Baicalin protects against hepatocyte injury caused by aflatoxin B1 via the TP53-related ferroptosis Pathway.

OBJECTIVE: Baicalin has antioxidative, antiviral, and anti-inflammatory properties. However, its ability to alleviate oxidative stress (OS) and DNA damage in liver cells exposed to aflatoxin B1 (AFB1), a highly hepatotoxic compound, remains uncertain. In this study, the protective effects of baicalin on AFB1-induced hepatocyte injury and the mechanisms underlying those effects were investigated. METHODS: Stable cell lines expressing CYP3A4 were established using lentiviral vectors to assess oxidative stress levels by conducting assays to determine the content of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Additionally, DNA damage was evaluated by 8-hydroxy-2-deoxyguanosine (8-OHdG) and comet assays. Transcriptome sequencing, molecular docking, and in vitro experiments were conducted to determine the mechanisms underlying the effects of baicalin on AFB1-induced hepatocyte injury. In vivo, a rat model of hepatocyte injury induced by AFB1 was used to evaluate the effects of baicalin. RESULTS: In vitro, baicalin significantly attenuated AFB1-induced injury caused due to OS, as determined by a decrease in ROS, MDA, and SOD levels. Baicalin also considerably decreased AFB1-induced DNA damage in hepatocytes. This protective effect of baicalin was found to be closely associated with the TP53-mediated ferroptosis pathway. To elaborate, baicalin physically interacts with P53, leading to the suppression of the expression of GPX4 and SLC7A11, which in turn inhibits ferroptosis. In vivo findings showed that baicalin decreased DNA damage and ferroptosis in AFB1-treated rat liver tissues, as determined by a decrease in the expression of γ-H2AX and an increase in GPX4 and SLC7A11 levels. Overexpression of TP53 weakened the protective effects of baicalin. CONCLUSIONS: Baicalin can alleviate AFB1-induced OS and DNA damage in liver cells via the TP53-mediated ferroptosis pathway. In this study, a theoretical foundation was established for the use of baicalin in protecting the liver from the toxic effects of AFB1.

Case report: TP53 c.848G>A germline mutation as a possible screening target at initial diagnosis for acute lymphoblastic leukemia.

BACKGROUD: Li-Fraumeni syndrome is a hereditary tumor syndrome characterized by an elevated risk of malignancy, particularly acute lymphoblastic leukemia (ALL), which can be caused by the heterozygous germline mutation. TP53 gene germline mutation is considered a potential risk factor and crucial prognostic parameter for acute leukemia development and diagnosis, but rarely occurs in adults, and its specific pathogenic significance in acute leukemia is unclear. CASE PRESENTATION: We describes a case of a 45-year-old woman diagnosed with ALL. Whole-exome sequencing approach identified one of the TP53 germline mutations from her bone marrow sample with possible pathogenic significance, c.848G>A (p.Arg283His) heterozygous missense mutation located on exon 8, which was further verified in her hair, oral mucous and nail samples. Family pedigree screening revealed that the same TP53 genetic variant was present in the patient's father and non-donor son, whereas not in the donor. Digital PCR observed that this point mutation frequency dropped post-transplantation but remained low during maintenance therapy when the patient was leukemia-free. CONCLUSION: This suspected Li-Fraumeni syndrome case report with a likely pathogenic heterozygous TP53 variant expands the cancer genetic spectrum. Screening her family members for mutations facilitates identifying the optimal relative donor and avoids unnecessary treatment by monitoring TP53 germline mutations for minimal residual disease following hematopoietic stem cell transplantation. Its potential roles in hematological malignant tumor development and clinical pathogenic implications necessitate further probing.

Genetic Testing of Breast Cancer Patients with Very Early-Onset Breast Cancer (≤30 Years) Yields a High Rate of Germline Pathogenic Variants, Mainly in the BRCA1, TP53, and BRCA2 Genes.

