TP53 Gene Research Articles

A comparative analysis of somatic mutational profiles according to HIV status among women with cervical intraepithelial neoplasia 3 (CIN3): a focus on hotspots in TP53, PIK3CA, PTEN, and EGFR

BackgroundDespite the success of antiretroviral therapy in HIV treatment, cervical cancer remains a leading malignancy in HIV-infected women. Additionally, co-infection by HIV and HPV further accelerates cervical cancer development. There are limited studies on the role of host somatic variations in HIV infected and HIV-negative women with cervical cancer. Therefore, this study aimed to investigate and compare host somatic genetic variation in cervical biopsies obtained from HIV infected and HIV-negative women with cervical intraepithelial neoplasia 3 to understand the genomic landscape. The distribution of HPV types was also investigated between HIV infected and HIV-negative women.MethodsThe project used an age-matched case–control study utilizing archived cervical biopsies from 88 women (44 HIV infected, 44 HIV-negative) attending Groote Schuur Hospital Cancer Clinic between 2020 and 2022. HPV infection and type were confirmed using the Anyplex™ II HPV28 Detection kit. Six hotspot regions in the four commonly mutated genes (TP53, PIK3CA, PTEN, and EGFR) in cervical cancer were genotyped using PCR and Sanger Sequencing. Variant pathogenicity was assessed using SIFT, Polyphen-2, and ClinVar tools.ResultsThe median age was 37 years (IQR: 34–41) for HIV infected women and 35 years (IQR:32- 43) for HIV-negative women. Significantly more HIV-negative women (51% vs. 12%) reported tobacco smoking (p < 0.0001), menstruation irregularities (74% vs. 35%; p = 0.005), and contraception usage (77% vs. 59%; p = 0.019), when compared to their HIV-infected counterparts. Common HPV types identified were HPV16 (n = 43/88, 49%), HPV35 (n = 12/88, 14%), and HPV58 (n = 10/88, 11%). A total of 232 genetic variants were reported. HIV infected women had a significantly higher (p = 0.0406) burden of pathogenic variants (31%) compared to the HIV-negative (15%). The spectrum of observed mutations included stop-gain, missense, synonymous, and intronic changes. Most of the stop gain mutations in TP53 and PIK3CA were reported among HIV infected women (n = 4/5), compared to HIV-negative women (n = 1/5). Damaging variants were more prevalent in women under 50 in both cohorts. We also report on rare HPV subtypes currently not included in the diagnostic HPV test kits in this cohort (HPV 82, 42, 43 and 53).ConclusionHIV-infection status and age appear to be risk factors for higher burden of pathogenic mutations in genes that predispose to cervical cancer. Mutation profiles in PIK3CA and TP53 genes could be biomarkers of cervical cancer progression but more studies are needed.

Carcinoma arising in microglandular adenosis of the breast: clinicopathological and genetic analysis

AimsTo study the clinicopathological, immunohistochemical and molecular features of carcinoma arising in microglandular adenosis (MGACA) of the breast.MethodsClinicopathological features of 13 cases of MGACA were analysed. All tumours were molecular...

Exploring shared therapeutic targets for Alzheimer’s disease and glioblastoma using network pharmacology and protein-protein interaction approach

