Week 2026-W29

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 study performed an integrated multi-omic analysis on a cohort of 48 bladder cancer patients to explore the molecular mechanisms of disease progression. Researchers identified frequent and active somatic LINE-1 (L1) insertions occurring early in cancer development. These L1 insertions are linked to downstream genomic rearrangements, chromosomal instability, and an increase in structural variants and extrachromosomal DNA (ecDNA). The study proposes a model where L1 retrotransposition triggers genomic instability and a viral mimicry response.

This study details the analytical validation of the Illumina TruSight Oncology 500 (TSO500) assay within a CAP-certified clinical laboratory in Brazil. It also presents real-world findings from Comprehensive Genomic Profiling (CGP) performed on 454 patients with solid tumors. The research highlighted the genomic landscape of these tumors, including the detection of both novel and canonical gene fusions. The analytical performance of the assay was assessed, demonstrating high specificity and positive predictive value. The authors conclude that TSO500 provides crucial insights for diagnosis, prognosis, and treatment decisions in oncology.

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 in-silico study investigated gene expression differences between right-sided (RCC) and left-sided colon cancer (LCC) using the TCGA-COAD database to clarify their distinct molecular and clinical features. Researchers identified age and gender-related genes, including TG, INSL5, EREG, AIRE, HOXB8, and FLT3. High expression of AIRE and LEP, and low expression of EREG, were correlated with poorer survival in specific RCC patient subgroups. These three genes, which are involved in the EGFR pathway, are proposed to hold significant predictive and prognostic value for anti-EGFR therapies.

This study investigates predictive biomarkers for immune checkpoint inhibitor (ICI) response in metastatic urothelial carcinoma. Researchers found that ICI responders exhibited higher tumor mutational burden (TMB) and enriched mutations in genes such as PIK3CA. Functional in vitro and in vivo studies demonstrated that PIK3CA mutations enhance tumor immunogenicity by activating the IRF1-NLRC5-MHC-I axis, thereby improving antigen presentation and CD8+ T-cell cytotoxic response. These findings suggest that PIK3CA mutation could serve as a biomarker to predict ICI sensitivity and represents a novel immune-modulating mechanism.

Managing tumor heterogeneity, especially in metastatic cancers, presents a significant challenge. This article introduces SOPA (Single-Omic Pathway Analysis) and SIMPA (Single-sample Integrated Multiomics Pathway Analysis), two bioinformatics pipelines designed for supervised differential pathway analysis at the single-sample level. These tools compare the molecular profile of each sample against a range of predefined controls. They proved more effective than existing methods in identifying sample-specific perturbations and distinct tumor subgroups, particularly concerning immune and metabolic pathway activity, with implications for patient survival.

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 study introduces MOCDT, an innovative bioinformatics framework for multi-cancer detection and tissue-of-origin classification using cell-free DNA (cfDNA). MOCDT employs a two-stage pipeline: high-specificity cancer detection followed by conditional tissue-of-origin classification. The model integrates a supervised multi-modal autoencoder with a patient similarity network and a Graph Convolutional Network for relational learning. Applied to a cohort of healthy controls and eight cancer types, MOCDT achieved 95.74% specificity and 96.22% sensitivity for cancer detection, alongside 75.2% Top1 and 91.06% Top3 accuracy for tissue-of-origin classification.

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 study assessed the cost-effectiveness of ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) testing to guide initial treatment in stage III/IV primary advanced or recurrent endometrial cancer. Using a decision tree and partitioned survival model, researchers compared lifetime costs and outcomes with and without molecular testing. The findings indicate that ProMisE testing is cost-effective from a payer perspective, with an incremental cost-effectiveness ratio (ICER) of $66,321 USD per quality-adjusted life-year (QALY) gained, well below the $150,000 USD threshold. From a societal perspective, ProMisE testing even resulted in lower costs and higher QALYs. This personalized approach is considered clinically meaningful and of high value.

A novel machine learning framework, FFixR, has been developed to address the challenges of somatic mutation detection from RNA sequencing (RNA-seq) data derived from formalin-fixed paraffin-embedded (FFPE) tissues. These tissues are prone to introducing artifacts that hinder accurate variant identification. FFixR effectively filters these artefactual mutations without requiring matched-normal samples. The tool demonstrated the ability to remove up to 98% of artifacts while maintaining good recall for true variants. This advancement enables more reliable analysis of archived FFPE samples, expanding their potential for research and clinical applications.

This study introduces an innovative and cost-effective method for detecting gene fusions in bone and soft tissue tumors, particularly sarcomas. The protocol integrates a custom capture panel with Nanopore sequencing and TEQUILA-based probe synthesis. Validated on 24 samples, including FFPE tissues, it demonstrated reliable fusion detection and gene expression quantification concordant with short-read sequencing. This approach promises to enhance the accessibility of molecular diagnostics for rare cancers due to its flexibility and reduced cost.