Early-onset breast cancer constitutes a major criterion for genetic testing referral. Nevertheless, studies focusing on breast cancer patients (≤30 years) are limited. We investigated the contribution and spectrum of known breast-cancer-associated genes in 267 Greek women with breast cancer ≤30 years while monitoring their clinicopathological characteristics and outcomes. In this cohort, a significant proportion (39.7%) carried germline pathogenic variants (PVs) distributed in 8 genes. The majority, namely 36.7%, involved BRCA1, TP53, and BRCA2. PVs in BRCA1 were the most prevalent (28.1%), followed by TP53 (4.5%) and BRCA2 (4.1%) PVs. The contribution of PVs in CHEK2, ATM, PALB2, PTEN, and RAD51C was limited to 3%. In the patient group ≤26 years, TP53 PVs were significantly higher compared to the group 26-30 years (p = 0.0023). A total of 74.8% of TP53 carriers did not report a family history of cancer. Carriers of PVs receiving neoadjuvant chemotherapy showed an improved event-free survival (p < 0.0001) compared to non-carriers. Overall, many women with early-onset breast cancer carry clinically actionable variants, mainly in the BRCA1/2 and TP53 genes. The inclusion of timely testing of TP53 in these patients provides essential information for appropriate clinical management. This is important for countries where reimbursement involves the cost of genetic analysis of BRCA1/2 only.

Dermatomyositis-like skin eruptions under hydroxyurea therapy conceal TP53-mutated atypical keratinocytes: A histopathologic and molecular pathologic case series.

Hydroxyurea is an antimetabolite that inhibits DNA synthesis and is used as a treatment option in chronic myeloproliferative disorders. Rarely, "dermatomyositis (DM)-like" skin lesions are observed after long-term therapy. In this case series, five skin biopsies of four patients were evaluated by histology, immunohistochemistry, and next-generation sequencing of the TP53 gene locus. All biopsies showed focal basal pleomorphic keratinocytes and suprabasal aberrant p53 expression as well as sparse to severe vacuolar interface dermatitis. Histopathologically, "DM-like" skin lesions can be clearly distinguished from DM by marked subepidermal fibrosis, vascular proliferation, and the absence of dermal mucin deposits. In 75% of the specimens multiple, partly inactivating and/or pathogenic point mutations of TP53 were found in low frequencies. "DM-like" skin eruptions as a long-term consequence of hydroxyurea therapy are possibly not chemotherapy-associated benign toxic changes, but rather inflammatory reactions to complex keratinocyte alterations that clinically mimic the picture of DM. Synergistic mutagenic effects of hydroxyurea and sunlight might be responsible for this unique drug side effect and could provide a pathogenic link to the known increased risk of skin cancer in these patients.

Methylation of the Selected TP53 Introns in Advanced-Stage Ovarian Carcinomas.

Objective: Advanced-stage ovarian cancer (OC) is among the most fatal female genital tract neoplasms worldwide. Although different genetic mechanisms have been shown to be involved in ovarian carcinogenesis, the role of TP53 introns methylation is still unresolved. We performed methylation analysis of introns 1, 3, and 4 of the TP53 to identify patterns in primary stage III OCs, corresponding metastases, and healthy tissues. Methods: The study involved samples of paraffin-embedded tissues obtained from 80 patients with stage III OCs, who underwent surgery at the Department of Gynecology and Gynecologic Oncology of the Military Institute of Medicine in Warsaw, Poland. Altogether, 40 serous-type G2/3 OCs and 40 endometrioid-type G2/3 OCs were included. From the same patient, metastatic and normal tissues were simultaneously analyzed. As a control group, 80 tissue samples were collected from patients after bariatric operations. Human ovarian cancer A2780 cell line was also investigated. Total genomic DNA was isolated from paraffin-embedded tissue blocks and the methylation analysis was performed by bisulfite DNA conversion, DNA amplification with specific primers, cloning, and DNA sequencing. Results: All of the samples of intron 1 of TP53 were un-methylated in OCs, metastatic tissues, and in healthy tissues from the same patient. Also, no methylation of TP53 intron 1 was detected in cells from the human A2780 ovarian cancer cell line and in all samples from control group. In all samples, introns 3 and 4 of the TP53 were methylated in primary tumors, metastatic tissue, and in healthy tissue from the same patient, in human A2780 ovarian cell line, and in DNA samples from healthy patients. None of the clinicopatholocal features was related to the TP53 introns methylation status. Conclusions: Our data on TP53 introns methylation sheds new light on the mechanism of p53 activity for a better understanding of cancer biology. The study suggests the existence of an additional regulation rule of TP53 activity that involves demethylation-methylation mechanisms. Methylation at introns 3 and 4 may also overall help in protecting TP53 against damage by viral restrictases or viral DNA integration.