BackgroundAlzheimer’s disease (AD) and glioblastoma (GBM) are complex neurological disorders with distinct pathologies but overlapping molecular mechanisms, including neuroinflammation, oxidative stress, and dysregulated signaling pathways. Despite significant advancements in research, effective therapies targeting both conditions remain elusive. Identifying shared molecular targets and potential therapeutic agents could offer novel treatment strategies for these disorders.MethodologyThe study employs an integrative network pharmacology approach to explore the therapeutic potential of bioactive compounds from Eclipta alba, a medicinal herb known for its neuroprotective and anti-inflammatory properties. A systematic methodology was adopted, starting with network pharmacology analysis using STRING and DisGeNET databases, which identified 617 common genes associated with AD and GBM. Among these, key hub genes—TP53, STAT3, AKT1, and IL6—were prioritized using Cytoscape for network visualization and analysis.ResultsMolecular docking studies were conducted using PyRx software to assess the binding interactions of 26 phytochemicals from Eclipta alba against the identified target genes. Luteolin exhibited the highest binding affinity to IL6 (−7.8 kcal/mol), forming stable hydrogen bonds and hydrophobic interactions. To further validate this interaction, molecular dynamics simulations (MDS) were performed using GROMACS, confirming the stability of the Luteolin-IL6 complex. Additionally, MM-PBSA binding energy calculations using AmberTools (−145.44 kJ/mol) provided further evidence of a strong and stable interaction. Pharmacokinetic and toxicity evaluations, conducted using SwissADME and pkCSM, highlighted luteolin’s favorable drug-like properties, including good bioavailability and low toxicity. These findings suggest that luteolin may serve as a promising multi-target therapeutic agent for AD and GBM by modulating key pathological pathways.ConclusionThe present study provides a strong computational foundation for further in vitro and in vivo validation. The results highlight the potential of luteolin in developing dual-target treatment strategies for neurodegenerative and oncological disorders, offering new avenues for therapeutic advancements.

The deubiquitinase inhibitor WP1130 drives nuclear aggregation and reactivation of mutant p53 for selective cancer cell targeting.

Mutations in the TP53 gene may lead to the loss of its tumor suppressor function and the acquisition of oncogenic properties. The enhanced stability of mutant p53 (mutp53) is one of the pivotal factors for its oncogenic functions, rendering proteins implicated in mutp53 stabilization as promising targets for therapeutic intervention. Although deubiquitinases (DUBs) are commonly deregulated in various cancers, their specific impact on mutp53 stabilization remains largely unexplored. In this study, we demonstrated the involvement of DUBs-USP5 and USP9X in-enhancing mutp53 stability while revealing the effects of DUB inhibitor WP1130 in selectively destabilizing different p53 mutants in cancer cells of various origins. Mechanistically, WP1130 induced mutp53 ubiquitination and nuclear aggregation, resulting in its partitioning to the detergent-insoluble fraction. Moreover, combined treatment with the proteasome inhibitor augmented mutp53 accumulation in this fraction, indicating proteasomal degradation of these aggregates. Interestingly, WP1130 did not alter the stability or induce aggregation of WTp53 protein, suggesting its selective targeting of mutp53. Furthermore, WP1130 disrupted the interaction of mutp53 with HSP40 and HSP90 while promoting its association with ubiquitin ligase CHIP, thereby facilitating mutp53 destabilization. Notably, WP1130 reactivated mutp53 via induction of a wild-type-like p53 conformation, upregulating its downstream effectors and inducing apoptosis, possibly due to its targeted binding near the mutation site, as suggested by our in silico analysis. These findings highlight the roles of USP9X and USP5 in mutp53 stabilization and underscore the therapeutic potential of DUB inhibitor WP1130 for the selective targeting of mutp53-expressing cancer cells.

Abstract A011: ATM inhibitors exploit checkpoint defects and ATM-dependent double strand break repair to induce mitotic cell death in TP53-mutant glioblastoma

