Recently, the WHO-5 and the ICC 2022 criteria have emphasized poor prognosis in AML/MDS patients with multi-hit TP53 mutations, whereas mutated TP53 plays a critical role in tumorigenesis, drawing substantial interest in exploring its biological behaviors. Diverse characteristics of TP53 mutations, including types, VAF, CNVs, allelic status, karyotypes, and concurrent mutations have been extensively studied. Novel potential targets and comprehensive treatment strategies nowadays are under swift development, owing to great advances in technology. However, accurately predicting prognosis of patients with TP53-mutated myeloid neoplasms remains challenging. And there is still a lack of effective treatment for those patients.

TP53 mutation is one of the most common genetic alterations in urothelial carcinoma (UrCa), and heterogeneity of TP53 mutants leads to heterogeneous clinical outcomes. This study aimed to investigate the clinical relevance of specific TP53 mutations in UrCa. In this study, a total of eight cohorts were enrolled, along with matched clinical annotation. TP53 mutations were classified as disruptive and nondisruptive according to the degree of disturbance of p53 protein function and structure. We evaluated the clinical significance of TP53 mutations in our local datasets and publicly available datasets. The co-occurring events of TP53 mutations in UrCa, along with their therapeutic indications, functional effects, and the tumor immune microenvironment, were also investigated. TP53 mutations were identified in 49.7% of the UrCa patients. Within this group, 25.1% of patients carried TP53Disruptive mutations, a genetic alteration correlated with a significantly poorer overall survival (OS) when compared to individuals with TP53Nondisruptive mutations and those with wild-type TP53. Significantly, patients with TP53Disruptive mutations exhibit an increased probability of responding favorably to PD-1/PD-L1 blockade and chemoimmunotherapy. Meanwhile, there was no noteworthy distinction in OS among patients with varying TP53 mutation status who underwent chemotherapy. Samples with TP53Disruptive mutations showed an enriched APOBEC- and POLE-related mutational signature, as well as an elevated tumor mutation burden. The sensitivity to immunotherapy in tumors carrying TP53Disruptive mutation may be attributed to the inflamed tumor microenvironment characterized by increased CD8+T cell infiltration and interferon-gamma signaling activation. In conclusion, UrCa patients with TP53Disruptive mutations have shown reduced survival rates, yet they may respond well to PD-1/PD-L1 blockade therapy and chemoimmunotherapy. By distinguishing specific TP53 mutations, we can improve risk stratification and offer personalized genomics-guided therapy to UrCa patients. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Hypopharyngeal squamous cell carcinoma (HPSCC) has the worst prognosis among head and neck squamous cell carcinomas. The lack of available tumor cell lines poses a significant obstacle to the development of efficient treatments for HPSCC. In this study, we successfully established a novel cell line, named CZH1, from the postcricoid region of a Chinese male patient with a T3N0M0 HPSCC. Short tandem repeat analysis confirmed the uniqueness of CZH1. The cell line was characterized by its phenotypes, biomarkers, and genetics. Importantly, CZH1 cells retained the typical features of epithelial malignancy, similar to the primary tumor tissue. Furthermore, CZH1 demonstrated a greater capacity for invasion and increased susceptibility to irradiation in comparison to FaDu, which is the most commonly used HPSCC cell line. Whole-exome sequencing analysis revealed that CZH1 cells had typical genomic features of HNSCC, including mutations of TP53 and amplifications of multiple transcripts. Therefore, our newly developed CZH1 cell line could serve as an efficient tool for the in vitro investigation of the etiology, pathogenesis, and preclinical treatment of HPSCC.

UNASSIGNED: Head and neck squamous cell carcinoma (HNSCC) is an epithelial malignant tumor originating from the oral cavity, oropharynx, nasal cavity, sinuses, nasopharynx, hypopharynx, or larynx. Mutations in TP53 are the most common of all somatic genomic changes in HNSCC, and TP53 mutations are associated with the response to immunotherapy and chemotherapy. Tumor-derived circulating cell-free DNA (cfDNA) is a minimally invasive method to determining genetic alterations in cancer. This study aimed to explore the therapeutic responses of patients with HNSCC with TP53 mutation and the accuracy of cfDNA for detecting TP53 mutation.
UNASSIGNED: Information on TP53 mutations, patient survival time, and clinical data in HNSCC were downloaded from The Cancer Genome Atlas database. The difference in immune infiltration between the TP53-mutant group and the wild-type group was compared. We applied the single-sample gene set enrichment analysis method on the transcriptome of HNSCC samples to assess the distribution of immune cell types between the two groups. The chemotherapy response was constructed using the R software package, \"pRRophetic\". Gene set enrichment analysis was performed based on the TP53 mutation. The next-generation sequencing was executed on cfDNA from nine patients with HNSCC to detect genetic alterations. Tumor biopsy (n=9) was sequenced using the same technique.
UNASSIGNED: TP53 was the most frequently mutated gene in HNSCC. The TP53 mutation was related to immune cells and the expression of immune-associated genes. The TP53 mutation group showed lower response to immunotherapy but high sensitivity to some chemotherapies compared with the wild-type group. TP53 was the most frequently mutated gene (6/9; 66.67%) in cfDNA. Only 27.27% of TP53 mutations in tumor tissue were detected outside of cfDNA.
UNASSIGNED: TP53 mutation could be used as a specific predictor of treatment response in patients with HNSCC. Using cfDNA to detect the TP53 mutations in patients with HSNCC is a feasible method. The results suggested that the therapeutic response in patients could be predicted by detecting TP53 mutations in cfDNA, and large-scale and prospective studies are needed to validate this hypothesis.

