TP53 mutations in urothelial carcinoma: not all one and the same† DOI Creative Commons
Alexis R. Barr, Amy Burley, Anna Wilkins

и другие.

The Journal of Pathology, Год журнала: 2024, Номер 264(2), С. 125 - 128

Опубликована: Июль 24, 2024

Abstract Systemic therapy options for urothelial carcinoma have expanded in recent years, with both immunotherapy and cytotoxic chemotherapy being widely available. However, we lack biomarkers to select which drug is likely work best individual patients. A new article this journal by Jin, Xu, Su, et al reports that disruptive versus non‐disruptive TP53 mutations may guide these personalised choices. Intriguingly, patients tumour had poor overall survival those or wild type but responded particularly well immunotherapy. Of relevance, an increased mutational burden effector CD8 + T‐cell infiltration was seen tumours mutations. The impact of different on prognosis choices appears be tumour‐ therapy‐type specific, no clear consensus phenotype according mutation. Nonetheless, profiling specific types mutation increasingly clinically feasible targeted sequencing immunohistochemistry. There urgent need additional studies cancer clarifying how the present within a can used as predictive biomarker. Further important remaining questions include other aspects microenvironment, including cancer‐associated fibroblasts. Furthermore, gain‐of‐function related genes signalling upstream downstream wide interest. © 2024 Author(s). Journal Pathology published John Wiley & Sons Ltd behalf Pathological Society Great Britain Ireland.

Язык: Английский

Lethal clinical outcome and chemotherapy and immunotherapy resistance in patients with urothelial carcinoma with MDM2 amplification or overexpression DOI Creative Commons
Kaifeng Jin, Ya-Wei Ding, Jingtong Xu

и другие.

Journal for ImmunoTherapy of Cancer, Год журнала: 2025, Номер 13(1), С. e010964 - e010964

Опубликована: Янв. 1, 2025

The E3 ubiquitin ligase murine double minute 2 (MDM2) binds the p53 transcriptional activation domain and acts as a potent inhibitor of TP53 pathway, one three most crucial oncogenic pathways in urothelial carcinoma (UC). However, clinical significance impact on tumor immune contexture MDM2 amplification UC remain unclear. This study analyzed 240 patients with matched annotations from two local cohorts (ZSHS cohort FUSCC cohort). We assessed correlation between status outcomes, therapeutic efficacy, immunological characteristics by immunohistochemical analysis targeted sequencing. Additionally, 2264 samples five independent external cohorts, genomic, transcriptomic, data, were used for validation. (MDM2 Amp) or protein overexpression (MDM2OE) was associated inferior overall survival cohort, Log-rank p<0.001; p=0.030) reduced response to platinum-based chemotherapy p<0.001) well anti-PD-1/PD-L1 immunotherapy (FUSCC p=0.016) UC, irrespective TP53/p53 status. further linked high-grade tumors dedifferentiated morphology. In addition, an immuno-evasive characterized lower proportion tertiary lymphoid structure infiltration, abundance CD8+ T cells, IFN-γ+ GZMB+ decreased expression checkpoint molecules including programmed death-ligand 1 (PD-L1), death-1 (PD-1) cytotoxic T-lymphocyte-associated 4 (CTLA-4). defines lethal subset prognosis resistance both These are morphology immunosuppressive microenvironment. Accurate assessment can improve risk stratification enable personalized genomics-guided treatment UC.

Язык: Английский

Процитировано

1
Association Between TP53 Mutations and Platinum Resistance in a Cohort of High-Grade Serous Ovarian Cancer Patients: Novel Implications for Personalized Therapeutics DOI Open Access
Clelia Madeddu, Eleonora Lai, Manuela Neri

и другие.

