TP53

This study developed and evaluated an optimized intramuscular patient-derived xenograft (PDX) platform for gastric cancer. The model achieved a high engraftment rate of 71.7%, significantly exceeding conventional methods. Researchers utilized whole exome sequencing to identify divergent driver mutations between fast- and slow-growing tumors. The findings suggest that PDX-guided chemotherapy selection is associated with improved progression-free survival, and that driver mutation profiles can serve as prognostic biomarkers.

This Japanese real-world study investigated comprehensive genomic profiling and tumor mutational burden (TMB) in parathyroid carcinoma, a rare endocrine malignancy. Among 25 patients, 28% exhibited elevated TMB (≥ 10 mut/Mb), with frequent alterations observed in CDC73, TP53, and MEN1 genes. POLE alterations and microsatellite instability (MSI-high) were also identified in some cases. These findings highlight the molecular heterogeneity of the disease and the value of genomic profiling for uncovering potential therapeutic opportunities.

This study investigated the TP53 mutation landscape in oral squamous cell carcinoma (OSCC) and its association with patient survival. Using next-generation sequencing on 124 samples, pathogenic TP53 mutations were detected in 65% of patients, encompassing 75 distinct variant patterns. Patients harboring these mutations exhibited significantly shorter cancer-specific survival, particularly those with advanced-stage (III/IV) disease. Truncating or splice mutations were associated with an even worse prognosis. These findings highlight the importance of TP53-based molecular classification for developing novel precision strategies against OSCC.

This study investigated additional genetic alterations in MET-amplified gastric cancers (GCs), which are associated with poor prognosis and limited response to targeted therapies. Researchers found that MET amplification is frequently accompanied by co-amplifications of other oncogenes located on chromosome 7, such as BRAF, CDK6, and EGFR, in 54% of cases. These co-amplifications exhibit significant intra- and intertumoral heterogeneity. This complex heterogeneity may explain the diagnostic and therapeutic challenges, subclonal evolution, and the failure of targeted therapies in MET-amplified GCs.

This real-world study analyzed the genomic landscape of GNAQ and GNA11 mutations in 5,416 patients with metastatic solid tumors. It revealed that these mutations, while known in uveal melanoma, are also present in other cancers such as colorectal, melanoma, and gastric cancer. An immunogenic subgroup, characterized by non-hotspot mutations and high TMB or MSI, was identified and associated with potential benefit from immune checkpoint inhibitors. Canonical hotspot mutations, conversely, were predominant in TMB-low/MSS tumors. These findings highlight the importance of differentiating driver mutations from bystander mutations to guide therapeutic strategies.

This retrospective study investigated the clinical, surgical, and molecular characteristics and outcomes of 52 adult patients with H3 K27-altered diffuse midline glioma (DMG) treated with surgical resection. The median overall survival was 17.8 months. Genomic profiling revealed a distinct molecular landscape dominated by H3F3A mutations, frequently co-occurring with TP53 mutations, and a significant enrichment of mutations within the RTK/RAS/PI3K signaling pathway, involving NF1, FGFR1, and PIK3CA. Postoperative adjuvant radiotherapy combined with temozolomide emerged as the sole independent protective factor for overall survival. While maximal safe resection is considered essential, molecular targeted therapies did not achieve independent statistical significance.

This international study aimed to identify genetic prognostic biomarkers in a specific subgroup of intermediate-risk neuroblastoma patients, over 18 months old, without MYCN amplification, with localized unresectable or stage 3 tumors, and unfavorable histology, who experience poorer outcomes. Researchers analyzed chromosomal copy number alterations, next-generation DNA sequencing, telomere maintenance mechanisms, and gene expression. The findings revealed that oncogene amplifications, p53 pathway alterations, and typical segmental chromosomal aberrations (tSCAs) are independent prognostic markers associated with significantly reduced event-free and overall survival. These discoveries suggest that these patients might benefit from intensified or alternative treatments.

This study characterized the genomic landscape of leiomyosarcoma, a rare and aggressive tumor, by analyzing a large dataset from the AACR Project GENIE. Researchers examined over 1,000 tumor samples, identifying the most frequent somatic mutations and copy number alterations. TP53, RB1, and ATRX were the most commonly altered genes, with homozygous deletions of RB1 and TP53, and MAP2K4 amplifications. The study also highlighted enriched IGF2 and AXIN1 alterations in metastatic samples, suggesting their potential role in disease progression. These findings enhance the understanding of leiomyosarcoma biology and could guide future precision oncology strategies.