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 study investigated the dynamics of circulating tumor cells (CTCs) in 18 patients with advanced KRASG12C-mutated solid tumors treated with glecirasib, a KRASG12C inhibitor. Researchers observed an evolution in CTC subtypes (epithelial, mesenchymal, mixed) during treatment, particularly an increase in mixed CTCs at progression. Baseline CTC levels and their changes correlated with progression-free survival and overall survival. Furthermore, adding local radiotherapy for progressive lesions in patients with more than one CTC at progression significantly prolonged survival.

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.

The COSMOS-CRC study investigated the diagnostic performance of a blood-based cell-free DNA (cfDNA) test for colorectal cancer (CRC) and advanced precancerous lesions (APLs). This multimodal assay was applied to 451 patients with histologically confirmed CRC or APLs. It demonstrated an overall sensitivity of 87.9% for CRC, with stage-specific sensitivities of 71.2% for stage I and 97.4% for stages II-IV. Notably, for T1 CRC patients, the test achieved 100% sensitivity for detecting lymph node metastasis (LNM). The findings suggest that this cfDNA test could enhance risk stratification and potentially reduce unnecessary radical surgeries in T1 CRC management.

Results from the LIBRETTO-432 study indicate that adjuvant selpercatinib substantially improves event-free survival in patients with early-stage RET fusion-positive non-small cell lung cancer (NSCLC). This finding establishes selpercatinib as a new standard of care for this rare disease. Nevertheless, challenges persist regarding patient identification and access to RET fusion screening.

This study investigated pan-TRK expression and NTRK gene aberrations in meningiomas. The findings indicate that pan-TRK expression is common in these tumors, especially in high-grade cases and those with high proliferative activity. While pan-TRK immunohistochemistry may assist in differentiating meningiomas from other central nervous system tumors, NTRK gene aberrations are rare. Therefore, molecular confirmation is crucial to identify patients who could benefit from TRK-targeted therapies.

A novel study developed a non-invasive biomarker, the regional motif diversity score (rMDS), based on whole-genome sequencing of plasma cell-free DNA (cfDNA). This biomarker predicts immunotherapy response in patients with head and neck squamous cell carcinoma (HNSCC). The rMDS demonstrated superior performance compared to existing metrics in distinguishing responders from non-responders to pembrolizumab. Longitudinal rMDS changes were associated with genomic regions linked to immunity and keratinization, suggesting a connection to telomere biology. An rMDS-based classifier achieved a high AUC (0.89-0.99) and was associated with improved disease-free survival.

Homozygous MTAP loss is frequently observed in oncogene-driven non-small-cell lung cancers (NSCLC), particularly in EGFR, ALK, and RET altered subtypes. While this loss did not significantly impact the response to first-line targeted therapies, it creates a selective vulnerability to PRMT5 inhibitors. Preclinical studies demonstrated that the PRMT5 inhibitor BMS-986504 is active in MTAP-deleted NSCLC models and can enhance the efficacy of existing targeted therapies. These findings suggest a novel combined therapeutic strategy for NSCLC patients with MTAP loss.

This article introduces OLIVE, a rule-constrained large language model (LLM) framework designed for somatic variant interpretation in clinical oncology. The system integrates gene-specific biology, tumor context, and multiple evidence sources to classify variants. Evaluated on 200 clinical next-generation sequencing cases, OLIVE demonstrated a mean concordance of 97.5% with historical laboratory classifications. Observed discordances were primarily attributed to interpretive ambiguity or evolving evidence rather than model instability, and were deemed equally valid by expert adjudication. These findings indicate that OLIVE can reproducibly support expert somatic variant interpretation in a real-world clinical setting.

This study developed a functional precision oncology platform using patient-derived organoids (PDOs) and xenografts (PDOXs) from BRAFV600E-mutant colorectal cancer (CRC). The platform faithfully recapitulated tumor heterogeneity and drug responses. Researchers discovered that RNF43 mutations predict enhanced sensitivity to the encorafenib-cetuximab combination and increase tumor immunogenicity. These findings provide a mechanistic rationale for combining targeted therapies with immunotherapy in this aggressive CRC subtype.

This study established a biobank of 29 patient-derived sarcoma cell cultures from 19 patients, encompassing 11 sarcoma subtypes. The primary goal was to create preclinical models that accurately preserve tumor biology to enhance the understanding of disease heterogeneity and identify novel therapeutic vulnerabilities. Comprehensive multi-omic profiling (genomic, transcriptomic, proteomic) and functional drug screens were performed. The findings highlighted significant inter- and intra-subtype heterogeneity and recurrent alterations, underscoring the value of functional models for translational sarcoma research.