Abstract Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ) and show that HR and MMEJ are therapeutically-targetable treatment resistance mechanisms in glioblastoma. Using a targeted screen of clinically relevant small molecules, we identify the ATM kinase inhibitor, AZD1390, as a potent dual HR/MMEJ inhibitor. Mechanistic studies in GBM cell lines show that AZD1390 suppresses DSB end resection and blocks radiation-induced phosphorylation of DSBR proteins including nibrin, Rad50, and Mettl16. Interestingly, AZD1390 enhances the cytotoxic effects of TMZ and radiation in both treatment-naïve and treatment-resistant GBM samples harboring mutations in the TP53 gene. We show that TP53 mutation is associated with upregulation of ATM pathway genes in GBM patient samples along with heightened ATM-dependent HR and MMEJ in GBM cell lines. Finally, we show that TP53-mutant GBMs fail to arrest in G2 phase after radiation/AZD1390 or TMZ/AZD1390 combinations and instead attempt mitosis, leading to mitotic cell death. Expression of the mitotic DSBR factor, RHINO1, is associated with poor prognosis in patients with TP53-mutant GBMs, suggesting that factors that promote efficient mitotic DSBR protect TP53-mutant GBMs from treatment-induced cell death. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes ATM inhibition as a potential strategy for overcoming intrinsic and acquired treatment resistance in TP53-mutant GBMs. Citation Format: Daniel J Laverty, Shiv Gupta, Gary Bradshaw, Jiajia Chen, Brett L Carlson, Nery Matias Calmo, Shulan Tian, Jann N Sarkaria, Zachary D Nagel. ATM inhibitors exploit checkpoint defects and ATM-dependent double strand break repair to induce mitotic cell death in TP53-mutant glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A011.

Abstract A002: Immunotherapy responses in liver cancer: How TERT and TP53 mutations affect outcomes

Abstract Background: Genomic profiling has revolutionized therapeutic approaches and clinical management for liver cancer. However, the pathogenetic mechanisms, molecular drivers of recurrence, and predictive biomarkers remain only partially understood. An analysis of the United States Hepatocellular Carcinoma (HCC) cohort from The Cancer Genome Atlas showed that common mutations are mainly located in the TERT promoter region, TP53, and CTNNB1 genes. Recent studies on smaller Chinese have also identified TP53, TERT, and CTNNB1 as the most frequently mutated genes among Chinese HCC patients. Our study further explores the correlation between specific genomic mutations (TERT, TP53), and immunotherapy response in HCC cases. Methods: The cBioPorta was used for genomic profiling in multiple cohort studies of hepatobiliary cancer cases. Only HCC cases with TERT and TP53 mutation, and patients who had received immunotherapy, were included. Cases involving cholangiocarcinoma (CCA), HCC with CCA, other genetic mutations, or patients treated with chemotherapy were excluded from this study. Kaplan-Meier survival curves were created to assess the median overall survival (OS) based on immunotherapy response, and we calculated pooled 95% confidence intervals (CIs) to determine the reliability and precision of our result. The log-rank P-value was used to assess differences in OS between mutated genes. Results: The total cases were 1915 of hepatobiliary cancer after excluding 873 cases remaining with HCC among them, 400 patients (45.8%) had mutations in TERT, and 403 patients (46.2%) had mutations in TP53. The finalized number was 65 (64.4%) with TERT and 43 (42.4%) with TP53 who received immunotherapy. The median OS differed substantially across mutation types: 42 months for TERT mutations, 37 months for TP53 mutations, and 58 months for cases with both mutations (p=0.5). Conclusion: Our study observed improved OS in patients with both TERT and TP53 mutations. Although patients with only TERT mutations had better OS compared to those with TP53 mutations alone. Further research is required to clarify the specific associations between TERT mutations and treatment outcomes. Citation Format: Ebtesam Al-Najjar, Bayan Khasawneh, Waseem Abdelrahim, Abdullah Esmail, Ala Abudayyeh. Immunotherapy responses in liver cancer: How TERT and TP53 mutations affect outcomes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A002.

TP53-Mutated Myeloid Neoplasms: 2024 Update onDiagnosis, Risk-Stratification, and Management.

