Medullary thyroid carcinoma (MTC) is characterized by frequent RET mutations, while non-RET alterations remain less well studied. Previous reports have identified a recurrent STK11 c.1062 C > G (p.Phe354Leu) variant in MTC, but its clinicopathologic and functional significance remains uncertain.

This study describes the development and analytical validation of a DNA-based quantitative PCR (qPCR) assay for detecting the NPM1 Type A mutation (NPM1-A mut) in acute myeloid leukemia (AML). The assay employs a modified wild-type blocker (WTB) to preferentially suppress amplification of wild-type (WT) alleles, thereby enriching mutant targets.

Dihydropyrimidine dehydrogenase (DPD), which is encoded by the DPYD gene, plays an important role in the metabolism of fluoropyrimidine (FP) drugs, including tegafur, in S-1. A decrease in DPD activity can cause severe FP-related toxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for FP and DPYD polymorphisms recommend FP dose adjustments based on the four major DPYD polymorphisms. However, multiple rare variants of DPYD have been reported. We present the case of a man in his 50s with cT3N0M0 tongue squamous cell carcinoma who developed severe myelosuppression and diarrhea after the initiation of S-1 (tegafur/gimeracil/oteracil) despite appropriate dosing. On day 20 of treatment, the patient developed grade 4 neutropenia and septic shock and required ICU admission. Genetic testing identified a rare heterozygous DPYD variant (c. 812delT) that causes a frameshift and a presumed loss of enzyme function, suggesting an underlying cause of the severe adverse events. Although severe toxicity occurred, marked tumor shrinkage allowed for less invasive surgery. This case highlights the need for expanded genetic screening beyond the guideline-listed variants, particularly in Asian populations, where common variants differ. Combining genotypic and phenotypic evaluations of DPD activity may improve the prediction and prevention of FP-related toxicities, supporting safer and more effective use of FP drugs.

Exosome-mediated delivery of small interfering RNA (siRNA) has emerged as a promising therapeutic strategy for cancer treatment, offering precise gene silencing with minimal off-target effects. Exosomes, naturally secreted extracellular vesicles, provide biocompatible carriers that protect siRNA from enzymatic degradation and facilitate efficient uptake by tumor cells. Their natural tropism, driven by surface proteins such as integrins and tetraspanins, promotes cellular adhesion and interactions within the tumor microenvironment, facilitating the delivery of therapeutic cargo. Preclinical studies have demonstrated that exosome-delivered siRNAs can suppress oncogenes, inhibit tumor growth, reverse chemoresistance, and modulate immune responses by targeting stromal and immune components. Engineering approaches, including surface functionalization and hybrid exosome-nanoparticle systems, further enhance stability, payload capacity, and tumor-homing efficiency. Combination strategies with chemotherapy, immunotherapy, or phototherapy have shown synergistic effects, allowing simultaneous inhibition of survival pathways, promotion of apoptosis, and remodeling of the immunosuppressive microenvironment. Early-phase clinical studies indicate safety, effective biodistribution, and functional gene silencing, highlighting the translational potential of exosome-mediated siRNA therapeutics. Challenges such as scalable production, cargo heterogeneity, and regulatory considerations remain, but ongoing advances in exosome engineering and patient-derived vesicles are poised to overcome these barriers. This review aims to comprehensively summarize the current state, therapeutic applications, and translational prospects of exosome-mediated siRNA delivery in cancer.

Osteosarcoma (OS) is the most common bone cancer, known for its aggressive nature, high chemoresistance, and strong metastatic potential responsible for poor clinical outcomes. In this context, identifying reliable biomarkers and therapeutic targets is therefore critical. This study investigates the role of paraoxonase-2 (PON2), an intracellular enzyme known for its anti-oxidative and anti-apoptotic properties. PON2 overexpression has been observed in various cancers and is implicated in tumor development and progression.