The occurrence and development of esophageal cancer involve multiple genetic abnormalities that contribute to the malignant transformation of esophageal epithelial cells, followed by invasion and metastasis, leading to a poor outcome. Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal malignancy in East Asia, with approximately half of newly diagnosed ESCC cases occurring in China. The TP53 tumor suppressor gene mutation is one of the most common mutations in ESCC. TP53 mutations are observed even in the early phases of esophageal carcinogenesis. Normal functions of the p53 network are lost in cells of ESCC patients who harbor the mutant TP53 gene, inducing tumor development, radiation resistance, chemotherapy resistance, and immune suppression, promoting progression and metastasis, thereby resulting in an overall poor prognosis. Although clinical trials of several pharmacological compounds targeting mutational TP53 have been explored, novel approaches are still urgently required to improve the observed dismal survival. A better understanding of the role of the mutant TP53 gene in human ESCC might lead to the discovery of innovative targeted therapies to treat this malignancy.

How concurrent TP53 mutations affect targeted therapy of advanced Epidermal Growth Factor Receptor (EGFR) mutant lung adenocarcinoma remains controversial, particularly the deep classification of TP53 mutations.
This study retrospectively analyzed the clinical data of advanced EGFR mutant lung adenocarcinoma patients treated with EGFR-tyrosine kinase inhibitors (TKIs) in the First Affiliated Hospital of Soochow University. The survival rates were compared using Log-rank tests. Potential prognostic factors were identified using multivariate Cox hazard regression models.
Total 156 advanced lung adenocarcinoma patients treated with EGFR-TKIs were included in this study. Multivariate analysis showed that male [hazard rate (HR): 1.537, 95% confidence interval (CI): 1.055-2.240, P = 0.025], brain metastasis (HR: 1.707, 95%CI: 1.086-2.682, P = 0.020) and concurrent TP53 mutations (HR: 1.569, 95%CI: 1.051-2.341, P = 0.028) were independent negative predictors of progression-free survival (PFS). EGFR L858R mutations (HR: 2.475, 95%CI: 1.443-4.248, p = 0.001), smoking history (HR: 2.530, 95%CI: 1.352-4.733, P = 0.004) and concurrent TP53 mutations (HR: 2.326, 95%CI: 1.283-4.218, P = 0.005) were associated with worse survival. Further analysis revealed that mutations in TP53 exons 4, 5 and 8 (P<0.05), missense mutations (P = 0.006) and nondisruptive mutations (P<0.001) were associated with shorter PFS, whereas mutations in TP53 exons 5 and 7 (P<0.05), missense mutations and non-missense mutations (P = 0.006; P = 0.007), disruptive mutations and nondisruptive mutations (P = 0.013; P = 0.013) were all associated with poorer survival times. In addition, the PFS and overall survival (OS) of nondisruptive mutations in exon 7 were worse than those in other exons (P = 0.041; P<0.001).
Concurrent TP53 mutations conferred worse EGFR-TKIs efficacy and prognosis in advanced EGFR mutant lung adenocarcinoma and the effects of different TP53 mutation types were heterogeneous.