Alterations in the tumor suppressor gene TP53 are common in human cancers and are associated with an aggressive nature. Approximately 8%-12% of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) harbor TP53 mutations (TP53mut) and present immense challenges due to inherent chemoresistance and poor outcomes. As TP53mut are more common in older individuals and those with secondary/therapy-related myeloid neoplasms (MN), their incidence is expected to increase with an aging population and rising proportion of cancer survivors. Treatments used for other MN-intensive chemotherapy, hypomethylating agents, and the BCL-2 inhibitor venetoclax-do not improve the survival of TP53mut MN patients meaningfully. Additionally, further development of many promising agents has been discontinued, highlighting the challenges. Widespread acknowledgment of these problems led to the recognition of TP53mut MN as a distinct entity in the 5th edition of the World Health Organization and International Consensus Classifications. However, critical discrepancies between the two classifications may lead to under- or overestimation of the prognostic risk. Here, we review recent advances in the biology, diagnosis, and treatment of TP53mut MN. The development of TP53mut MN is positioned at the intersection of age, hereditary predisposition, and anti-cancer therapies. Precursor TP53mut clones can be detected years prior to the eventual leukemic transformation-raising the possibility of early intervention. We discuss the two classification systems and the bearing of the discrepancies between the two on timely and effective management. We provide novel evidence in the areas of discrepancies. Finally, we review the current therapeutic landscape and the obvious limitations of the currently used therapies.

Tumor protein 53 gene polymorphism, demographic attributes and associated risk factors among liver cancer patients in Calabar, Nigeria

Mutations in the TP53 gene had been attributed to the development of liver cancer. Hepatocellular carcinoma (HCC) and liver tumour are liver diseases having high mortality rates in several populations. There is no information on the TP53 gene polymorphism among liver diseases patients in Calabar, Nigeria. This study investigated the genetic polymorphism of TP53 among HCC and liver tumour in Calabar. This research was carried out in the University of Calabar Teaching Hospital, Calabar. Blood samples were collected from 35 clinically diagnosed hepatocellular carcinoma and 10 tumour patients and 10 healthy controls. DNA was extracted from all blood samples and Polymerase Chain Reaction (PCR) was performed using specific primers. The PCR amplicons were digested using Hae III restriction enzyme and the genotypic and allelic frequencies was determined. Demographic data among participants showed that males were 68.9% (31), females (31.1%; 14), sex ratio (2.2: 0.5), mean age was 41.51 ± 2.13 years with an odds ratio of 1.25. The distribution of participants according to marital status were 33(73.3%), 10(22.2%), and 2(4.4%) for married, single, and widowed respectively. The participants were from different extractions with varied representations of Yakurr (22.2%, 10), Efik (20%, 9), Boki (13.3%, 6), Ogoja (13.3%, 6), Annang (8.8%, 4), Ibibio (2.2%, 1) and Igbo (2.2%, 1) and respectively. Approximately, 64.7% (30) of the chronic liver diseases were from the Central and Northern part of Cross River State. The risk factors were HCV infection, HBsAg+, alcoholism, smoking, consumption of groundnuts that may have been contaminated with aflatoxin and family history of the disease. PCR product yielded 254 bp and digested PCR product showed homozygous TT mutation (27), heterozygous GT mutation (17) and homozygous GG wild type (1) in cases. The overall TP53 gene mutation frequency was 46.32% (44). The frequency of G allele, T allele, GG, GT and TT were 0.21, 0.79, 0.04, 0.33 and 0.62 respectively among cases, while GG (wild type) was only detected among controls in the study population. The genotypic and allelic frequencies conform to Hardy-Weinberg equilibrium meaning that the forces of evolution were not acting on the locus. There were significant differences in the genotypic proportions of the TP53 gene polymorphism among patients and controls. This study on the TP53 gene polymorphism will serve as baseline information on the molecular etiology of hepatocellular carcinoma and liver tumour in Cross River State.

