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PubMed2026

Developmental genetic determinants of the human cerebrospinal fluid-ventricular system.

Primary enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles, known as congenital cerebral ventriculomegaly (CCV), is a hallmark of congenital hydrocephalus. CCV is also enigmatically but frequently associated with autism and other neurodevelopmental disorders. To gain insight into the developmental genetic regulation of the human CSF-ventricular system, we conducted an integrated, multiomic study of about 2700 trio-based exomes from patients with primary CCV. We found that about 25% of cases were associated with rare, damaging de novo variants in mutation-intolerant genes, many of which are linked to other dominant Mendelian disorders. Thirty-five exome-wide significant CCV genes and dozens of other high-confidence CCV genes converged on pathways involved in ATP-dependent Brahma-related gene 1/Brahma-associated factor chromatin remodeling, histone H3 lysine 4 methylation, and phosphoinositide 3-kinase signaling. Knockout of selected CCV genes in mouse models supported that de novo variants in CCV genes caused ventriculomegaly by impairing both CSF dynamics and cortical cytoarchitecture through dysregulation of neuroprogenitor cell growth and maturation in the ventricular and subventricular zones. These findings indicated that genetic and epigenetic programs coordinate the "hand-in-glove" development of the CSF-ventricular system with that of the cerebral cortex and establish a genetic connection between CCV and neurodevelopmental disorders, potentially explaining why some patients with hydrocephalus continue to exhibit CCV and neurodevelopmental disorders despite CSF shunting. We suggest that combined brain imaging and whole-exome sequencing could enable early detection of, and intervention for, autism and other neurodevelopmental disorders.

Humans↗
PubMed2026

Repeated emergence and fitness heterogeneity of KPC-33 in ST11 Klebsiella pneumoniae under ceftazidime-avibactam pressure.

Ceftazidime-avibactam (CZA) is an important therapeutic option for infections caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae. However, CZA exposure also selects for emergent KPC variants. Their in vivo evolutionary patterns, fitness consequences, and underlying molecular mechanisms remain unclear. We performed a longitudinal multiomics analysis of 35 clonally related ST11 KPC-producing K. pneumoniae isolates collected from eight hospitalized patients during clinical follow-up, most of whom had received CZA therapy. Whole-genome sequencing, antimicrobial susceptibility testing, in vitro competition assays, enzyme kinetic analysis, and transcriptomic sequencing were used to systematically characterize the within-host evolutionary dynamics of KPC variants and the fitness heterogeneity of KPC-33. Multiple KPC variants were identified during longitudinal follow-up, among which KPC-33 was the most frequently detected. Among the seven patients who received CZA treatment, KPC-33 was detected in longitudinal isolates from four patients. It was also identified in patient P3, who had not received CZA, whereas other variants were only sporadically identified. Biochemical analysis showed that KPC-33 exhibited an altered kinetic profile relative to KPC-2, characterized by reduced catalytic turnover and altered substrate affinity. KPC-33 did not exhibit a uniform and pronounced fitness defect but instead showed marked strain-dependent heterogeneity. Strains with higher competitive fitness generally showed only limited transcriptional changes, whereas those with lower fitness were accompanied by broader transcriptional remodeling. In this longitudinal cohort, KPC-33 was repeatedly detected, predominantly under CZA-associated selective conditions. Its fitness consequences were clearly strain background dependent and may be associated with the extent of transcriptional remodeling. These findings provide new evidence for understanding the in vivo evolution of CZA resistance.

KPC-33↗
PubMed2026

The Pathogenesis of Epithelial Ovarian Cancer.

Epithelial ovarian cancer is not a single disease but a group of biologically distinct malignancies that include serous (high-grade and low-grade), endometrioid, clear cell, and mucinous carcinomas, along with other rare subtypes. Integrating clinicopathological analyses, genomic and multiomic data, and experimental investigations in model systems has revealed the pathogenesis of the various histologic subtypes. A unique feature of epithelial ovarian cancer is that most of these tumors are now recognized to arise not from ovarian tissue but from the fallopian tube or endometrium, the latter in the context of ovarian endometriosis. Studies of precursor lesions have revealed complex evolutionary trajectories and the earliest molecular events in their development. Recent single-cell and spatial technologies further elucidate the roles of intratumoral heterogeneity and the tumor microenvironment in disease progression. This review summarizes these advances from the perspective of tissue of origin and highlights their implications for prevention, early detection, and therapeutic development.

Journal Article↗
PubMed2026

Comprehensive transcriptomics and proteomics analysis of neointima formation in human saphenous vein: implications for bypass graft disease.