The NOTCH1 gene and its signaling pathway play a critical role in the oncogenesis and progression of various carcinomas through complex cellular and molecular mechanisms. This integrative literature review examines 21 selected studies across multiple carcinoma types, including head and neck, prostate, penis, breast, and hepatocellular carcinomas, to elucidate the functional impact of notch1 alterations on tumor behavior and clinical outcomes. NOTCH1 functions as a context-dependent regulator, acting either as an oncogene or tumor suppressor according to cellular environment and molecular context. Aberrations in notch1 signaling influence cell proliferation, differentiation, apoptosis, and angiogenesis, thereby contributing to cancer initiation and progression. Despite some variability in findings, the majority of studies indicate that notch1-related molecular changes have significant implications for prognosis and potential therapeutic targeting. This review highlights the importance of understanding notch1 signaling pathways in the cellular and molecular biology of carcinomas, aiming to pave the way for novel diagnostic and treatment strategies.

Colon cancer is one of the most prevalent cancers globally, characterized by the abnormal growth of cells in the intestines. Numerous studies have explored the effects of pomegranate-derived products, such as pomegranate seed oil (PSO), as anti-proliferative, anti-invasive, and pro-apoptotic agents against various cancer cell lines. Additionally, previous research has highlighted the anti-cancer properties of low-frequency electromagnetic fields (LF-EMF). In the present study, we investigated the combined effects of these two factors on the expression of the Caspase 3, Caspase 9, BAX, and Bcl2 genes. Human colon cancer cells of the HT29 line were sourced from the Pasteur Institute of Iran cell bank and maintained in a complete culture medium. The cells were categorized into four groups: control, PSO, EMF, and PSO+EMF. To assess cell viability and the type of cell death, MTT and Annexin V-FITC assays were employed. Changes in the expression levels of Caspase 3, Caspase 9, BAX, and Bcl2 were analyzed using Real-Time PCR. The results from the MTT and Annexin V-FITC assays indicated that both PSO and EMF reduced cell viability and promoted apoptosis in colon cancer cells. The Real-Time PCR results showed an upregulation of Caspase 3, Caspase 9, and BAX genes, along with a downregulation of Bcl2 expression in the treatment groups compared to the control group. This study demonstrated that the combination of PSO and EMF enhances apoptotic gene expression, thereby diminishing the proliferation and viability of cancer cells. Based on these findings, both PSO and LF-EMF exhibit cytotoxic effects on colon cancer cells, suggesting their potential as candidates for future research in the field of colon cancer.

Epidemiological data show that approximately 80% of cancer patients experience pain of varying degrees throughout the course of their disease, with nearly one-third experiencing severe pain, significantly impacting their quality of life and the effectiveness of antitumor treatment. Triple-negative (TN) breast cancer tissues typically exhibit increased stromal stiffness and abnormally elevated mechanical stress; these biomechanical alterations may amplify pain signals by activating mechanosensitive channels. Utilizing single-cell RNA sequencing analysis, this study aims to elucidate the potential biological links between fibroblast mechanotransduction and cancer-associated pain, thereby providing a theoretical basis for clinical diagnosis and treatment.

To explore the correlation between CD269 expression patterns in multiple myeloma (MM) cells and the expression of other antigens and molecular cytogenetics.

To investigate the relationship between TP53 and MYD88 mutations and treatment efficacy in patients with diffuse large B-cell lymphoma (DLBCL) who received rituximab-based standard chemoimmunotherapy.

To investigate the gene mutations in tumor tissues of patients with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL), and analyze its relationship with clinical features and prognosis.

To explore the genetic characteristics and clinical efficacy of pediatric acute myeloid leukemia (AML) with NUP98∷KDM5A fusion gene positive.

We reported LINGO1 as a potential marker on Ewing sarcoma cells that could enable targeted drug delivery, improving treatment effectiveness while reducing side effects.

The cGAS/STING pathway is a central innate immune DNA-sensing system that links aberrant DNA species to innate immune and stress-response transcriptional programs and has emerged as a key regulator of tumor-immune interactions. In cancer, pathway outputs are shaped by interconnected downstream signaling modules, including type I IFN, NF-κB, autophagy, and stress-metabolic checkpoints, as well as by stringent spatial and biochemical regulation of both cGAS and STING. When activation is acute and appropriately compartmentalized, cGAS/STING signaling promotes antitumor immunity across multiple cellular compartments in the tumor microenvironment, supporting DC cross-priming and cytotoxic lymphocyte responses. In contrast, chronic or dysregulated activation rewires downstream signaling toward stress-adaptive and inflammatory programs that promote tumor progression, metastasis, and immune dysfunction, including deleterious effects in lymphocytes and the induction of suppressive myeloid and B cell populations. Here, we examine how context determines the consequences of cGAS/STING activation in cancer, review emerging therapeutic strategies that modulate this pathway, and discuss how its antitumor potential can be maximized while minimizing systemic toxicity and immune dysregulation.