Suppression of stress granule formation is a vulnerability imposed by mutant p53

Missense mutations in the TP53 (p53) gene have been linked to malignant progression. However, our in-silico analyses reveal that hepatocellular carcinoma (HCC) patients with mutant p53 (mutp53) have better overall survival compared to those with p53-null (p53null) HCC, unlike other cancer types. Given the historical use of sorafenib (SOR) monotherapy for advanced HCC, we hypothesize that mutp53 increases sensitivity to SOR, a multikinase inhibitor that induces endoplasmic reticulum (ER) stress. Here we show that mutp53 inhibits stress granule (SG) formation by binding to an ER stress sensor, PKR-like ER kinase (PERK), and a key SG component, GAP SH3 domain-binding protein 1 (G3BP1), contributing to increased sensitivity of SG-competent cells and xenografts to ER stress inducers including SOR. Our study identifies a unique vulnerability imposed by mutp53, suggesting mutp53 as a biomarker for ER stress-inducing agents and highlighting the importance of SG inhibition for cancer treatment.

18F-FDG PET/CT predicts the prognosis of patients with hepatocellular carcinoma undergoing liver transplantation

Introduction: In addition to radical resection, liver transplantation (LTx) is an effective treatment for hepatocellular carcinoma (HCC). However, tumor recurrence limits the efficacy of LTx in some patients. This study investigated the role of 18F-fludeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in predicting the prognosis of patients with HCC after LTx. Methods: A total of 278 consecutive patients with HCC who underwent pre-LTx PET/CT were divided into derivation (n = 178) and temporal validation (n = 100) cohorts and evaluated for PET/CT values, immunohistochemical (IHC) findings, and DNA sequencing of tumor tissues. Results: Patients with post-LTx recurrence exhibited significantly higher tumor maximum standardized uptake values (SUVmax) in pre-LTx PET/CT scans. Receiver operating characteristic (ROC) curve analyses identified the tumor SUVmax to liver SUVmax ratio (TSUVmax/LSUVmax) as the strongest predictor of post-LTx recurrence, with an optimal cutoff value of 1.43. Kaplan-Meier analyses demonstrated that a TSUVmax/LSUVmax &gt; 1.43 was associated with a shorter time to recurrence (TTR) and overall survival (OS) in both cohorts (p &lt; 0.001 for both). Multivariate Cox regression analyses confirmed that TSUVmax/LSUVmax &gt; 1.43 was an independent risk factor for tumor recurrence in both cohorts. IHC revealed that TSUVmax/LSUVmax &gt; 1.43 correlated with higher Ki-67 and CK19 expression. Next-generation sequencing (NGS) indicated that tumors with TSUVmax/LSUVmax &gt; 1.43 had more mutations and a higher tumor mutational burden (TMB). Furthermore, TSUVmax/LSUVmax &gt; 1.43 was significantly associated with mutations in TP53, EPPK1, MDM4, SLAMF7, SDHC, B4GALT3, RXRG and FCGR family genes, as well as TP53 and PI3K signaling pathway alterations. Conclusions: The preoperative TSUVmax/LSUVmax is a potential predictor of tumor recurrence in patients with HCC following LTx. Its use improves candidate selection and post-LTx management.

Frequency and Clinical Significance of Clonal and Subclonal Driver Mutations in High-Risk Neuroblastoma at Diagnosis: A Children's Oncology Group Study.