Interactive Association of XRCC1, XRCC2, XRCC3, and TP53 Gene Polymorphisms With Gastrointestinal Cancer Risk: Insights From a Hospital-Based Case-Control Study.

BACKGROUND AND AIM: Gastrointestinal (GI) cancer presents a significant worldwide health burden, influenced by a combination of genetic and environmental factors. This study endeavors to explore the combined effects of the XRCC1, XRCC2, XRCC3, and TP53 genes that contribute to the heightened risk of GI cancer, shedding light on their combined influence on cancer susceptibility. MATERIALS AND METHODS: A total of 200 histologically confirmed cases of GI cancer and an equal number of controls were selected to examine genetic polymorphisms within the XRCC1, XRCC2, XRCC3, and TP53 genes using the polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). Odds ratios (OR) with 95% confidence intervals (CI) were calculated to assess the association of these polymorphisms with GI cancer susceptibility, with statistical significance (p ≤ 0.05). RESULTS: Logistic regression analysis confirmed strong evidence of synergistic interactions among specific variant genotypes. Notably, combinations such as heterozygous Arg/Ser+Ser/Ser genotype of TP53 Arg249Ser polymorphism with Arg/Trp+Trp/Trp genotype of XRCC1 Arg194Trp polymorphism (OR=2.64; 95% CI: 1.35-5.18; p=0.004), Arg/Gln+Gln/Gln genotype of XRCC1 at codon 399 (OR=5.04; 95% CI: 2.81-9.05; p=0.0001), Arg/His and His/His genotypes of XRCC2 Arg188His (OR=2.16; 95% CI: 1.06-4.39; p<0.032), and Thr/Met+Met/Met genotype of XRCC3 Thr242Met (OR=3.48; 95% CI: 1.79-6.77; p=0.0002) showed significant associations with GI cancer risk in the study population. CONCLUSIONS: The findings indicate a notable association between the combined effect of heterozygous variant genotypes of TP53 and variant genotypes of XRCC1, XRCC2, and XRCC3 on GI cancer risk. However, further research with a larger sample size and broad single nucleotide polymorphism (SNP) spectra is necessary to understand the interaction between genetic variations and environmental factors influencing GI cancer susceptibility.

Identification and prognostic analysis of metabolic genes associated with TP53 mutation in multiple myeloma.

BACKGROUND: TP53 gene mutation is crucial in determining the prognosis of Multiple Myeloma (MM) patients. Understanding metabolic genes linked to TP53 mutation is vital for developing targeted therapies for these patients. METHOD: We analyzed The Cancer Genome Atlas (TCGA) dataset to identify genes related to TP53 mutation and metabolism. Using univariate Cox regression and protein-protein interaction (PPI) analysis, we identified key genes. We categorized patients into high and low metabolism groups via non-negative matrix factorization (NMF) clustering, which led to the discovery of relevant differential genes. Integrating these with genes from the Gene Expression Omnibus (GEO) datasets and PPI interactions, we pinpointed crucial metabolic genes associated with TP53 mutation in MM. Additionally, we conducted prognostic analyses involving survival curves and receiver operating characteristic (ROC) charts. RESULTS: Our study reveals that the metabolic gene ribonucleotide reductase M2 (RRM2), linked to TP53 mutation, correlates positively with the International Staging System (ISS) stage in MM patients and is an independent prognostic risk factor. In the TCGA dataset, among the 767 patients, the 35 MM patients with TP53 mutation generally had poor survival outcomes. Specifically, the patients with both TP53 mutation and high RRM2 expression had a 2-year survival rate of only 38.87%, whereas those with normal TP53 function and low RRM2 expression had a 2-year survival rate of 86.31% (p < 0.001). CONCLUSION: RRM2 significantly impacts MM prognosis and is associated with TP53 mutation, presenting itself as a potential therapeutic target and prognostic marker for MM.