Fibroblast growth factor receptor 3 (FGFR3) is one of the most frequently altered genes in bladder cancer, primarily through activating mutations that drive oncogenesis and are enriched in luminal tumors. However, the underlying gene regulatory network (GRN) remains poorly characterized. Here, we constructed an FGFR3-mutated GRN using a bottom-up bioinformatics approach, integrating transcriptomic data from bladder cancer cell lines, FGFR3-mutated tumors, and FGFR3 perturbation experiments in human and mouse models. Using publicly available CRISPR/Cas9 screening data, we identified transcription factors from this GRN that regulate the viability of FGFR3-mutated cells, with a focus on p63 (TP63). We showed that FGFR3 activation upregulates p63 in patient-derived xenografts and cell lines, while single-cell RNA sequencing revealed heterogeneous p63 activation associated with basal differentiation. Functional studies, including TP63 knockdown in FGFR3-dependent in vitro and in vivo models and RNA-seq along with p63 ChIP-seq, demonstrated that p63 directly promotes cell proliferation and migration and uncovered a positive feedback loop between FGFR3 and p63. Together, these findings support p63 as a protumorigenic regulator in FGFR3-mutated tumors despite their luminal differentiation and provide a detailed FGFR3-driven GRN, offering insights into FGFR3-induced oncogenic dependency and potential strategies to circumvent resistance to FGFR inhibitors.

BRAF inhibitors have advanced treatment for patients with BRAF-altered high and low-grade glioma (HGG and LGG, respectively). Clinically-available therapies are effective but require selection by mutation type and careful, proactive toxicity management to maximize patient quality of life and treatment duration. While pediatric LGG patients often experience durable responses, adults with LGG and patients with HGG frequently develop treatment resistance and disease progression while on treatment. Strategies to prevent or overcome resistant disease are under active preclinical and clinical investigation. This review serves as a primer to BRAF-altered therapy in glioma, outlines best practices for using available BRAF inhibitors, and highlights emerging therapeutic approaches aimed at improving outcomes in resistant disease. It serves as a forward-looking, practical guide for clinicians treating patients with BRAF-altered glioma.Article highlightsBRAF inhibitors are effective in both pediatric and adult low- and high-grade gliomas (LGG and HGG), but treatment should be tailored to the specific BRAF alteration (Table 1).Dabrafenib combined with trametinib is FDA-approved for BRAF V600E-mutant gliomas, while tovorafenib is approved for pediatric LGGs harboring BRAF V600 mutations or BRAF fusions.Proactive management, including anticipatory guidance and dose reduction for some patients, is essential to mitigate toxicity and avoid treatment interruptions.Tumor progression can occur during treatment interruptions or drug cessation; however, some patients may respond to BRAF inhibitor rechallenge.Emerging strategies focus on combination with other therapies including radiation, autophagy inhibitors, additional targeted agents, and others to overcome acquired resistance.Next-generation BRAF inhibitors-including paradox breakers, dimer disruptors, and protein degraders-are under clinical investigation (Table 2).

Brady and colleagues investigated the mutational consequences of cancer treatment on the genomes of 160 childhood cancer survivors who developed a subsequent neoplasm (SN). Their research aids in directing the next steps toward the prevention of SNs. See related article by Brady et al., p. 1590.

Beyond established rare fusions, such as ALK and ROS1, emerging ultrarare fusions involving receptor tyrosine kinases or their ligands, including EGFR-SHC1, further guide us to uncover novel mechanisms of oncogenic activation and corresponding treatment strategies. Collectively, rare and ultrarare genomic events are driving precision oncology toward an increasingly individualized era of "ultraprecision" cancer therapy. See related article by Zheng et al., p. 1573.

Metastatic colorectal cancer (mCRC) remains a major contributor to cancer-related mortality worldwide. Real-world data from low- and middle-income countries remain limited.

Thrombotic events are a major morbidity among Philadelphia chromosome-negative myeloproliferative neoplasm (Ph-MPN) patients. There is a lack of data from Kerala regarding the profile of Ph-MPN and the prevalence of thrombosis among these patients.