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PubMed2026

High-grade serous ovarian cancer is associated with increased TP53 mutation burden in uterine lavage.

High grade serous ovarian cancer (HGSC) has low survival partly due to the lack of methods for detection, diagnosis, and risk prediction. TP53 mutations, which drive HGSC, are found in gynecological tissues as the result of somatic evolution, but it is unknown whether an excess of mutations is linked to ovarian cancer. Here we investigate if TP53 mutation burden measured in uterine lavage, a minimally invasive gynecological liquid biopsy, can discriminate between patients with and without HGSC. We used ultradeep TP53 duplex sequencing (>15,000x duplex depth) to detect TP53 mutations in uterine lavage collected pre-operatively in 278 patients undergoing gynecological surgery for pelvic masses (average risk) or cancer risk-reduction (high risk). All lavages contained multiple TP53 mutant clones, which were used to quantify TP53 mutation burden frequency (MBF). Average risk patients with HGSC had significantly higher TP53 MBF independently of age and other risk factors (77% sensitivity, 89% specificity, AUC = 0.88). Excluding tumor TP53 clonal mutations from the lavage MBF calculation maintains this association, suggesting that it is the overall TP53 somatic mutation burden (rather than the discovery of the specific tumor driver mutation) that identifies HGSC. These results demonstrate that TP53 somatic mutations are common in uterine lavage but more abundant in patients with HGSC, highlighting a connection between TP53 somatic evolution and ovarian cancer. Uterine lavage offers a minimally invasive approach that could be valuable to identify patients with HGSC.

Journal Article↗

PubMed2025

Molecular alterations in TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathways in gastric cancer among ethnically heterogeneous cohorts.

BACKGROUND/OBJECTIVES: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with significant racial and ethnic disparities in incidence, molecular characteristics, and patient outcomes. However, genomic studies focusing on Hispanic/Latino (H/L) populations remain scarce, limiting our understanding of ethnicity-specific molecular alterations. This study aims to characterize pathway-specific mutations in TP53, WNT, PI3K, TGF-Beta and RTK/RAS signaling pathways in GC and compare mutation frequencies between H/L and Non-Hispanic White (NHW) patients. Additionally, we evaluate the impact of these alterations on overall survival using publicly available datasets. METHODS: We conducted a bioinformatics analysis using publicly available GC datasets to assess mutation frequencies in TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway genes. A total of 800 patients were included in the analysis, comprising 83 H/L patients and 717 NHW patients. Patients were stratified by ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups, and Kaplan-Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW patients. RESULTS: Significant differences were observed in the TP53 pathway and related genes when comparing GC in H/L patients to NHW patients. TP53 mutations were less prevalent in H/L patients (9.6% vs. 19%, p = 0.03). Borderline significant differences were noted in the WNT pathway when comparing GC in H/L patients to NHW GC patients, with WNT alterations more frequent in H/L GC (8.4% vs. 4%, p = 0.08), and APC mutations significantly higher (3.6% vs. 0.8%, p = 0.05). Although alterations in PI3K, TGF-Beta and RTK/RAS pathways were not statistically significant, borderline significance was observed in genes related to these pathways, including EGFR (p = 0.07), FGFR1 (p = 0.05), FGFR2 (p = 0.05), and PTPN11 (p = 0.05) in the PI3K pathway, and SMAD4 (p = 0.08) in the TGF-Beta pathway. Survival analysis revealed no significant differences among H/L patients. However, NHW patients with TP53 and PI3K pathway alterations exhibited significant differences in overall survival, while those without TGF-Beta pathway alterations also showed a significant survival impact. In contrast, WNT pathway alterations were not associated with significant survival differences. These findings suggest that TP53, PI3K, and TGF-Beta pathway disruptions may have distinct prognostic implications in NHW GC patients. CONCLUSIONS: This study provides one of the first ethnicity-focused analyses of TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway alterations in GC, revealing significant racial/ethnic differences in pathway dysregulation. The findings suggest that TP53 and WNT alterations may play a critical role in GC among H/L patients, while PI3K and TGF-Beta alterations may have greater prognostic significance in NHW patients. These insights emphasize the need for precision medicine approaches that account for genetic heterogeneity and ethnicity-specific pathway alterations to improve cancer care and outcomes for underrepresented populations.