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(5), С. 2232 - 2232

Опубликована: Март 1, 2025

The integrity of p53 machinery is crucial for platinum activity, while mutation frequent in high-grade serous ovarian cancer (HGS-OC). This study aimed to evaluate the link between mutations, sensitivity (PS), and platinum-free interval (PFI) patients with HGS-OC. We prospectively analyzed 159 consecutive women who underwent surgery. somatic mutational status BRCA, HRD, TP53 (according structural, hotspot, functional classification) was evaluated. Among enrolled patients, 82.4% cases were TP53-mutated (MT), 27.8% BRCA-MT. distribution categories did not differ significantly BRCA-MT wild-type (WT) cases. In entire population, proportion PS lower TP53-MT compared TP53-WT (p = 0.0208), nonsense/frameshift/splicing missense 0.0319), loss-of-function (LOF) GOF 0.0048) MT For structural mutations different PR patients. Conversely, BRCA WT differed a multivariate regression analysis, LOF found be independent negative predictors (HR: 0.1717; 95% CI: 0.0661-0.4461; p-value: 0.0003). Kaplan-Meier curves showed PFI overall population (log-rank p 0.0020) BRCA-WT 0.0140). Via COX testing, it that independently associated decreased 0.0036). conclusion, our data show HGS-OC harboring poorest prognostic subgroup regarding PFI. Further studies are needed confirm findings.

Язык: Английский

Процитировано

1
Natural history of bladder cancer: Validation of the multiple pathway model in multi-omics era DOI Creative Commons
Stacy R. Bedore, Karina Aguilar, Vinata B. Lokeshwar

и другие.

Urologic Oncology Seminars and Original Investigations, Год журнала: 2025, Номер 43(2), С. 88 - 93

Опубликована: Фев. 1, 2025

First recognized about 2 hundred years ago, bladder cancer has continued to challenge both clinicians and researchers due its inherent heterogeneity in frequent recurrence progression. Forty-three Droller proposed a multiple pathway model explain the disparate clinical behaviors of low-grade high-grade tumors. The suggested genetic alterations that promote hyperplasia generate papillary tumors recur but do not metastasize. Separate dysplasia, dysplastic-hyperplastic tumor cells may invade Initial preclinical studies current multi-omics approaches show while arise from KRT5+ stem basal layer urothelium, more differentiated intermediate cell layer. Mutations genes on chromosome 9p (e.g., CDKN2A/p16INK4a), 9q PTCH1, TSC1), STAG2, KDM6A, FGFR3, RAS PI3KCA characterize tumors, hyperproliferative phenotype. Conversely, mutations TP53, MDM2, PTEN, genomic instability are prevalent especially muscle-invasive cancer. development molecular classification systems, including subtypes, have further affirmed model. These developments underpin hopes for personalized treatment.

Язык: Английский

Процитировано

0
Experimental evaluation and simulation of stimuli-responsive doxorubicin-loaded nanofibers based on triblock copolymers for melanoma cancer treatment: A comparative study on star- and linear-shaped (PCL-b-PDMAEMA-b-PNIPAAm) DOI
Kiana Sakhaee,

Parastoo Ahmadpour-Samani,

Kiarash Bastani

и другие.

Materials Today Chemistry, Год журнала: 2024, Номер 43, С. 102454 - 102454

Опубликована: Дек. 10, 2024

Язык: Английский

Процитировано

1
TP53 mutations in urothelial carcinoma: not all one and the same† DOI Creative Commons
Alexis R. Barr, Amy Burley, Anna Wilkins

и другие.

The Journal of Pathology, Год журнала: 2024, Номер 264(2), С. 125 - 128

Опубликована: Июль 24, 2024

Abstract Systemic therapy options for urothelial carcinoma have expanded in recent years, with both immunotherapy and cytotoxic chemotherapy being widely available. However, we lack biomarkers to select which drug is likely work best individual patients. A new article this journal by Jin, Xu, Su, et al reports that disruptive versus non‐disruptive TP53 mutations may guide these personalised choices. Intriguingly, patients tumour had poor overall survival those or wild type but responded particularly well immunotherapy. Of relevance, an increased mutational burden effector CD8 + T‐cell infiltration was seen tumours mutations. The impact of different on prognosis choices appears be tumour‐ therapy‐type specific, no clear consensus phenotype according mutation. Nonetheless, profiling specific types mutation increasingly clinically feasible targeted sequencing immunohistochemistry. There urgent need additional studies cancer clarifying how the present within a can used as predictive biomarker. Further important remaining questions include other aspects microenvironment, including cancer‐associated fibroblasts. Furthermore, gain‐of‐function related genes signalling upstream downstream wide interest. © 2024 Author(s). Journal Pathology published John Wiley & Sons Ltd behalf Pathological Society Great Britain Ireland.

Язык: Английский

Процитировано

0