UNASSIGNED: Mutations of the tumor protein p53 (TP53) gene were considered to be associated with an unfavorable prognosis in acute myeloid leukemia (AML). This meta-analysis aimed to systematically elucidate the prognostic value of TP53 mutation in adult patients with AML.
UNASSIGNED: A comprehensive literature search was conducted for eligible studies published before August 2021. The primary endpoint was overall survival (OS). Pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated for prognostic parameters. Subgroup analyses based on intensive treatment were performed.
UNASSIGNED: Thirty-two studies with 7,062 patients were included. As compared to wild-type carriers, AML patients with TP53 mutations had significantly shorter OS (HR: 2.40, 95% CI: 2.16-2.67, I2: 46.6%). Similar results were found in DFS (HR: 2.87, 95% CI: 1.88-4.38), EFS (HR: 2.56, 95% CI: 1.97-3.31), and RFS (HR: 2.40, 95% CI: 1.79-3.22). Mutant TP53 predicted inferior OS (HR: 2.77, 95% CI: 2.41-3.18) in the intensively treated AML subgroup, compared with the non-intensively treated group (HR: 1.89, 95% CI: 1.58-2.26). Among intensively-treated AML patients, the age of 65 did not affect the prognostic value of TP53 mutations. Besides, TP53 mutation was also strongly associated with an elevated risk of adverse cytogenetics, which conferred a dismal OS in AML patients (HR: 2.03, 95% CI: 1.74-2.37).
UNASSIGNED: TP53 mutation exhibits a promising potential for discriminating AML patients with a worse prognosis, thus being capable of serving as a novel tool for prognostication and therapeutic decision-making in the management of AML.

Burkitt\'s lymphoma (BL) with TP53 mutation often has poor outcome after standard chemoimmunotherapy. Adoptive chimeric antigen receptor (CAR)-T cell therapy may be a new paradigm for treating refractory/relapsed (r/r) BL, but its therapeutic effects remain inconclusive. Here, we report a patient with r/r BL who failed to achieve complete remission (CR) and progressed rapidly after multiple protocol chemotherapy. The patient achieved CR with CAR19 and CAR22 T-cell cocktail therapy and obtained long-term disease-free survival after autologous hematopoietic stem cells (ASCT) and subsequential CAR19 and CAR22 T-cell cocktail therapy. The clinical evolution and genetic features of this case may provide some guidance for CAR-T therapy in overcoming relapses associated with TP53 gene mutations.

BACKGROUND: Non-small cell cancer (NSCLC) patients with concomitant epidermal growth factor receptor (EGFR) and TP53 mutations have a poor prognosis with the treatment of tyrosine kinase inhibitors (TKIs), and may benefit from a combination regimen preferentially. The present study aims to compare the benefits of EGFR-TKIs and its combination with antiangiogenic drugs or chemotherapy in patients with NSCLC harboring EGFR and TP53 co-mutation in a real-life setting.
METHODS: This retrospective analysis included 124 patients with advanced NSCLC having concomitant EGFR and TP53 mutations, who underwent next-generation sequencing prior to treatment. Patients were classified into the EGFR-TKI group and combination therapy group. The primary end point of this study was progression-free survival (PFS). The Kaplan-Meier (KM) curve was drawn to analyze PFS, and the differences between the groups were compared using the logarithmic rank test. Univariate and multivariate cox regression analysis was performed on the risk factors associated with survival.
RESULTS: The combination group included 72 patients who received the regimen of EGFR-TKIs combined with antiangiogenic drugs or chemotherapy, while the EGFR-TKI monotherapy group included 52 patients treated with TKI only. The median PFS was significantly longer in the combination group than in the EGFR-TKI group (18.0 months; 95% confidence interval [CI]: 12.1-23.9 vs. 7.0 months; 95% CI: 6.1-7.9; p < 0.001) with greater PFS benefit in TP53 exon 4 or 7 mutations subgroup. Subgroup analysis showed a similar trend. The median duration of response was significantly longer in the combination group than in the EGFR-TKI group. Patients with 19 deletions or L858R mutations both achieved a significant PFS benefit with combination therapy versus EGFR-TKI alone.
CONCLUSIONS: Combination therapy had a higher efficacy than EGFR-TKI alone for patients with NSCLC having concomitant EGFR and TP53 mutations. Future prospective clinical trials are needed to determine the role of combination therapy for this patient population.

Although the incidence of multiple primary malignancies (MPMs) is increasing, synchronous triple primary malignant tumours with prostate, bladder and lung is rarely reported. Gene mutation is thought to be a reason for MPMs, and severe cardiovascular diseases may interrupt the cancer treatment. Here we reported a 64-year-old male patient with synchronous triple primary malignant tumours of the bladder urothelial carcinoma, prostate adenocarcinoma, and non-small cell lung cancer (NSCLC) with mutations in TP53 and MEK1, all the three malignancies were diagnosed within 10 days. Although being interrupted by severe cardiovascular diseases (including myocardial infarction, venous thrombosis, and aneurism of the aortic root), he was successfully treated with radical cystoprostatectomy, chemotherapy plus pembrolizumab (a PD-1 antibody), and radiotherapy of the lung lesion, followed by maintenance monotherapy of pembrolizumab, overall survival was more than 26 months. In conclusion, a patient of synchronous triple primary malignant tumours with prostate, bladder, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases was treated successfully, which may suggest that comprehensive treatment, especially radical treatment such as operation and radiation, is very important for MPMs.