PI3K pathway↗

PubMed2025

Designated primers targeted canine TP53 gene hotspot regions.

BACKGROUND: Tumor protein 53 gene (TP53) is a critical factor that controls different cell activities such as cell cycle, DNA repair mechanism, autophagy, apoptosis, and metabolism. The TP53 gene is the most commonly mutated gene, especially in the 4-8 exons region. This mutation enhances the development of many abnormalities, such as the initiation of different types of cancer. AIM: The main objective of this study was to design and evaluate the efficacy of three different primer sets that targeted the TP53 gene at the hotspot regions. METHODS: To do that, twelve blood samples were collected from dogs belonging to the German Shepherd breed/K9 aged between 8-12 years. Then, the DNA extraction and polymerase chain reaction (PCR) took place by using the three primer sets, which were designed using SnapGene. The primer sets, namely, first primer, the second and the third targeted exons 5-9 located in the canine TP53 gene. In the following step, all the PCR products were sent for Sanger sequencing and then phylogenetic analysis. RESULTS: Our findings indicated that the first primer set consistently showed higher amplification signal efficiency and reduced dimer formation compared with the second and third primer sets, respectively, with a 60ºC annealing temperature. In addition, all the sequenced samples aligned with the reference canine TP53 gene in the phylogenetic tree. CONCLUSION: This study offered the best TP53 primer design that targeted the hotspot regions of the canine TP53 gene for researchers who are interested in targeting such regions in this gene.

Animals↗

PubMed2026

sWGS Identifies a Copy-Number-High Subset of TP53-mutated Multiple-Classifier Endometrial Carcinomas With Adverse Clinicopathological Features.

TP53-mutated "multiple-classifier" endometrial carcinomas represent a diagnostically challenging subgroup within current molecular classification algorithms. Although these tumors are assigned to POLE-mutated or mismatch repair-deficient categories according to current ESGO/FIGO-based algorithms, their biological heterogeneity remains incompletely characterized. Herein, we retrospectively analyzed TP53-mutated multiple-classifier endometrial carcinomas identified through routine molecular profiling at our institution between 2022 and 2025 using an integrated histopathological, immunohistochemical, targeted sequencing, and shallow whole-genome sequencing approach. Copy-number alteration-high (CNA-high) status was defined as ≥5 large-scale genomic alterations, corresponding to copy-number gains or losses ≥3 Mb within a single chromosomal arm excluding whole-arm alterations. Among 33 analyzable TP53-mutated multiple-classifier endometrial carcinomas, sWGS identified 12 CNA-high tumors (36.4%) and 21 CNA-low tumors (63.6%). CNA-high tumors were more frequently non-endometrioid, high-grade, and advanced-stage according to FIGO 2023. They showed higher TP53 variant allele frequencies (VAF) and higher TP53 VAF-to-tumor-cellularity ratios. After a median follow-up of 12.8 months, recurrences (6/33; 18.2%) and disease-related deaths (3/33; 9.1%) were observed in the CNA-high subgroup, whereas no recurrence or disease-related death was observed among CNA-low patients. These findings indicate that TP53-mutated multiple-classifier endometrial carcinomas comprise biologically distinct subsets that are not fully captured by current 4-tier TCGA-based molecular classification and ESGO-based risk stratification. In this cohort, sWGS identified a CNA-high group with adverse clinicopathological features and clinical events suggesting a potentially more aggressive clinical course. Integration of genome-wide copy-number profiling may therefore refine the biological interpretation of TP53 alterations in multiple-classifier endometrial carcinomas and warrants validation in larger multicenter cohorts.

