Epidermal Growth Factor Receptor (EGFR) is often present on the cell surface of a wide variety human malignancies, including non-small-cell lung cancer (NSCLC), glioblastoma (GBM), pancreatic ductal carcinoma (PDC), and castration-resistant prostate cancer (CRPC). Efforts to optimize immunotherapies targeting EGFR are limited by murine intolerance of human EGFR. To overcome this obstacle, we developed C57BL/6 mice in which a truncated variant of human EGFR (hEGFRt), lacking the ligand binding domain and cytoplasmic domain, is expressed from the CAG regulatory elements comprised of the CMV enhancer, β-actin promoter, and β-globin poly-adenylation signals. Cetuximab, a high-affinity, clinically available anti-human EGFR antibody, retains affinity for hEGFRt. The hEGFRt cDNA in the CAG-hEGFRt transgene is flanked by loxP sites to enable its excision thereby reducing interaction of hEGFRt-directed immunotherapies with normal tissues. The CAG-hEGFRt(f/f) transgene is abundantly expressed in hematopoietic lymphoid and myeloid cells, with low-level expression evident also in non-hematopoietic liver, lung, kidney, and brain. Mx1-Cre-mediated transgene excision in adult mice reduces hEGFRt ~ 5-fold in blood mononuclear cells. CAG-hEGFRt(f/f) adult mice are tolerant of syngeneic NSCLC, GBM, prostate, and PDC lines expressing hEGFRt. These mice retain hEGFRt tolerance after transgene deletion. CAG-hEGFRt(f/f) mice provide a new and important tool for the development of immunotherapies targeting hEGFR.

Atezolizumab plus bevacizumab (ATZ/BEV) is a standard first-line therapy for advanced hepatocellular carcinoma (HCC); however, many patients do not achieve meaningful tumor regression. The temporal and spatial immune remodeling associated with ATZ/BEV remains poorly understood.

In recent years, chronic lymphocytic leukemia (CLL) has undergone a radical change in the therapeutic landscape, allowing for the complete omission of chemotherapy in favor of targeted drugs. This reflects the improved understanding of the pathogenesis and biology of the disease, including both the genetic landscape of the leukemic clones and the crucial role of the numerous connections with the tumor microenvironment (TME). Regarding the latter, both in the bone marrow and in the lymph nodes, tissue architecture and function are reshaped by the lymphoid infiltrate to co-opt surrounding bystander cells, thereby supporting leukemic cell proliferation and survival. In this review, we explore the peculiarities of the CLL TME and how they translate into remarkable changes in the lymph nodal structure and in the inter-cellular interactions. We will elaborate on the potential that new multi-omics technologies might have in understanding the complex interplay occurring between CLL cells and TME.

Prostate-specific antigen (PSA) screening lacks specificity, particularly within the 4-10 ng/mL diagnostic gray zone, leading to unnecessary prostate biopsies and overtreatment. Here, we developed and validated a streamlined urine DNA methylation assay for non-invasive prostate cancer (PCa) detection and biopsy decision-making. Tissue-based Methylated DNA Immunoprecipitation Sequencing (MeDIP-seq) was integrated with large-scale public methylome cohorts to identify PCa-specific hypermethylated regions. Candidate markers were further refined by targeted bisulfite sequencing (TBS) and translated into quantitative PCR (qPCR) assays using post-prostatic massage urine samples. In a retrospective development cohort of 348 participants, stepwise marker selection and logistic regression modelling generated a compact two-gene methylation assay comprising ADD3_2 and GSX2_2. The model was then evaluated in an independent prospective multicenter cohort of 200 participants. The assay achieved robust diagnostic performance, with areas under curve (AUC) of 0.86 in the development cohort and 0.91 in the validation cohort, while maintaining specificity above 90%. Performance was preserved in the PSA gray zone and for clinically significant PCa (csPCa). Decision curve analysis (DCA) indicated that integrating this tool could safely avert approximately 55% of unnecessary biopsies without compromising cancer detection. This simple qPCR-based two-gene urine methylation assay provides a scalable, cost-effective and non-invasive complement to PSA-based PCa screening.