An efficient method for immortalizing mouse embryonic fibroblasts.

Mouse embryonic fibroblasts (MEFs) derived from genetically modified mice are a valuable resource for studying gene function and regulation. The MEF system can also be combined with rescue studies to characterize the function of mutant genes/proteins, such as disease-causing variants. However, primary MEFs undergo senescence soon after isolation and passaging, making long-term genetic manipulations difficult. Previously described methods for MEF immortalization are often inefficient or alter the physiological properties of the cells. Here, we describe an optimized protocol for immortalizing MEFs via CRISPR-mediated deletion of the Tp53 gene. This method is highly efficient and consistently generates immortalized MEFs, or iMEFs, within 14 days. Importantly, iMEFs closely resemble the parent cell populations, and individual iMEFs can be cloned and expanded for subsequent genetic manipulation and characterization. We envision that this protocol can be adopted to immortalize other mouse primary cell types.

Transcriptomic response of prostate cancer cells to carbon ion and photon irradiation with focus on androgen receptor and TP53 signaling.

BACKGROUND: Radiotherapy is essential in the treatment of prostate cancer. An alternative to conventional photon radiotherapy is the application of carbon ions, which provide a superior intratumoral dose distribution and less induced damage to adjacent healthy tissue. A common characteristic of prostate cancer cells is their dependence on androgens which is exploited therapeutically by androgen deprivation therapy in the advanced prostate cancer stage. Here, we aimed to analyze the transcriptomic response of prostate cancer cells to irradiation by photons in comparison to carbon ions, focusing on DNA damage, DNA repair and androgen receptor signaling. METHODS: Prostate cancer cell lines LNCaP (functional TP53 and androgen receptor signaling) and DU145 (dysfunctional TP53 and androgen receptor signaling) were irradiated by photons or carbon ions and the subsequent DNA damage was assessed by immuno-cytofluorescence. Furthermore, the cells were treated with an androgen-receptor agonist. The effects of irradiation and androgen treatment on the gene regulation and the transcriptome were investigated by RT-qPCR and RNA sequencing, followed by bioinformatic analysis. RESULTS: Following photon or carbon ion irradiation, both LNCaP and DU145 cells showed a dose-dependent amount of visible DNA damage that decreased over time, indicating occurring DNA repair. In terms of gene regulation, mRNAs involved in the TP53-dependent DNA damage response were significantly upregulated by photons and carbon ions in LNCaP but not in DU145 cells, which generally showed low levels of gene regulation after irradiation. Both LNCaP and DU145 cells responded to photons and carbon ions by downregulation of genes involved in DNA repair and cell cycle, partially resembling the transcriptome response to the applied androgen receptor agonist. Neither photons nor carbon ions significantly affected canonical androgen receptor-dependent gene regulation. Furthermore, certain genes that were specifically regulated by either photon or carbon ion irradiation were identified. CONCLUSION: Photon and carbon ion irradiation showed a significant congruence in terms of induced signaling pathways and transcriptomic responses. These responses were strongly impacted by the TP53 status. Nevertheless, irradiation mode-dependent distinct gene regulations with undefined implication for radiotherapy outcome were revealed. Androgen receptor signaling and irradiations shared regulation of certain genes with respect to DNA-repair and cell-cycle.

Clinical utility of DNA methylation profiling for choroid plexus tumors.