TP53↗

PubMed2026

Coagulation activation is associated with genomic-instability-related features in TP53-mutated AML and MDS: routine laboratory patterns beyond classical disseminated intravascular coagulation.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication of acute myeloid leukemia (AML) associated with poor prognosis. In TP53-mutated AML and myelodysplastic syndrome (MDS), however, the classical ISTH criteria rarely identify overt DIC, although bleeding and thrombotic complications are well documented in acute leukaemia. We hypothesized that these patients exhibit a lower-grade, subclinical coagulation activation that is associated with the underlying genomic-instability-related features of TP53-mutant disease. METHODS: We retrospectively analyzed 107 consecutive patients with TP53-mutated AML (n = 52) or high-risk MDS (MDS, n = 55), median age 65 years, diagnosed and initially evaluated at our centre between 2018 and 2025. Seven routine coagulation markers and 46 co-mutated genes were evaluated for associations with overall survival (OS) using univariate and multivariable Cox regression, continuous dose-response modeling, and unsupervised k-means clustering. Internal validity was assessed by 1000 bootstrap resamples. RESULTS: Overt DIC according to ISTH criteria was rare (15%). Subclinical activation was common: 50% of patients had a D-dimer ≥1 μg/mL, 41% a fibrinogen ≥4 g/L, and 29% an INR ≥1.2. In univariate analysis, D-dimer, fibrinogen, INR, prothrombin time, and activated partial thromboplastin time were each associated with OS (HR 1.33-1.38 per SD; all p < 0.05). Complex karyotype correlated with higher D-dimer (median 1.39 vs. 0.60 μg/mL, p = 0.022) and fibrinogen (3.91 vs. 2.53 g/L, p = 0.007), while TP53 variant allele frequency (VAF) showed modest positive correlations with D-dimer (ρ = 0.21), INR (ρ = 0.27), and PT (ρ = 0.27; all p < 0.05). Clustering identified three coagulation phenotypes: Silent (51%), Thrombo-inflammatory (31%), and Consumption-like (18%), showing a graded but statistically non-significant gradient in molecular features and a stepwise decline in median OS (14, 10 and 8 months; log-rank p = 0.041). After adjustment for complex karyotype, TP53 VAF, and favorable co-mutation count, the Consumption-like phenotype was associated with a non-significant increased risk (HR 1.83, 95% CI 0.92-3.65, p = 0.084), whereas favorable co-mutation pathways remained independently protective (HR 0.56, 95% CI 0.35-0.90, p = 0.016). CONCLUSION: In TP53-mutated AML/MDS, coagulation activation intensity is associated with the degree of genomic instability. The three phenotypes may add biological resolution beyond classical DIC and cytogenetic risk groups, but represent laboratory patterns rather than validated bleeding or thrombosis prediction tools. However, after accounting for genomic features, phenotypes were not independent predictors of outcome, with complex karyotype, TP53 VAF, and favorable co-mutation count driving prognosis. Because treatment intensity and other clinical confounders were not available, these survival associations are hypothesis-generating. Coagulation profiling remains inexpensive, widely accessible, and offers a practical window into disease biology that warrants prospective validation.

TP53↗

PubMed2026

Epigenetic Repression of TP53 Transcription Underlies Cancer Cell Persistence for Carboplatin Resistance in Non-Small Cell Lung Cancer.

While chemoresistance in non-small cell lung cancer (NSCLC) cells has historically been attributed to permanent genetic mutations, emerging evidence highlights the role of nongenetic transcriptional plasticity and 'drug-tolerant persister' cells. To systematically map these epigenetic vulnerabilities, we utilized a genome-wide CRISPR interference library to screen wild-type TP53 NSCLC (A549) cells under carboplatin selection. Using the DrugZ algorithm and subsequent pathway enrichment analyses, this screen revealed that transcriptional suppression of interstrand crosslink DNA repair networks, including the Fanconi anemia pathway, markedly sensitized cells to carboplatin. Unexpectedly, transcriptional silencing of TP53 and its downstream target CDKN1A emerged as the strongest drivers of resistance, enabling cells to bypass therapy-induced senescence and maintain their proliferative potential later. To validate these findings in a clinically relevant context, we established a chronic carboplatin-resistant cell model (A549CarboR cells). A549CarboR exhibited a reduction in TP53 transcripts, along with decreased H3K27 acetylation and increased DNA hypermethylation on its promoter. Epigenetic remodeling using the DNA methyltransferase inhibitor (DNMTi) was associated with unblocking TP53 transcription, restored p53 signaling, and resensitization of resistant cells to carboplatin. Conversely, histone deacetylase inhibitors induced CDKN1A transcription to bypass TP53, indicating distinct epigenetic circuits. Collectively, the results demonstrate for the first time that TP53 expression is dynamically regulated at the transcriptional level through promoter methylation related to the drug tolerance. These insights emphasize that epigenetic silencing, rather than exclusive genetic loss-of-function, contribute to platinum resistance and underscore the therapeutic potential of pairing platinum regimens with DNMTi to target the transcriptomic plasticity of persistent cancer cell populations.