Despite advances in treating acute lymphoblastic leukemia (ALL), resistance to asparaginase (ASNase) remains a major clinical hurdle. Recent evidence suggests that leukemic cells may evade ASNase-induced cytotoxicity by upregulating the glutamate/aspartate transporter EAAT1 (SLC1A3). This study aimed to evaluate whether pharmacological inhibition of EAAT1 using UCPH-101 could enhance the inhibitory effects of ASNase in T-ALL models.

High-level MET gene amplification is a rare but potentially actionable alteration in gastric cancer. Previous phase III trials of MET-targeted therapies enrolled broadly MET-positive populations without prospective selection for high-level MET amplification, and no MET-directed therapy is currently established for this disease. Here, we report a 74-year-old woman with heavily pretreated metastatic gastric adenocarcinoma harboring high-level MET amplification (copy number 21) identified by comprehensive genomic profiling. Following expert panel review, the patient received capmatinib through the BELIEVE trial (NCCH1901; jRCTs031190104) and achieved a confirmed partial response at 8 weeks, with a 43.7% reduction in the sum of target lesion diameters. The response was maintained at 16 weeks; disease progression was observed at 24 weeks, with a progression-free survival of approximately 5.5 months. In the context of a literature review of MET-targeted therapies in gastric cancer, this case supports further investigation of selective MET inhibition in gastric cancer with high-level MET amplification, a rare molecular subset not prospectively enriched in previous clinical trials.

Targeted immunotherapies have transformed the treatment of relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), yet their efficacy depends on sustained expression of lineage-associated surface antigens. This review examines how antigen-directed pressure reshapes the biology of resistance, distinguishes canonical antigen escape from lineage plasticity, and clarifies the genomic contexts, diagnostic challenges, and therapeutic implications of these distinct escape routes.

Total neoadjuvant therapy (TNT) has emerged as a key treatment paradigm for locally advanced rectal cancer, reducing distant metastasis rates and facilitating organ preservation in selected patients. However, treatment response remains heterogeneous, highlighting the need for biomarkers that can guide treatment selection and optimise outcomes. This narrative review synthesises the current evidence regarding tumour-intrinsic genomic biomarkers associated with response to neoadjuvant therapy, encompassing somatic mutations, germline polymorphisms, gene expression profiles, mismatch repair (MMR) status, protein expression, epigenetic markers, and circulating tumour-derived biomarkers across conventional chemoradiotherapy (CRT) and TNT paradigms. Across the reviewed literature, individual somatic mutations, including KRAS, TP53, and BRAF, demonstrated limited reproducibility as predictive biomarkers, although KRAS mutations were recurrently associated with lower pathological complete response (pCR) rates in CRT-era cohorts. Germline polymorphisms in DNA repair (XRCC1) and folate metabolism (MTHFR) genes showed inconsistent associations with treatment response. In contrast, transcriptomic biomarkers demonstrated greater biological coherence, with proliferative, epithelial-mesenchymal transition, and metabolic signatures frequently associated with treatment resistance, while multi-gene classifiers generally outperformed single-gene markers. Among currently available tumour-intrinsic biomarkers, MMR deficiency was the most consistently reported biomarker associated with reduced response to fluoropyrimidine-based regimens, including TNT, although TNT-specific evidence remains comparatively limited. Dynamic circulating tumour DNA (ctDNA) monitoring, particularly ctDNA clearance during or after therapy, was consistently associated with pathological response and long-term oncologic outcomes across reviewed studies, whereas baseline ctDNA levels showed limited predictive value. Overall, the reviewed literature suggests that biomarker research in rectal cancer has evolved from single-gene analyses towards pathway-level and dynamic biomarkers. The integration of transcriptomic signatures, MMR status, and dynamic ctDNA monitoring may represent a promising strategy for personalising neoadjuvant therapy, improving patient selection for organ-preserving approaches, and enhancing oncologic outcomes in locally advanced rectal cancer. Nevertheless, the evidence base remains heterogeneous, and further prospective validation, assay standardisation, and evaluation within contemporary TNT cohorts are required before these biomarkers can be routinely incorporated into clinical decision-making.