Background: Choroid plexus tumors (CPTs) are rare, potentially aggressive CNS tumors with defined histologic criteria for grading. In recent years, several patients within our practice have demonstrated discordance between the histologic diagnosis and clinical behavior. DNA methylation profiling has emerged as a potential diagnostic adjunct for aiding the clinical approach. Methods: We reviewed the clinical and pathologic data of all CPTs diagnosed at Boston Children's Hospital from 1995 to 2023. All cases with available material (38/48) underwent DNA methylation profiling at NIH/NCI, and the classifier results were correlated with the WHO histologic grade and patient outcomes. Survival information was analyzed using Kaplan-Meier curves. Results: There was good correlation (11/12, 92%) between methylation class and WHO histologic grade for choroid plexus carcinomas (CPC); one histologic CPC grouped with choroid plexus papilloma (CPP) group pediatric (P). Five CPPs grouped with methylation class CPC (5/17, 29%). In the group of atypical CPPs (n = 9), there were two that grouped with methylation class CPC. Survival analysis showed utility of methylation classes in the prediction of biologic behavior. Conclusions: Results indicated that methylation profiling may serve as a valuable tool in the clinical decision-making process for patients with CPTs, providing additional prognostic information compared to WHO histologic grade alone. The value of methylation array analysis is particularly important given the lack of consensus on treatment regimens for CPTs.

TUSC3, p53 and p21 genetic association with development of oral submucous fibrosis and oral squamous cell carcinoma among addictive tobacco chewers of Pakistan.

BACKGROUND: This study delves into the intricate landscape of oral cancer, a global concern with a high incidence in Asian countries. We focus on oral squamous cell carcinoma (OSCC), primarily driven by the consumption of betel nut and its derivatives. OSCC often arises from premalignant lesions like oral submucous fibrosis (OSF). In Pakistan, OSCC is prevalent among men due to various addictive substances, including smokeless tobacco and chewing materials. Mutations in tumor suppressor genes, such as TP53 and p21, play crucial roles in this malignancy's development. We also explore the involvement of TUSC3 gene deletion in OSCC and OSF. METHODS: In this study we investigated demographics, TUSC3 gene expression, deletion analysis, and TP53 and p21 genetic alterations in OSCC and OSF patients (blood and tissue of 50 samples in each condition) who had tobacco derivates usage history. The association analysis was carried out mainly through PCR based genotyping. RESULTS: The study's patient cohort (OSCC and OSF) displayed a wide age range from 13 to 65 years (Mean = 32.96 years). Both conditions were more prevalent in males, with a male-female ratio of approximately 2.5:1. Chewing habits analysis revealed high frequencies of gutka use in both OSF and OSCC patients. TUSC3 expression analysis in OSCC cell lines indicated significant downregulation. Genotyping showed no TUSC3 deletion in OSF cases, but a deletion rate of over 22% in OSCC tissue samples. Analysis supported a significant association of TUSC3 deletion with OSCC development but not with OSF. Polymorphism in p53 exon 4 and p21 (rs1801270) were significantly associated with both OSCC and OSF, adding to their pathogenesis. Our findings further revealed a strong correlation between TUSC3 deletion and the excessive use of tobacco and related products, shedding light on the genetic underpinnings of OSCC development. CONCLUSIONS: Notably, our study provides a crucial insight into genetic aspects underlying OSCC and OSF in response of addictive consumption of areca nut, betel quid, and tobacco derivatives. A significant association between TUSC3 deletion and OSCC development, along with polymorphisms in TP53 and p21, underscores the importance of further research into the molecular mechanisms driving oral cancer progression for improved diagnosis and treatment outcomes.

Chromothripsis is a novel biomarker for prognosis and differentiation diagnosis of pancreatic neuroendocrine neoplasms.