CRISPR interference screening↗

PubMed2026

Shared inheritance reveals landscape of somatic and germline cancer risk in TP53.

Pathogenic variants in TP53, the key tumor suppressor gene underlying Li-Fraumeni syndrome (LFS), are among the best-established causes of inherited cancer predisposition. However, large-scale sequencing has revealed that many apparently pathogenic TP53 variants detected in blood are the result of somatic clonal expansions, complicating risk interpretation. Using blood-derived whole-exome data from 469,391 UK Biobank participants, we combined the variant allele fraction (VAF) with haplotype-sharing analysis to distinguish germline and somatic TP53 variants. Germline variants were concentrated at sites linked to partial loss of p53 function and lower disease penetrance, whereas classic LFS alleles appeared to be predominantly somatically acquired. Classic LFS alleles at high VAF conferred markedly increased risk of hematological malignancy but not solid tumors, indicating an important contribution from large TP53-mutant clonal expansions. The prevalence of somatic clonal expansion also correlated with missense variant pathogenicity, suggesting that somatic activity provides an informative in vivo proxy for functional impact. These results provide new insights into TP53-associated cancer risk at the population level, demonstrate that somatic rather than germline risk predominates in middle-aged healthy adults, and provide a scalable framework for variant classification in large-scale population genomics.

Humans↗

PubMed2026

Evidence for the prognostic value of TP53 mutations in circulating tumor DNA across solid malignancies: a systematic review and meta-analysis.

BACKGROUND: The purpose of this meta-analysis study is to provide evidence for the clinical utility of TP53 mutations in circulating tumor DNA (ctDNA) as a prognostic biomarker. METHODS: We searched the PubMed, Embase, Cochrane, and Web of Science databases (last update May 2025) for studies on TP53 mutations in ctDNA or cfDNA as prognosis overall survival and in solid tumors. A total of 21 studies that met the criteria were utilized and data was collected regarding the authors, year of publication, study design, site of the study, number of patients, detection, mutation sample size and outcome measures were collected. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the study, and meta-analysis was done by using STATA 16.0. Effect sizes were in the form of hazard ratios (HR) that had 95% confidence intervals (CI). The models used were fixed-effects and random-effects based on heterogeneity. Funnel plots, and Egger's test was used to measure publication bias, and sensitivity analysis conducted through a leave-one-out method. RESULTS: A total of 21 studies (2,685 TP53-mutated patients, one unreported) showed: Mutated patients had worse progression-free survival (PFS) (HR=2.10, p=0.000; 12 studies, heterogeneity resolved after excluding Yoshida 2023), shorter OS (HR=1.74, p=0.014; 9 studies), and reduced DFS (HR=1.73, p=0.007; 3 studies), but RFS (2 items) showed no statistically significant differences. Subgroup analyses revealed: Prospective studies showed stronger PFS (HR=2.14 vs retrospective 1.90) with Japanese subgroup HR=4.90; Lung/liver cancers had higher HRs than breast. Prospective OS HR=2.25 (lung 3.14, endometrial 0.75). Retrospective DFS HR=1.89 vs Japanese breast RFS HR=4.00. Heterogeneity originated from study design, region, and cancer type variations, with no significant publication bias (Egger's test p>0.05). CONCLUSION: Current evidence suggests that TP53 mutations detected in ctDNA are significantly associated with poor prognosis in various solid tumors, particularly lung cancer. The association is robust for PFS and OS, though high heterogeneity and biological complexity warrant cautious interpretation. These findings support the potential incorporation of ctDNA-based TP53 mutation status into clinical prognostic assessment systems as an adjunctive parameter; however, further standardization of detection protocols, functional annotation of mutation types (e.g., LOF vs. GOF), incorporation of VAF and clonality analysis, and validation in large prospective multicenter cohorts are needed before routine clinical implementation. PROSPERO REGISTRATION NUMBER: CRD420251021095.

Humans↗

PubMed2026

The Novel Hypomethylating Agent NTX-301 Reprograms Epigenetic and Hippo Signaling Pathways and Exhibits Preclinical Activity in Venetoclax-Resistant and TP53-Mutant AML.