Extranodal involvement (ENI) is incorporated into routine risk assessment for diffuse large B-cell lymphoma (DLBCL), but treating ENI as a single binary adverse feature may conceal clinically relevant heterogeneity in extranodal burden, anatomical distribution, treatment feasibility, and immune-molecular context. We evaluated ENI as a burden- and site-aware phenotype rather than as a uniform descriptor. We retrospectively studied 710 adults with newly diagnosed DLBCL treated with first-line immunochemotherapy between June 2011 and December 2024. Outcomes were analyzed according to ENI status, number of extranodal sites, and involved organs. Targeted sequencing was available in 176 tumors, and RNA sequencing was performed in 107 quality-controlled tumor samples. Clinical models were interpreted as adjustment models because ENI burden overlaps with established risk factors; site-specific and molecular analyses were prespecified as exploratory and were interpreted with attention to available-case denominators, treatment heterogeneity, sparse subgroups, and multiplicity. ENI was associated with inferior overall survival (OS) and progression-free survival (PFS) in unadjusted analyses. Multisite ENI was enriched for adverse baseline features, including advanced Ann Arbor stage, elevated lactate dehydrogenase (LDH), higher International Prognostic Index (IPI), and impaired performance status. After multivariable adjustment, the independent prognostic contribution of ENI burden was attenuated, indicating substantial clinical overlap with systemic disease burden and host fitness. Several anatomical sites showed candidate adverse signals, but rare-site estimates were limited by small subgroup sizes, wide confidence intervals, and multiple testing. Targeted sequencing and RNA-seq suggested heterogeneous genomic and immune-transcriptional patterns across ENI categories; these results should be regarded as hypothesis-generating because of tissue availability, tumor-only sequencing in many cases, modest molecular sample sizes, and lack of orthogonal immune validation. ENI in DLBCL is best interpreted as a clinically heterogeneous disease descriptor rather than a single uniform prognostic category. ENI burden and anatomical distribution provide useful descriptive and prognostic context, but they should be interpreted alongside established clinical risk, treatment intensity, censoring patterns, tissue-sampling constraints, and molecular ascertainment limitations. Exploratory genomic and immune-transcriptional correlates identified in this study require prospective multicenter validation with harmonized staging, treatment-intensity annotation, matched-normal sequencing, and spatial or cellular immune profiling before ENI-informed biological or therapeutic stratification can be applied clinically.

Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator implicated in tumor progression; however, its expression pattern and subcellular localization across different stages of endometrial carcinogenesis remain incompletely characterized. This study evaluated EZH2 expression in two biologically distinct endometrial carcinoma cell lines (Ishikawa and MFE-319) and in archived human endometrial tissues representing proliferative and secretory endometrium, hyperplasia, and Type I and Type II endometrial carcinomas. Histopathological evaluation was performed using hematoxylin and eosin staining. EZH2 expression was assessed by immunocytochemistry and Western blot analysis in the cell lines and by immunohistochemistry in tissue specimens, while apoptosis was evaluated by TUNEL assay in tissue samples. MFE-319 cells demonstrated significantly higher EZH2 expression than Ishikawa cells (H-score: 352.9 ± 78.9 vs. 137.6 ± 31.5, p < 0.0001), and Western blot analysis confirmed the same direction of change. Among tissue specimens, the highest EZH2 immunoreactivity was observed in Type II endometrial carcinoma (366.0 ± 63.7), with significantly higher expression than proliferative endometrium (231.5 ± 59.3), secretory endometrium (190.5 ± 52.4), and hyperplasia without atypia (261.0 ± 56.9), whereas no significant differences were detected among several intermediate histopathological groups. Nuclear localization of EZH2 became more prominent in atypical hyperplasia and carcinoma tissues. Apoptotic indices were significantly higher in both Type I and Type II carcinomas than in normal endometrium and hyperplasia groups, representing an association with increased EZH2 expression rather than evidence of a direct mechanistic relationship. These findings demonstrate that EZH2 expression differs across histopathological categories of endometrial lesions, with the highest expression observed in Type II endometrial carcinoma. The observed predominance of nuclear EZH2 in atypical hyperplasia and carcinoma further supports its association with aggressive tumor biology, although additional functional and clinicopathological studies are required to establish its clinical and biological significance.