This study assesses the performance of in silico prediction tools for genetic variant curation within a panel of cancer predisposition genes. Researchers applied ClinGen SVI Working Group recommended thresholds and AlphaMissense predictions to variants in genes such as BRCA1, BRCA2, TP53, TERT, and ATM, which have established pathogenicity or benignity. The findings indicated insufficient sensitivity for pathogenic TERT variants and benign TP53 variants. The study emphasizes that the performance of these tools can be gene-specific and is influenced by their training datasets. Consequently, it is crucial to validate these tools for individual genes, especially for missense variants.

This prospective observational study assessed the utility of circulating tumor DNA (ctDNA) for mutational profiling and dynamic monitoring in 33 patients with metastatic colorectal cancer receiving palliative chemotherapy. ctDNA was detected in most patients at baseline, revealing frequent mutations in APC, TP53, KRAS, and PIK3CA. Good concordance was observed between plasma ctDNA profiles and tissue data. Longitudinal analysis showed the emergence of acquired mutations, particularly RAS mutations under anti-EGFR therapy, and correlated high ctDNA levels with shorter overall survival. These findings highlight ctDNA's potential to guide personalized treatment strategies and monitor resistance.

This prospective study evaluated gene expression profiling of seven genes (EGFR, FGFR2, PIK3CA, PTEN, SMAD4, STK11, TP53) in cell-free RNA (cfRNA) from exhaled breath condensate (EBC) in patients with advanced lung adenocarcinoma. Results indicated that PIK3CA showed the best diagnostic performance in distinguishing patients from healthy controls. High expression of FGFR2 and PIK3CA was associated with significantly shorter overall survival, highlighting their prognostic relevance. EGFR expression demonstrated a strong correlation between EBC and plasma, and low EGFR expression was linked to longer survival in patients receiving chemotherapy alone. This non-invasive EBC-based approach offers potential for molecular characterization and patient stratification.

This large genomic analysis of 2901 endometrial carcinomas refines molecular classification by addressing several clinical questions. The study confirms that all four mismatch repair genes (MLH1, MSH2, MSH6, PMS2) confer an equivalently favorable prognosis, validating dMMR status as a class-level prognostic designation. It demonstrates that the exceptional survival benefit associated with POLE-ultramutated tumors is confined to canonical exonuclease-domain hotspot mutations, excluding variants of uncertain significance. Finally, patients with TP53 mutations and high copy-number instability (CNH) are identified as having the most urgent unmet therapeutic need.

This retrospective study analyzed 120 cases of lung adenocarcinoma (LUAD) with malignant serous effusions (MSE) to characterize their clinicopathologic, molecular, and prognostic features. Pleural effusions were most common, but pericardial involvement was associated with the shortest overall survival. Molecular profiling revealed TP53 mutations and actionable alterations in genes such as EGFR, KRAS, BRAF, ALK, and ROS1. NKX2-1 (TTF-1) negativity and the absence of actionable alterations were independent adverse prognostic factors, with dual NKX2-1/CD274 (PD-L1) negativity defining the poorest prognosis subgroup. Immunotherapy-based regimens and tyrosine kinase inhibitors showed varying survival benefits.

Somatic mutations in GC-rich promoter regions are significant drivers of cancer, yet their detection is challenging due to poor sequencing coverage in these areas. This study introduces a hybrid capture assay optimized for over 3000 cancer gene promoters, enabling deep sequencing of these complex regions. This method facilitates the discovery of reliable point mutations, short insertions/deletions, copy number variants, and mutational signatures. The assay nominated candidate noncoding driver mutations in CDK4, SMAD3, and GATA3 in breast cancer, paving the way for future functional follow-up.

This study analyzed the genomic profile of 480 patients with metastatic adenocarcinoma of unknown primary (ACUP) using the FoundationOne CDx platform. The most frequent mutations included TP53, KRAS, and CDKN2A. Results showed that GNAS and PIK3CA mutations were associated with better overall survival. Conversely, ARID1A and NOTCH1 alterations were linked to a worse prognosis. These findings highlight the significance of specific genomic alterations as prognostic markers in ACUP.

The FIGO staging system for endometrial cancer underwent a significant revision in 2023, incorporating refined anatomical criteria and molecular determinants. This update aims to optimize adjuvant treatment selection by maximizing therapeutic benefits while minimizing harm. Molecular subgroups include POLEmut, p53abn, MMRd, and NSMP. The 2025 ESGO-ESTRO-ESP recommendations further enhance this framework by mandating estrogen receptor (ER) assessment within the NSMP category, identifying early-stage disease with an increased risk of recurrence and mortality.