PURPOSE: Hypomethylating agent (HMA) and the BCL-2 inhibitor venetoclax (VEN) combinations have evolved into first-line therapies for patients with acute myeloid leukemia (AML), yielding high response rates. However, most patients ultimately relapse, particularly those with TP53 mutations. We investigated mechanisms of action and therapeutic efficacy of NTX-301, a next-generation HMA. EXPERIMENTAL DESIGN: Methods used include flow cytometry-based cell viability assays, Western blotting, reverse-phase protein arrays, RNA sequencing, Cytometry by Time-Of-Flight single-cell mass cytometry, and methylation profiling in various therapy-resistant AML models. RESULTS: We demonstrate that NTX-301 exhibits superior efficacy compared with 5-azacytidine (5-AZA) in 5-AZA- or VEN-resistant AML. It synergizes with VEN in VEN- or VEN/HMA-resistant and TP53-mutant AML blasts and stem/progenitor cells (combination index <1). NTX-301 inhibits DNA methyltransferase 1 (DNMT1) and increases p73 and caspase 8 (CASP8)/activated CASP8 levels in TP53 wild-type and TP53-mutant AML and activates p53 signaling. It extends survival (≥45%) in both xenograft and patient-derived xenograft models. Methylation profiling revealed that NTX-301 is a more targeted HMA compared with 5-AZA, enabling suppression of functionally enriched genes/pathways. Pathway analysis of 954 commonly hypomethylated genes showed profoundly greater enrichment of Hippo signaling in NTX-301-treated compared with 5-AZA-treated cells and enrichment of insulin signaling, VEGF pathway, and cell cycle selectively in NTX-301- but not in 5-AZA-treated cells. NTX-301-mediated Hippo signaling was validated at protein levels. CONCLUSIONS: Data suggest that NTX-301 exerts potent antileukemic activities superior to 5-AZA and synergizes with VEN in VEN-resistant and TP53-mutant AML, in part by suppressing DNMT1, inducing DNA damage responses and apoptosis through p53 signaling, and demethylating LATS1/2, thereby activating Hippo signaling.

Humans↗

PubMed2026

Targeting TP53 in triple-negative breast cancer: Molecular pathogenesis, therapeutic implications, and emerging pharmacological strategies.

Triple-negative breast cancer (TNBC) remains a highly aggressive and therapeutically challenging subtype, defined by the absence of oestrogen, progesterone, and HER2 expression. Tumour Protein 53 (TP53) mutations represent the most frequent genetic alteration, occurring in over 80% of cases and driving tumour initiation, progression, and therapeutic resistance. Mutant p53 proteins not only lose canonical tumour-suppressive functions but also often acquire gain-of-function (GOF) oncogenic properties that promote metastasis, genomic instability, and resistance to mechanisms like ferroptosis. This review examines the biological role of TP53 in TNBC pathogenesis and evaluates emerging pharmacological strategies aimed at targeting these vulnerabilities. Key approaches include the pharmacological reactivation of mutant p53 using small molecules such as APR-246, COTI-2, and the mutation-specific reactivator rezatapopt (PC14586), which has shown significant clinical tumour reduction in Y220C-mutant patients. Other strategies involve targeted protein degradation, the exploitation of synthetic lethal interactions (e.g., Chk1 or Aurora kinase B inhibition), and the use of natural products like cryptolepine or piperine derivatives. Recent clinical evidence further highlights the potential of combining epigenetic agents like decitabine with chemotherapy in TP53-mutant populations. Integrating TP53 mutation status into biomarker-driven treatment paradigms is a pivotal step toward achieving precision oncology and improving clinical outcomes for patients with TNBC.

Precision oncology↗

PubMed2026

The impact of EGFR subtype combined with TP53 co-mutation status on survival outcomes with front-line osimertinib in non-small cell lung cancer (NSCLC).