Soft tissue tumors with chondroid matrix represent a heterogeneous group with persistent diagnostic challenges. Advances in molecular diagnostics have identified recurrent gene fusions in several chondroid neoplasms, predominantly involving FN1. Here, we report two cases of chondroid tumors harboring a novel FOS::PABPN1 fusion. The patients were young and presented with small, deep, peri-osseous nodules located in the extremities. Histologically, the tumors were well-circumscribed and lobulated. Both cases presented fibro-cartilaginous and spindle cell areas. No cytonuclear atypia, mitoses, or necrosis were observed. Immunohistochemistry (performed in Case 2) revealed positivity for S100, CD34, and FOS, with negativity for MDM2, HMGA2, PLAG1, and desmin. RNA sequencing identified an identical in-frame FOS::PABPN1 fusion transcript in both tumors. Unsupervised transcriptomic clustering positioned the cases near synovial chondromatoses and other chondroid lesions, despite the absence of FN1 rearrangements. Massive overexpression of the WIF1 (Wnt Inhibitory Factor1) gene was also observed. To our knowledge, this is the first description of FOS rearrangement in mesenchymal tumors exhibiting chondroid differentiation. The FOS::PABPN1 fusion expands the spectrum of FOS-altered neoplasms beyond osteoblastic and vascular lesions and defines a potential new molecular subset of benign chondroid tumors. These findings highlight the utility of RNA sequencing in the diagnosis of chondroid neoplasms in order to identify rearrangement (of FN1, THBS1 or FOS) or IDH1/2. The consistent upregulation of WIF1 may represent a potential diagnostic biomarker.

Colorectal cancer is a common gastrointestinal malignancy worldwide. KRAS gene mutation is an important molecular feature of colorectal cancer, but the clinical significance of different mutation sites remains unclear. This study aims to investigate the distribution characteristics of specific KRAS gene mutation sites and analyze their associations with clinicopathological parameters and survival outcomes in patients with colorectal cancer, thereby providing a basis for precise stratified diagnosis and treatment.

Osteosarcoma (OS) is a malignant bone tumor that predominantly affects adolescents. Due to its early metastatic tendency and chemoresistance, long-term survival rates in patients have not shown significant improvement over time, highlighting the urgent need for novel molecular targets and therapeutic strategies. Ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation, offers a promising avenue for overcoming drug-resistant tumors. ATP-binding cassette subfamily B member 6 (ABCB6) belongs to the ATP-binding cassette (ABC) transporter superfamily and is mainly localised to the outer mitochondrial membrane, where it participates in haem synthesis and intracellular iron transport. Recent studies have indicated that ABCB6 is aberrantly expressed in various malignancies and regulates tumor progression, yet its role and mechanism in OS remain unexplored. The present study aims to systematically characterise the expression pattern, clinical prognostic significance, and biological functions of ABCB6 in OS, and to dissect the molecular mechanism by which ABCB6 governs ferroptosis in OS cells, thereby providing a theoretical foundation for ABCB6-targeted therapy.