This study aimed to identify the role of chromothripsis as a novel biomarker in the prognosis and differentiation diagnosis of pancreatic neuroendocrine neoplasms (pNENs). We conducted next-generation gene sequencing in a cohort of 30 patients with high-grade (G3) pNENs. As a reference, a similar analysis was also performed on 25 patients with low-grade (G1/G2) pancreatic neuroendocrine tumors (pNETs). Chromothripsis and its relationship with clinicopathological features and prognosis were investigated. The results showed that DNA damage response and repair gene alteration and TP53 mutation were found in 29 and 11 patients, respectively. A total of 14 out of 55 patients had chromothripsis involving different chromosomes. Chromothripsis had a close relationship with TP53 alteration and higher grade. In the entire cohort, chromothripsis was associated with a higher risk of distant metastasis; both chromothripsis and metastasis (ENETS Stage IV) suggested a significantly shorter overall survival (OS). Importantly, in the high-grade pNENs group, chromothripsis was the only independent prognostic indicator significantly associated with a shorter OS, other than TP53 alteration or pathological pancreatic neuroendocrine carcinomas (pNECs) diagnosis. Chromothripsis can guide worse prognosis in pNENs, and help differentiate pNECs from high-grade (G3) pNETs.

Pathogenic variants in human DNA damage repair genes mostly arose after the latest human out-of-Africa migration.

Introduction: The DNA damage repair (DDR) system in human genome is pivotal in maintaining genomic integrity. Pathogenic variation (PV) in DDR genes impairs their function, leading to genome instability and increased susceptibility to diseases, especially cancer. Understanding the evolution origin and arising time of DDR PV is crucial for comprehending disease susceptibility in modern humans. Methods: We used big data approach to identify the PVs in DDR genes in modern humans. We mined multiple genomic databases derived from 251,214 modern humans of African and non-Africans. We compared the DDR PVs between African and non-African. We also mined the DDR PVs in the genomic data derived from 5,031 ancient humans. We used the DDR PVs from ancient humans as the intermediate to further the DDR PVs between African and non-African. Results and discussion: We identified 1,060 single-base DDR PVs across 77 DDR genes in modern humans of African and non-African. Direct comparison of the DDR PVs between African and non-African showed that 82.1% of the non-African PVs were not present in African. We further identified 397 single-base DDR PVs in 56 DDR genes in the 5,031 ancient humans dated between 45,045 and 100 years before present (BP) lived in Eurasian continent therefore the descendants of the latest out-of-Africa human migrants occurred 50,000-60,000 years ago. By referring to the ancient DDR PVs, we observed that 276 of the 397 (70.3%) ancient DDR PVs were exclusive in non-African, 106 (26.7%) were shared between non-African and African, and only 15 (3.8%) were exclusive in African. We further validated the distribution pattern by testing the PVs in BRCA and TP53, two of the important genes in genome stability maintenance, in African, non-African, and Ancient humans. Our study revealed that DDR PVs in modern humans mostly emerged after the latest out-of-Africa migration. The data provides a foundation to understand the evolutionary basis of disease susceptibility, in particular cancer, in modern humans.

Germline rare variants in HER2-positive breast cancer predisposition: a systematic review and meta-analysis.

Introduction: Approximately 10% of breast cancer (BC) cases result from hereditary causes. Genetic testing has been widely implemented in BC care to determine hereditary cancer syndromes and personalized medicine. Thus, identification of individuals carrying germline pathogenic variants could be useful to provide appropriate prophylactic or screening measures for each BC subtype, however, there are few formal recommendations for genetic testing in this sense so far. In this study, we assessed rare germline variants in a specific group of genes in order to determine the association with human epidermal growth factor 2 enriched (HER2+) BC phenotype through a systematic review and meta-analysis comparing subtypes overexpressing HER2 with other clinically recognized subtypes of BC. This review was registered with PROSPERO (ID: CRD42023447571). Methods: We conducted an online literature search in PubMed (MEDLINE), Scopus, and EMBASE databases. We included original studies that investigated germline variants in HER2+ BC patients and selected the studies that reported only rare and/or pathogenic germline variants. We assessed the risk of bias and quality of the studies using the Joanna Briggs Institute Critical Appraisal checklists and the Modified Newcastle-Ottawa Scale for Genetic Studies, respectively. Considering hormone receptor and HER2 expression status, we compared gene-based risks initially in HR-HER2-, HR+HER2-, HR+HER2+, and HR-HER2+ groups, conducting separate meta-analyses using the random effects model for each comparison, and within them for each gene. Results: Of the total 36 studies describing germline variants, 11 studies provided information on the prevalence of variants in the different clinically relevant BC subtypes and allowed comparisons. Germline variants within eight genes showed significant differences when meta-analyzed between the BC groups: BRCA1, BRCA2, TP53, ATM, CHEK2, PALB2, RAD51C, and BARD1. Notably, TP53, ATM, and CHEK2 germline variants were identified as predisposing factors for HER2+ subtypes, whereas BRCA1, BRCA2, PALB2, RAD51C, and BARD1 germline variants were associated with a predisposition to low HER2 expression. Main concerns about bias and quality assessment were the lack of confounding factors control; and comparability or outcome assessment, respectively. Discussion: Our findings underscore the connection between germline variants and differential expression of the HER2 protein and BC subtypes. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023447571.