BACKGROUND: Osimertinib is a standard therapy for EGFR-mutant NSCLC. However, markers to better identify those at risk for poor outcomes are needed. This is the largest study to date evaluating the impact of EGFR subtype combined with TP53 co-mutation status on survival endpoints with front-line osimertinib. METHODS: Patients from a U.S. clinical-genomic database with advanced EGFR-mutant NSCLC receiving front-line osimertinib were studied. Real-world progression-free survival (rwPFS) and overall survival (OS) were determined using Kaplan-Meier methods, and multivariable Cox regression compared outcomes after accounting for relevant clinical covariates. RESULTS: Of 606 patients, 277 (46%) had EGFR L858R, 384 (63%) had TP53 co-mutations, and 186 (30.7%) had both. Bearing L858R vs. exon 19 deletions (rwPFS: hazard ratio [HR] 1.4, P = 0.001; OS: HR 1.3, P = 0.01) or a TP53 co-mutation vs. wildtype (rwPFS: HR 1.5, P < 0.001; OS: HR 1.6, P < 0.001) predicted inferior outcomes. Especially short median rwPFS (10.1 vs. 21.4 months, HR 2.2, P < 0.001) and OS (21.3 vs. 53.4 months, HR 2.3, P < 0.001) were observed in patients with both markers (L858R/TP53-mutant) as compared to neither (exon 19 deletion/TP53-wildtype). CONCLUSIONS: Having EGFR L858R or a TP53 co-mutation were independent predictors of inferior rwPFS and OS with front-line osimertinib. Patients with both unfavorable alterations had the shortest survival. Risk stratifying using a combination of these markers can assist in identifying patients for novel trials or approved intensified therapies.

Humans↗

PubMed2022

High tumor amplification burden is associated with TP53 mutations in the pan-cancer setting.

Next-generation sequencing data is fundamentally changing the clinical management of patients with cancer. The most frequent genomic alterations in malignancy are mutations and amplifications, with a subset of tumors having multiple amplifications - "amplificators". We sought to understand the molecular correlates of high tumor amplification burden in a pan-cancer context. Using both national registries and a single-institution dataset, our results demonstrate that cancers with TP53 mutations (as compared to those with wild-type TP53) exhibited significantly higher tumor amplification burden across all datasets. Amplifications, generally associated with overexpression, may be potentially actionable secondary consequences of TP53 mutations.

Biomarkers, Tumor↗

PubMed2026

Osimertinib With or Without Chemotherapy in Advanced Non-Small Cell Lung Cancer With EGFR and Concurrent TP53 Mutations: A Randomized Clinical Trial.

IMPORTANCE: Combination therapy has emerged as a promising therapeutic approach for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, its clinical benefit-risk profile remains a focus of ongoing debate. Identifying patients most likely to derive benefit from such regimens remains an unmet clinical need. OBJECTIVE: To prospectively compare the efficacy and safety of first-line osimertinib plus chemotherapy with osimertinib monotherapy for patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized, open-label, phase 3 study conducted at 17 sites in China. Between March 25, 2021, and July 11, 2024, a total of 294 eligible patients with treatment-naive, stage IV or recurrent nonsquamous NSCLC harboring concurrent TP53 and EGFR-sensitizing mutations were enrolled. INTERVENTIONS: Patients were randomized (1:1) to receive osimertinib plus chemotherapy (pemetrexed and carboplatin every 3 weeks for 4 cycles, followed by maintenance therapy of osimertinib plus pemetrexed; n = 146) or osimertinib monotherapy (n = 148). MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, response, safety, and quality of life. RESULTS: Among 294 enrolled patients, the median age was 57 years (range, 26-79 years), and 159 (54.1%) were female. The data cutoff date was November 11, 2025. At a median follow-up of 25.1 months for the osimertinib-chemotherapy group and 26.1 months for the osimertinib monotherapy group, median progression-free survival was significantly longer with osimertinib plus chemotherapy than with osimertinib monotherapy (34.0 vs 15.6 months; difference, 18.4 months [95% CI, 9.9-22.3]; hazard ratio, 0.44 [95% CI, 0.32-0.60]; P < .001). This benefit was consistent across prespecified subgroups, including those with brain metastases and L858R mutations. The overall survival data remained immature (30.6% maturity); however, a trend toward overall survival benefit with combination therapy was observed. The incidence of grade 3 or higher treatment-related adverse events was higher in the combination group, with no new safety signal identified. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, osimertinib plus chemotherapy significantly increased progression-free survival among patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. These findings provided a clinical rationale for individualized combination strategies in the management of patients with EGFR-mutated NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04695925.

