancer; however, research on the expression characteristics, biological roles and underlying regulatory pathways of SLC25A45 in hepatocellular carcinoma (HCC) is limited. This study aims to explore the expression, functional roles, and regulatory pathways of SLC25A45 in HCC. METHODS: This study examined SLC25A45 expression and clinical relevance in HCC using publicly available transcriptomic data. SLC25A45 knockdown cell lines were constructed using PLC/PRF/5, Huh7, and Huh1 cells. Functional assays, including cell proliferation and colony formation assays, were then conducted. To investigate the effects of SLC25A45 knockdown on the malignant phenotypes of HCC cells in vitro, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) analyses were performed to identify potential underlying mechanisms, which were subsequently validated by experimental assays. RESULTS: SLC25A45 was elevated in clinical HCC specimens, and high SLC25A45 expression was correlated with disease progression and poor overall survival (OS). In vitro functional assays demonstrated that SLC25A45 silencing reduced HCC cell proliferation and colony formation. Mechanistically, GSEA indicated that high SLC25A45 expression was significantly enriched in the p53 signaling pathways. SLC25A45 knockdown in HCC cells led to a significant increase in wild-type p53 protein expression, but a substantial decrease in mutant p53 expression. CONCLUSIONS: SLC25A45 is a potential prognostic indicator and may drive HCC tumorigenesis and progression through the differential modulation of the p53 signaling pathways.

SLC25A45↗

PubMed2026

Regulation of the lncRNA NEAT1 by p53-ΔNp63 crosstalk modulates the DNA damage response and therapeutic efficacy in HNSCC.

Head and neck squamous cell carcinomas (HNSCCs) are characterized by recurrent genetic alterations, including the inactivation of the tumor suppressor TP53 gene and dysregulation of the TP63 gene. The TP63 gene encodes multiple isoforms, among which the N-terminal truncated isoform ΔNp63 is fundamental for the integrity of stratified epithelial tissues. We previously demonstrated that ΔNp63 represses the expression of the lncRNA NEAT1. Here, we investigated the functional crosstalk between p53 and ΔNp63 in modulating NEAT1 expression following genotoxic stress. We found that upon genotoxic insults, p53 activation and the concomitant downregulation of ΔNp63 promote NEAT1 transcription. In p53-proficient HNSCC cells, NEAT1 targeting leads to increased DNA damage, highlighting its potential role in maintaining genomic stability and facilitating efficient DNA repair. Importantly, we showed that histone deacetylase inhibitors (HDACis) upregulate NEAT1 expression independently of p53, and NEAT1 silencing enhances HDACis-induced DNA damage. Overall, our findings establish NEAT1 as an early regulator of the DNA damage response in HNSCCs and suggest that combining NEAT1 targeting with HDAC inhibition may potentiate therapeutic efficacy, particularly in TP53-mutant HNSCCs.

DNA damage↗

PubMed2025

Mutant p53 disrupts antioxidant defense in fallopian tube epithelium via GSTAs suppression: A pathway to serous tubal carcinogenesis.

High grade serous ovarian cancer (HGSOC) is the most common and aggressive type of epithelial ovarian cancer. The fimbria of the fallopian tube is the likely site of origin based on the presence of distinct precancerous lesions with TP53 signatures known clinically as serous tubal intraepithelial carcinoma (STICs) detected in this region in individuals at genetically high risk or with HGSOC. Previously we identified that matched fallopian tube epithelia (FTE) from fimbria and ampulla of normal fallopian tubes from premenopausal women exhibit differential expression of genes associated with antioxidant and inflammatory pathways. One gene, glutathione S-transferase 2 (GSTA2), showed both higher expression in the fimbria and in the follicular phase (pre-ovulation) compared to the ampulla, suggesting that GSTA2 expression may regulate reactive oxygen homeostasis in these cells in response to ovulation-related stress. Here, to understand how preneoplastic genomic alterations influence regulation of oxidative stress, FTE cells were isolated from healthy tissue and introduced with p53 mutations, from which expression and function of GSTA2 and other antioxidant enzymes were investigated. Mutant p53 downregulated the expression of GSTA2 and subsequently increased DNA damage. The combination of p53 mutation and dysregulated oxidative response likely promotes the genomic instability that initially drives the transformation to high grade serous ovarian carcinoma.

Female↗

PubMed2026

Copy Number-low/TP53-mutated Endometrial Cancer With Wild-type p53 Immunoexpression: Implications for Risk Stratification and Management When Using Next-generation Sequencing for Molecular Classification.

Endometrial cancers with the Cancer Genome Atlas (TCGA) molecular profile of TP53-mutated, POLE-wild-type, and microsatellite-stable generally exhibit a high burden of copy number (CN) alterations and carry an increased risk for adverse outcomes, meriting maximal adjuvant therapy. In contrast, the prognosis associated with a TP53 mutation that coexists with a POLE mutation or microsatellite instability aligns with that of ultramutated or hypermutated cancers, respectively. In this study, we characterized a rare molecular subclass of endometrial cancers defined by TP53 mutation but low burden of CN alterations, wild-type p53 immunoexpression (immunohistochemistry [IHC]), and low TP53 variant allele frequency (median 13% and maximum 47%). Among 723 consecutive endometrial cancers prospectively classified using next-generation sequencing, 16 (2.2%) were CN-low/TP53-mutated/p53 wild-type IHC. Two additional cases were identified in a separate retrospective cohort of 32 recurrent low-grade early-stage endometrial cancers, bringing the total to 18 cases. They affected postmenopausal patients, exhibited low-grade endometrioid histotype, and were mostly confined to the uterus without lymphovascular space invasion. The recurrence rate was 6.25% (1/16) in the prospective cohort, and none died, placing their prognosis closer to that of CN-low than CN-high cancers. We conclude that next-generation sequencing-based TCGA classification of TP53-mutated, POLE-wild-type, microsatellite-stable endometrial cancers with TP53 variant allele frequency < 50% requires further evaluation using CN analysis and/or p53 IHC to detect this rare molecular category. IHC-based TCGA classification, such as the ProMisE protocol, will not be able to detect these cases because the p53 IHC pattern is wild-type and there are no distinguishing morphological features; this may be of relevance for analyzing ProMisE protocol-based clinical trials and outcomes studies. Long-term outcome studies are needed to refine risk stratification and treatment decisions for this unique molecular class of endometrial cancers that further contributes to the evolving understanding that the clinical significance of TP53 mutation in endometrial cancer is complex and depends on coexisting molecular alterations.

Humans↗