CircCFL1 Promotes TNBC Stemness and Immunoescape via Deacetylation-Mediated c-Myc Deubiquitylation to Facilitate Mutant TP53 Transcription.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. TP53, which has a mutation rate of ≈70%-80% in TNBC patients, plays oncogenic roles when mutated. However, whether circRNAs can exert their effects on TNBC through regulating mutant TP53 has not been well evaluated. In this study, circCFL1, which is highly expressed in TNBC cells and tissues and has prognostic potential is identified. Functionally, circCFL1 promoted the proliferation, metastasis and stemness of TNBC cells. Mechanistically, circCFL1 acted as a scaffold to enhance the interaction between HDAC1 and c-Myc, further promoting the stability of c-Myc via deacetylation-mediated inhibition of K48-linked ubiquitylation. Stably expressed c-Myc further enhanced the expression of mutp53 in TNBC cells with TP53 mutations by directly binding to the promoter of TP53, which promoted the stemness of TNBC cells via activation of the p-AKT/WIP/YAP/TAZ pathway. Moreover, circCFL1 can facilitate the immune escape of TNBC cells by promoting the expression of PD-L1 and suppressing the antitumor immunity of CD8+ T cells. In conclusion, the results revealed that circCFL1 plays an oncogenic role by promoting the HDAC1/c-Myc/mutp53 axis, which can serve as a potential diagnostic biomarker and therapeutic target for TNBC patients with TP53 mutations.

Molecular Subtypes and the Role of TP53 in Diffuse Large B-Cell Lymphoma and Richter Syndrome.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and a heterogeneous entity comprised of several biologically distinct subtypes. Recently, novel genetic classifications of DLBCL have been resolved based on common mutational patterns indicative of distinct pathways of transformation. However, the complicated and costly nature of the novel classifiers has precluded their inclusion into routine practice. In view of this, the status of the TP53 gene, which is mutated or deleted in 20-30% of the cases, has emerged as an important prognostic factor for DLBCL patients, setting itself apart from other predictors. TP53 genetic lesions are particularly enriched in a genetic subtype of DLBCL that shares genomic features with Richter Syndrome, highlighting the possibility of a subset of DLBCL arising from the transformation of an occult chronic lymphocytic leukemia-like malignancy, such as monoclonal B-cell lymphocytosis. Patients with TP53-mutated DLBCL, including those with Richter Syndrome, have a particularly poor prognosis and display inferior responses to standard chemoimmunotherapy regimens. The data presented in this manuscript argue for the need for improved and more practical risk-stratification models for patients with DLBCL and show the potential for the use of TP53 mutational status for prognostication and, in prospect, treatment stratification in DLBCL.

Therapeutic targeting of TP53 nonsense mutations in cancer.

Mutations in the TP53 tumor suppressor gene occur with high prevalence in a wide range of human tumors. A significant fraction of these mutations (around 10%) are nonsense mutations, creating a premature termination codon (PTC) that leads to the expression of truncated inactive p53 protein. Induction of translational readthrough across a PTC in nonsense mutant TP53 allows the production of full-length protein and potentially restoration of normal p53 function. Aminoglycoside antibiotics and a number of novel compounds have been shown to induce full-length p53 in tumor cells carrying various TP53 nonsense mutations. Full-length p53 protein generated by translational readthrough retains the capacity to transactivate p53 target genes and trigger tumor cell death. These findings raise hopes for efficient therapy of TP53 nonsense mutant tumors in the future.