Adult↗

PubMed2026

Acute Myeloid Leukemia With KMT2A Amplification: A TP53-Alteration-Enriched Subgroup Associated With Chromoanagenesis and Poor Prognosis.

KMT2A amplification (KMT2A-amp) is a rare but aggressive genomic abnormality in acute myeloid leukemia (AML), with limited characterization in prior studies. We retrospectively analyzed 96 patients with AML harboring KMT2A-amp, including 56 newly diagnosed (ND) and 40 relapsed/refractory (RR) cases, with a median age of 68 years. Approximately half of the cases had therapy-related or secondary AML. All cases demonstrated highly complex karyotypes, with frequent -5/del(5q), -7/del(7q), and -17/del(17p). TP53 alteration was present in 93% of patients, whereas other recurrent AML-associated mutations were uncommon, and no AML-defining gene fusions or mutations were identified. In cases evaluated by optical genome mapping, all showed chromoanagenesis involving chromosome 11q23 region. Clinical outcomes were poor, with a median overall survival of 5.5 months in ND and 2.3 months in RR patients. Intensive chemotherapy did not improve survival compared with lower-intensity therapy, whereas venetoclax-based regimens were associated with improved overall survival (7.1 vs 4.6 months; p = 0.04) and event-free survival (6.7 vs 0.17 months; p < 0.01). We conclude that KMT2A-amp AML represents an extremely high-risk subgroup occurring in the context of TP53-associated genomic instability and chromoanagenesis. Its refractoriness to conventional chemotherapy highlights the urgent need for more effective, targeted therapeutic strategies.

KMT2A amplification↗

PubMed2026

Nuclear export inhibition activates TP53 pathways and is a potent therapeutic strategy in atypical teratoid rhabdoid tumors.

BACKGROUND: Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor mostly affecting young children. Improved and less toxic therapies for children with ATRT are imperative due to the toxicities associated with current treatments. Furthermore, existing therapies do not address the underlying genetic drivers of ATRT. In this study, we sought to determine whether exportin-1 (XPO1) is a genetic dependency and therapeutic target in ATRT. METHODS: We utilized an integrative approach harnessing patient-derived ATRT cell lines, functional genomics, pharmacologic assays, transcriptomics, and in vivo intracranial xenograft models to systematically test the hypothesis that XPO1 is a novel dependency in ATRT. RESULTS: Analysis of RNA-sequencing datasets revealed high XPO1 expression in ATRT cells compared to other pediatric brain tumor cell lines. Both CRISPR/Cas9 genetic knockdown and pharmacologic inhibition of XPO1 using 6 selective inhibitors of nuclear export (SINEs) in patient-derived atypical teratoid/rhabdoid tumor (ATRT) cells led to significant reduction in cell viability and proliferation. Furthermore, we observed increased apoptosis, G0 phase cell cycle arrest, and upregulation of TP53 signaling pathways in cells treated with the SINE selinexor. Consistently, our transcriptomic data revealed the upregulation of apoptosis and TP53 signaling pathways and concomitant depletion of cell cycle gene sets. In vivo, selinexor in combination with radiation and cyclophosphamide led to significant reduction in tumor volume and increased animal survival in intracranial ATRT xenograft models. CONCLUSIONS: Our data reveals XPO1 as a novel genetic dependency and potent therapeutic target in ATRT.

atypical teratoid rhabdoid tumor↗

PubMed2026

Genetic insights into lung squamous cell carcinoma: how TP53 and CSMD3 co-mutations shape prognosis and immune response.