Relapsed high-risk neuroblastomas (NBLs) are enriched for targetable mutations in ALK and RAS-MAPK pathways, yet the prognostic effect of these aberrations and relevance of subclonal mutations at diagnosis remain undefined. We describe the spectrum and clinical significance of clonal and subclonal pathogenic alterations in high-risk NBL. We developed a focused high-risk NBL sequencing panel including ALK, NRAS, KRAS, HRAS, BRAF, PTPN11, TP53, and ATRX genes for ultra-deep sequencing and applied this assay to 242 pretherapy tumors from patients enrolled on the phase III trial Children's Oncology Group ANBL0532. We assessed the effect of clonal and subclonal mutations on event-free survival (EFS) and overall survival (OS). ALK-activating mutations occurred in 21.5% of tumors (n = 52, 30 clonal, 22 subclonal), and 3.3% (n = 8) showed ALK amplification. EFS and OS for patients with any ALK-aberrant tumor were inferior to patients with wild-type (WT) ALK tumors (5-year OS 37.7% v 66.3%; hazard ratio [HR], 1.992; P = .0007). EFS and OS for patients with tumors harboring activating ALK mutations ≥5% variant allele frequency (VAF) were inferior to ALK WT (5-year OS 37.7% v 66.3%; HR, 1.966; P = .0041). The 5-year EFS and OS for patients with ALK-amplified tumors were 25.0%. RAS pathway mutations occurred in 7.9% of tumors (n = 19; four clonal, 15 subclonal), with EFS and OS for those with VAF ≥5% inferior to RAS-WT patients (5-year OS 19.1% v 60.0%; HR, 3.021; P = .0168). Ultra-deep sequencing of high-risk NBLs demonstrates that oncogenic aberrations are more prevalent at diagnosis than previously recognized. ALK and RAS pathway aberrations confer inferior outcomes in patients treated with contemporary therapy, emphasizing the need for novel therapeutic approaches.

Dysregulated CDKN2A-MDM2-p53 axis in B cell of systemic lupus erythematosus.

Dysregulated CDKN2A-MDM2-p53 axis in B cell of systemic lupus erythematosus.

Oncogenic Mutations and the Tumor Microenvironment: Drivers of Non-Small Cell Lung Cancer Progression.

Non-small cell lung cancer (NSCLC) is a major cause of cancer-related deaths globally. The study focuses on understanding the interplay between genetic mutations, cancer stem cells (CSCs), and the tumor microenvironment (TME) in driving NSCLC progression, resistance to therapies, and relapse. A systematic search was conducted in PubMed and Scopus databases to identify significant and valuable studies relevant to NSCLC, focusing on genetic mutations, CSCs, and the TME. Articles were selected based on their relevance, methodological severity, date of publication, and scientific soundness related to NSCLC biology and therapeutic strategies. This review synthesized findings from these sources to highlight key mechanisms and potential therapeutic interventions. Mutations in critical genes in KRAS, EGFR, TP53, and other key genes interfere with stem cell regulation, promoting CSC-like behavior, resistance to therapy, and immune evasion. The tumor microenvironment (TME), including immune cells, fibroblasts, and extracellular matrix components, further supports tumor growth and reduction in treatment efficacy. Promising strategies, including CSC targeting, TME modulation, and the development of novel biomarkers, have shown potential in preclinical and clinical studies. The association between genetic alterations, CSCs, the TME, and other cellular pathways-including cell metabolism and immune evasion-plays a crucial role in therapy resistance, highlighting the need for comprehensive treatment strategies. The combination of genomic profiling with TME-targeting therapies could lead to personalized treatment approaches, offering hope for better clinical outcomes and reduced mortality in NSCLC patients.

Genomic characterization of metastatic patterns in prostate cancer using circulating tumor DNA data from the SCRUM-Japan MONSTAR SCREEN project.

Genomic characterization of metastatic patterns in prostate cancer using circulating tumor DNA data from the SCRUM-Japan MONSTAR SCREEN project.

Pathogenic germline variants in cancer predisposition genes in patients with multiple primary cancers in an Asian population and the role of extended panel genetic testing.

Pathogenic germline variants in cancer predisposition genes in patients with multiple primary cancers in an Asian population and the role of extended panel genetic testing.