The correlation between KRAS and TP53 gene mutations and early growth of pulmonary nodules.

PURPOSE: The purpose of this study is to investigate whether gene mutations can lead to the growth of malignant pulmonary nodules. METHODS: Retrospective analysis was conducted on patients with pulmonary nodules at Hebei Provincial People's Hospital, collecting basic clinical information such as gender, age, BMI, and hematological indicators. According to the inclusion and exclusion criteria, 85 patients with malignant pulmonary nodules were selected for screening, and gene mutation testing was performed on all patient tissues to explore the relationship between gene mutations and the growth of malignant pulmonary nodules. RESULTS: There is a correlation between KRAS and TP53 gene mutations and the growth of pulmonary nodules (P < 0.05), while there is a correlation between KRAS and TP53 gene mutations and the growth of pulmonary nodules in the subgroup of invasive malignant pulmonary nodules (P < 0.05). CONCLUSION: Mutations in the TP53 gene can lead to the growth of malignant pulmonary nodules and are correlated with the degree of invasion of malignant pulmonary nodules.

Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Mutations in the TP53, VEGFA, and CTH Genes as Key Molecular Markers for the Diagnosis of Glioblastoma.

Background Brain cancer, particularly glioblastoma (GBM), is a global health problem. Despite therapy advances, GBM patients have a poor prognosis. The progression and etiology of GBM may be linked to gene polymorphisms in the VEGFA, TP53, and CTH genes, among others. However, the genetic variations and their interaction in GBM are not fully understood. This study examines the effects of mutations in the VEGFA, TP53, and CTH genes on GBM. Methodology Tissue and blood samples were obtained for hematological, biochemical, and genetic analysis from 18 patients diagnosed with GBM as well as 28 healthy individuals. Standard methods were adopted to perform hematological and biochemical analyses, whereas mutational landscape and expression profiles were obtained from publicly accessible databases. Tissue samples were processed for genomic DNA extraction, and genotype determination was carried out through conventional polymerase chain reaction (PCR) and Sanger sequencing. Results The study involved 18 patients with grade IV GBM before treatment and 28 healthy individuals. The patients consisted of 11 men (61%) and seven females (39%), while healthy individuals included 14 (50%) males and 14 (50%) females. Sixty-seven percent of patients were under 50, 17% between 51 and 60, and 17% over 61, compared to healthy individuals who were 61% under 50, 7% between 51 and 60, and 32% over 60. GBM patients showed higher neutrophil and monocyte counts (median 81% (63.9, 83.5) and 4.2% (3.8-7.3)), respectively, and lower lymphocyte counts (median 13.4% (8.8, 28.40)) compared to controls. The median values of aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) showed no significant differences between the control and GBM groups. GBM patients had significantly higher median CRP levels of 2.55 (1.6, 98) than controls. Analysis of databases revealed a high prevalence of mutations in TP53, with splice region variants, missense variants, and intron variants being the most common. VEGFA and CTH also displayed mutations, primarily missense and intron variants. Gene expression analysis showed significantly higher levels of TP53 and VEGFA in GBM patients compared to controls. CTH expression also exhibited a slight increase in GBM patients. Sanger sequencing identified three mutations in the TP53 gene, including a novel mutation (11915C>A) not previously reported in external databases. Additionally, novel mutations were found in the VEGFA (841G>GA, 919T>TG) and CTH (28398A>AC, 28399A>AT) genes. Conclusions This study highlights the immune dysregulation, inflammation, and genetic variations in GBM. The findings emphasize the potential importance of the TP53, VEGFA, and CTH genes as targets for therapies and diagnostic biomarkers of GBM. Further study is necessary to comprehend these genetic variations' functional implications and their use in personalized GBM treatment.