BACKGROUND: Lung squamous cell carcinoma (LUSC) accounts for a significant proportion of lung cancer cases and is often associated with smoking and various environmental factors. The prognostic and immunologic implications of TP53 and CSMD3 co-mutations in LUSC remain poorly understood. This study aimed to investigate the role of TP53/CSMD3 co-mutations in LUSC using comprehensive bioinformatics analyses. METHODS: Data from 487 LUSC patients were obtained from The Cancer Genome Atlas (TCGA) database, with external validation performed using the combined cohort. Patients were stratified into TP53/CSMD3 co-mutation, single-mutation, and wild-type (WT) groups. Prognostic analysis was conducted using Kaplan-Meier survival curves. Tumor mutational burden (TMB) was calculated, and immune cell infiltration was assessed using multiple algorithms. Differentially expressed genes (DEGs) between co-mutated and WT groups were identified, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A nomogram incorporating mutation status, gender, age, and tumor stage (T stage) was developed for individualized prognostic prediction. RESULTS: The TP53/CSMD3 co-mutated group exhibited significantly better overall survival (OS) compared to single-mutation and WT groups. TMB scores were markedly higher in co-mutated patients, suggesting potential sensitivity to immune checkpoint inhibitors. Immune infiltration analysis revealed distinct profiles, including elevated CD8 T cells and reduced immunosuppressive components, in the co-mutation group. A total of 403 DEGs were identified between co-mutated and WT groups, with significant enrichment in immune-related pathways. Mechanistically, the co-mutation was associated with distinct downregulation of complement negative regulators (CFH/CFI), indicating complement hyperactivation independent of TMB. The constructed nomogram provided accurate individualized prognostic assessments. CONCLUSIONS: The co-mutation of TP53 and CSMD3 identifies a distinct LUSC subtype with favorable survival, marked by high TMB and an immune-activated microenvironment. Beyond TMB-driven neoantigen generation, the significant downregulation of complement negative regulators (CFH/CFI) reveals an independent complement hyperactivation pathway associated with CSMD3 loss. The constructed nomogram provides accurate individualized survival prediction. These findings establish TP53/CSMD3 co-mutation as a promising prognostic biomarker and offer mechanistic insights for personalized immunotherapy strategies. Future prospective cohorts are warranted to validate its predictive value.

Lung squamous cell carcinoma (LUSC)↗

PubMed2024

[Pathogenic large duplication in TP53 as a hereditary predisposing factor in breast cancer].

AIM: Germline pathogenic variants of TP53 are associated with Li-Fraumeni syndrome and represent a high risk for hereditary breast and ovarian cancer. We identified a germline, multi-exon heterozygous duplication variant in TP53, NM_000546.6:dup(ex2-5), in a young triple-negative breast cancer patient. We aimed to assign its pathogenicity. METHODS: DNA and RNA (cDNA) level specific amplification tests and sequencings were performed to identify the genomic duplication breakpoint and to detect the presence of defective transcripts. RESULTS: cDNA tests revealed aberrant transcript, which causes a shift in the reading frame. Allelic imbalance was also observed, indicating degradation of the defective RNA product. By locating the breakpoints at the DNA level, we determined that 6975 bp was repeated in tandem and in the same orientation. We also revealed the possible mechanism of the structural rearrangement. CONCLUSIONS: We established that the duplication identified at DNA level manifested in the mRNA and coded for a non-functional protein. Based on these data, we were able to classify this duplication variant as pathogenic, which affects the patient's therapeutic options and justifies genetic screening of family members.

Adult↗

PubMed2026

Minimizing Off-Target Effects of CRISPR-Cas9 With Optimized sgRNA: Evaluation of Efficiency and Specificity in the Tumor Protein 53 (TP53) Region.

CRISPR-Cas9 is a widely used genetic tool with therapeutic potential in molecular biology. CRISPR-Cas9 enables precise genome editing by its ability to target specific DNA sequence. After off-target and on-target regions are identified, CRISPR-Cas9 is applied to these regions based on the match between the guide RNA (gRNA) and target DNA sequence. This study points to the off-target impact of mismatches between the gRNA and target DNA on exon regions of the TP53 gene, which are involved in regulating multiple genes and cellular functions. Off-target positions are typically evaluated using scoring methods. In this study, we have used latent class analysis to reveal subclasses of off-target positions. Thus, we have created the levels of off-target positions and evaluated the effects of mismatching positions within these classes using machine learning classifiers. The results revealed that mismatching positions could be categorized into three levels: low, middle, and high off-target positions. We have improved a computational framework to minimize off-target effects and to identify the PAM sequences in the gRNA design. Thus, carefully designed gRNAs will ensure that desired genetic edits are performed and target variants are achieved. This work will avail the future research aimed at optimizing genome editing by customizing CRISPR-Cas9 to target specific protospacer DNA through gRNA.

CRISPR-Cas Systems↗