Comprehensive genetic variant analysis reveals combination of KRAS and LRP1B as a predictive biomarker of response to immunotherapy in patients with non-small cell lung cancer

BackgroundIn non-small cell lung cancer (NSCLC), the rapid advancement of predictive genetic testing of tumors by identifying specific pathogenic driver variants has significantly improved treatment guidance. However, immune checkpoint blockade (ICB) is typically administered to patients with tumors in the absence of such driver variants. Since only about 30% of patients will respond to ICB treatment, identifying novel genetic biomarkers of clinical response is crucial and will improve treatment decisions. This prospective clinical study aims to combine molecular biology, advanced bioinformatics and clinical data on response to treatment with ICB from a prospective cohort of NSCLC patients to identify single or combination of genetic variants in the tumor that can serve as predictive biomarkers of clinical response.MethodsIn this prospective bi-center clinical study, we performed next-generation sequencing (NGS) of 597 cancer-associated genes in a prospective cohort of 49 patients as the final cohort analyzed, with stage III or IV NSCLC, followed by establishment of an in-house developed bioinformatics-based molecular classification method that integrates, interprets and evaluates data from multiple databases and variant prediction tools. Overall survival (OS) and progression-free survival (PFS) were analyzed for selected candidate genes and variants identified using our novel methodology including molecular tools, databases and clinical information.ResultsOur novel molecular interpretation and classification method identified high impact variants in frequently altered genes KRAS, LRP1B, and TP53. Analysis of these genes as single predictive biomarkers in ICB-treated patients revealed that the presence of likely pathogenic variants and variants of unclear significance in LRP1B was associated with improved OS (p = 0.041). Importantly, further analysis of variant combinations in the tumor showed that co-occurrence of KRAS and LRP1B variants significantly improved OS (p = 0.003) and merged PFS (p = 0.008). Notably, the triple combination of variants in KRAS, LRP1B, and TP53 positively impacted both OS (p = 0.026) and merged PFS (p = 0.003).ConclusionsThis study suggests that combination of the LRP1B and KRAS variants identified through our novel molecular classification scheme leads to better outcomes following ICB treatment in NSCLC. The addition of TP53 improves the outcome even further. To our knowledge, this is the first report indicating that harboring a combination of KRAS, LRP1B, and TP53 variants can significantly enhance the response to ICB, suggesting a novel predictive biomarker combination for NSCLC patients.

Biomarkers in clonal haematopoiesis of indeterminate potential (CHIP) linking cardiovascular diseases, myeloid neoplasms and inflammation.

There is increasing evidence that points to ubiquity of clonal haematopoiesis of indeterminate potential (CHIP) especially with rising age. CHIP has been associated with a multitude of inflammatory, cardiovascular and malignant conditions. In this review article, we evaluate the current literature on CHIP and clinical associations with cardiovascular and haematological diseases. We also discuss high risk features of CHIP that predispose to haematological malignancies, as well as further zoom in on the association between clonal haematopoiesis and therapy-related myeloid neoplasm (tMN). CHIP increases risk of atherosclerotic cardiovascular disease and other cardiovascular conditions such as heart failure, arrhythmias and valvular disease. Hematopoietic clones with mutations in TP53 and spliceosome gene U2AF1 in particularly have repeatedly been shown to increase risk for AML. Other factors such as increased clonal size i.e. variant allele fraction (VAF), clonal complexity have also been shown to increase risk for haematological malignancy. In this comprehensive review, we consolidate the most recent advancements in the understanding of clonal haematopoiesis of indeterminate potential (CHIP) and its associations with cardiovascular and haematological disease. This review is also one of the first to focus on potential biochemical markers routinely utilized in clinical practice that may suggest a more sinister progression of CHIP. We hope to provide physicians with a nuanced perspective on the evolving landscape of CHIP, and offering valuable insights into its clinical implications and potential prognostic indicators.