Anaplastic lymphoma kinase (ALK) fusions are established oncogenic drivers and therapeutic targets in multiple malignancies, including non-small cell lung cancer, but are rare in colorectal cancer (CRC). Although ALK fusions in CRC have been associated with sensitivity to ALK inhibitors, their broader genomic context remains incompletely defined. We aimed to characterize the prevalence, clinicogenomic features, and therapeutic implications of ALK fusions in advanced CRC.

Isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion are key molecular markers for glioma classification. Amide proton transfer weighted (APTw) and nuclear Overhauser effect-weighted (NOEw) markers showed promise for glioma characterization, by probing protein-related tissue properties. However, their interpretation is confounded by direct water saturation, macromolecules (semi-solid magnetization transfer-ssMT), and T1 relaxation. Here, we aimed to assess the performance of three APTw and NOEw metrics-uncorrected, spillover/ssMT-corrected (FMC), and fully spillover/ssMT- and T1-corrected (FMTC)-for glioma stratification. Fifty patients with suspected gliomas were prospectively enrolled (12 IDH-wild-type, 38 IDH-mutant, of which 21 with 1p/19q codeletion). Acquisitions were performed at 3 T using a 3D gradient echo readout with chemical exchange saturation transfer (B1 = 2 μT for APTw, 0.6 μT for NOEw; T1sat = 2 s), WASABI (WAter Shift And B1) for B0/B1 mapping, and saturation recovery for T1 mapping. Glioma subtypes were compared using metrics extracted from manually segmented masks, using two-tailed Mann-Whitney U tests, and the Benjamini-Hochberg false discovery rate (FDR) correction. Effect sizes were quantified using Cliff's δ with 95% bootstrap confidence intervals and classification performance was assessed by receiver operating characteristic analyses (area under the curve, AUC). IDH-mutant and wild-type gliomas differed significantly for the uncorrected APTw metric (p = 0.005, AUC = 0.79), with stronger discrimination following correction-APTw-FMC (p < 0.001, AUC = 0.94) and APTw-FMTC (p < 0.001, AUC = 0.96), both with large effect sizes. Only APTw-FMTC distinguished 1p/19q codeleted from non-codeleted gliomas before FDR correction (uncorrected p = 0.01, AUC = 0.74). The NOEw metrics did not differ between any molecular subgroups, likely due to limited sensitivity of this contrast at 3 T. These results suggest that correcting for fluid, ssMT, and T1 effects enhances the accuracy of APTw metrics, offering a more robust and biophysically grounded approach to noninvasive glioma diagnosis.

Epidermal growth factor receptor (EGFR) mutation status plays a critical role in guiding targeted therapy for non-small cell lung cancer (NSCLC). However, molecular testing in patients with stage IA NSCLC may be limited by insufficient tissue availability, procedural invasiveness, and resource constraints. Therefore, developing a non-invasive approach for EGFR mutation prediction is of substantial clinical interest. This study aimed to develop a computed tomography (CT) radiomics based model integrating clinical variables for non-invasive prediction of EGFR mutation status in stage IA NSCLC patients.

Many tumours show deficiencies in DNA damage response (DDR), not only driving tumorigenesis but also exposing vulnerabilities with therapeutic potential. Assessing which patients might benefit from DDR-targeting therapy requires knowledge of tumour DDR deficiency (DDRd) status, with mutational signatures reportedly better predictors than loss-of-function mutations. Existing DDRd models offer effective prediction for pathways with well-characterized processes and mutational signatures. Nevertheless, development of models for additional DDRd and clinically relevant mechanisms could be hampered by the fact that most mutational signatures have unknown etiology. Using supervised non-negative matrix factorization (SNMF), we integrate mutational signature learning with multiclass DDR-deficiency prediction to enable etiology-guided learning of signatures from cell lines with confirmed gene knockouts. Applied to DDR gene knockout human-induced pluripotent stem cell lines, SNMF identified etiology-aligned representations of deficiency in homologous recombination, mismatch repair, and base excision repair. Even guided by pathway-level labels, SNMF captured gene-specific base excision repair submechanisms, showing the integration offered added granularity. Learned cell line signatures showed high similarity to tumour-derived COSMIC signatures, revealed associations with mutations in DDR genes, and enabled high recall of tumours with DDR deficiencies. We envision that SNMF-like methods could leverage knockout screens to learn etiology-guided signatures for improved DDRd annotation and treatment optimization. SNMF is available at: https://github.com/joanagoncalveslab/SNMF.