Diffusion imaging in gliomas: how ADC values forecast glioma genetics

PurposeThis study investigates the relationship between diffusion-weighted imaging (DWI) and mean apparent diffusion coefficient (ADC) values in predicting the genetic and molecular features of gliomas. The goal is to enhance non-invasive diagnostic methods and support personalised treatment strategies by clarifying the association between imaging biomarkers and tumour genotypes.Material and methodsA total of 91 glioma patients treated between August 2023 and March 2024 were included in the analysis. All patients underwent preoperative magnetic resonance imaging (MRI), including DWI, and had available histopathological and genetic test results. Clinical data, tumour characteristics, and genetic markers such as IDH1 mutation, MGMT promoter methylation, EGFR amplification, TERT pathogenic variant, and CDKN2A deletion were collected. Statistical analysis was performed to identify correlations between ADC values, MRI perfusion parameters, and genetic characteristics.ResultsSignificant associations were found between lower ADC values and aggressive tumour features, including IDH1-wildtype, MGMT unmethylated status, TERT pathogenic variant, and EGFR amplification. Additionally, distinct ADC patterns were observed in gliomas with CDKN2A, TP53, and PTEN gene deletions. These findings were further supported by contrast enhancement and other MRI parameters, indicating their role in tumour characteri­sation.ConclusionsDWI and ADC measurements demonstrate strong potential as non-invasive tools for predicting glioma genetics. These imaging biomarkers can aid in tumour characterisation and provide valuable insights for guiding personalised treatment strategies.

Quercetin inhibits proliferation and migration of clear cell renal cell carcinoma cells by regulating TP53 gene

To identify potential molecular targets of quercetin in the treatment of clear cell renal carcinoma (ccRCC). The therapeutic targets of quercetin were screened from multiple databases by network pharmacology analysis, and the targets significantly correlated with ccRCC were screened from 4907 plasma proteins using a Mendelian randomization method. The drug-disease network model was constructed to screen the potential key targets. The functions of these targets were evaluated via bioinformatics analysis, and the screened targets were verified in cultured ccRCC cells. Network pharmacology analysis combined with Mendelian randomization identified TP53 (OR=3.325, 95% CI: 1.805-6.124, P=0.0001), ARF4 (OR=0.173, 95% CI: 0.065-0.456, P=0.0003), and DPP4 (OR=0.463, 95% CI: 0.302-0.711, P=0.0004) as the core targets in quercetin treatment of ccRCC. Bioinformatics analysis showed that TP53 was highly expressed in ccRCC, and patients with high TP53 expressions had worse survival outcomes. Molecular docking studies showed that the binding energy between quercetin and TP53 was -5.83 kcal/mol. In cultured 786-O cells, CCK-8 assay and wound healing assay showed that treatment with quercetin significantly inhibited cell proliferation and migration. Quercetin treatment also strongly suppressed the expression of TP53 at both the mRNA and protein levels in 786-O cells as shown by RT-qPCR and Western blotting. TP53 may be the key target of quercetin in the treatment of ccRCC, which sheds light on potential molecular mechanism that mediate the therapeutic effect of quercetin.

Research on Precision Medicine AI Algorithm for Neuro Immune Gastrointestinal Diseases based on Quantum Biochemistry and Computational Cancer Genetics.

The objective of this study is to conduct network toxicology analysis based on smoking habits and develop a simpler and more effective toxicology product ingestion control system. Smoking behavior can affect the pathogenesis and prognosis of neuroimmune gastrointestinal diseases. The purpose of developing tools to assist clinical practice is to avoid the harm of cigarettes to the human body. Molecular dynamics method was used to elucidate the biophysical mechanism of TP53 gene mutation caused by harmful ingredients, and the signaling pathway of midbrain edge excitation was determined by molecular dynamics of nicotine and dopamine receptor D3. The possible involvement of nicotine in neuronal damage was determined through the molecular interaction between nicotine and ACHE. Molecular pathways were analyzed based on the aforementioned biological principles, developed artificial intelligence systems and brain computer interface systems. Several signaling pathways were elucidated, and effective AI algorithms were developed. The accuracy of artificial intelligence systems is over 70%. This study provides clinical doctors with a new precision medicine strategy and tool to regulate patient behavior and reduce disease risk. Other: This project was approved by the Ethics Committee of Chifeng Cancer Hospital and reported to the WHO.