V gene segments of the T cell receptor (TCR) β chain (TRBV) are crucial for antigen recognition, yet previous studies have treated them as fixed categories and neglected repertoire-specific immune dynamics that inform functional diversity.

Barrier-to-Autointegration Factor 1 (BANF1) is a self-associating protein encoded within the q13.1 locus of chromosome 11. It is integral to multiple cellular processes, including cell cycle regulation, chromatin organization, gene expression modulation, nuclear envelope (NE) repair, DNA damage repair (DDR), innate immune function, and viral infection control. While prior investigations have provided preliminary phenotypic and bioinformatic characterizations of BANF1 across various disease states, comprehensive analyses detailing its functional roles and mechanistic underpinnings in diverse pathological contexts remain scarce. In cancer, BANF1 is frequently upregulated, with cancer cells leveraging its functions to preserve NE integrity, inhibit activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) immune pathway, and facilitate epithelial-mesenchymal transition (EMT). These activities contribute to enhanced genomic stability and promote tumor cell proliferation and migration, thereby conferring oncogenic properties. In neurodegenerative diseases, BANF1 is implicated in disease pathogenesis, exemplified by its mediation of glutamate-induced oxidative stress and apoptosis in neuronal cells, as observed in Alzheimer's disease (AD). Additionally, rare mutations in BANF1 are associated with hereditary conditions: the recessive Ala12Thr (A12T) variant causes Néstor-Guillermo progeria syndrome (NGPS), whereas the dominant Gly16Arg (G16R) mutation results in dominant motor neuronopathy. This review further synthesizes recent progress in exploring BANF1 as a therapeutic target, encompassing the development of small-molecule inhibitors, immunomodulatory approaches, and its potential applications in cancer treatment. Overall, this article provides a comprehensive overview of BANF1's structural features, cellular functions, and involvement in disease initiation and progression, with particular emphasis on its expression profiles in malignancies and the therapeutic promise of BANF1-directed interventions.

Primary liver cancer is a major global cause of cancer death, and hepatocellular carcinoma (HCC) is the predominant histological subtype. This literature review synthesizes current evidence on the exposome, multi-omics landscape, and artificial intelligence (AI)-based integration strategies relevant to biomarker discovery in liver cancer, with a focus on biological rationale, emerging clinical applications, and translational limitations. Key etiologic drivers include viral hepatitis, alcohol-related liver disease, and metabolic dysfunction-associated steatotic liver disease, all of which interact with environmental exposures across the life course. Biomarker discovery increasingly relies on integrated assessment of exposure-related signals together with genomic, epigenomic, transcriptomic, proteomic, metabolomic, and spatially resolved data. Hepatocarcinogenesis involves a complex interplay of chronic liver injury, environmentally patterned molecular perturbation, and dynamic tumor-host interactions. We emphasize an exposome-informed, multimodal strategy in which interpretable AI models identify clinically relevant signatures for early detection, prognostic stratification, and treatment guidance. Critical limitations of current evidence include incomplete exposure assessment, heterogeneous data platforms, retrospective study design, limited external validation, and insufficient model transparency. Emerging approaches, including proteogenomic, lipidomic, single-cell, and digital pathology-based modeling, show promise but require further validation in etiologically diverse cohorts. The purpose of this review is to critically examine how AI can integrate exposome-related information with multi-omics data for biomarker discovery in liver cancer. Here, particular attention is given to the exposure-to-biomarker sequence, immune-metabolic remodeling, liquid-biopsy translation, and the reduction of high-dimensional signatures into clinically deployable assays.