Human saphenous veins (SVs) are widely used as grafts in coronary artery bypass (CABG) surgery but often fail due to neointima formation. Little is known, however, regarding the cellular, transcriptomic, and proteomic dynamics of neointima formation in human veins. Here, we performed transcriptomics and proteomics analysis in an ex vivo tissue culture model of neointima formation in human SVs procured for CABG surgery. Histological examination demonstrated significant elastin degradation and neointima formation (indicated by increased neointima area and neointima-to-media ratio) in SVs subjected to tissue culture. Analysis of data from 72 patients suggests that the progression of SV remodeling and neointima formation differs according to sex and body mass index, which is negatively associated with neointima formation in males only. RNA sequencing demonstrated upregulation of proinflammatory and proliferation-related genes during neointima formation and identified novel processes, including increased cellular stress and DNA damage responses, reflecting tissue trauma associated with vein harvesting. Proteomic analysis identified upregulated extracellular matrix-related and coagulation/thrombosis proteins and downregulated metabolic proteins. Spatial transcriptomics, used to infer regionally enriched gene expression, suggested dynamic alterations in fibroblast and vascular smooth muscle cell (VSMC) states during neointima formation. Specifically, we identified the emergence of HES1+ and matrix metalloproteinase 2- and 14-positive (MMP2+/MMP14+) expression in VSMCs and fibroblasts, respectively, during neointima formation. Furthermore, our data suggest that MIR647, identified through screening, maintains VSMC contractile gene expression. Our findings suggest dynamic transcriptomic and proteomic changes during neointima formation in human veins and provide useful mechanistic information for the pathogenesis of SV graft disease.NEW & NOTEWORTHY Using multiomics and spatial transcriptomics, we uncover dynamic molecular and cellular changes driving neointima proliferation in human saphenous veins, the most common conduit for bypass surgery. Our study highlights sex- and body mass index-associated differences, novel fibroblast and smooth muscle cell states, and a role for microRNA-647 in preserving vascular contractile phenotype. These findings provide new insight into the mechanisms of vein graft failure and may guide future strategies to improve coronary bypass outcomes.

Humans↗
PubMed2026

Integrative Pan-Cancer Characterization of lncRNA UPK1A-AS1 and Its Role in Hypoxia-Associated Sorafenib Resistance in Hepatocellular Carcinoma.

Long noncoding RNAs (lncRNAs) are emerging as critical regulators of tumor initiation and progression through transcriptional and posttranscriptional mechanisms. UPK1A antisense RNA 1 (UPK1A-AS1), a cancer-associated lncRNA, has been reported to participate in oncogenic processes; however, its overall landscape across human malignancies and its biological role in therapy resistance remain poorly understood. Given the increasing importance of identifying functional lncRNAs with prognostic and therapeutic potential, this study presents a comprehensive multiomics characterization of UPK1A-AS1 and its experimental validation in hepatocellular carcinoma (HCC). We integrated datasets from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression Project (GTEx), the cancer immunology data engine (CIDE), and the cBioPortal for cancer genomics (cBioPortal) to systematically assess its expression pattern, genomic alterations, clinical significance, and immunological associations. Our analyses revealed that UPK1A-AS1 is significantly upregulated in multiple tumor types, with copy-number amplification as the predominant genomic alteration driving its overexpression. Elevated UPK1A-AS1 expression was correlated with advanced disease stage, poor differentiation, immune exclusion, and unfavorable prognosis, supporting its potential as a cancer type-dependent biomarker. In parallel, functional studies demonstrated that hypoxia transcriptionally induces UPK1A-AS1 in HCC, where it promotes sorafenib resistance by suppressing apoptosis. Silencing UPK1A-AS1 restored apoptotic and enhanced sorafenib efficacy both in vitro and in vivo. Collectively, our findings suggest that UPK1A-AS1 is a hypoxia-inducible oncogenic lncRNA that plays dual roles in cancer, with cancer type-dependent associations with progression and immune modulation across malignancies and mechanistically mediating hypoxia-associated drug resistance in HCC.

Humans↗
PubMed2026

RAS-GTP Inhibition Overcomes Acquired Resistance to KRASG12C Inhibitors Mediated by Oncogenic and Wild-Type RAS Activation in Non-Small Cell Lung Cancer.

UNLABELLED: Small-molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C-mutant tumors, yet responses tend to be transient because of emergence of on-treatment resistance. Recently, RAS(ON) G12C-selective inhibitors, which bind to the active GTP-bound state of RAS, were described, and elironrasib is undergoing evaluation in multiple clinical trials. In this study, we generated resistant cell lines and patient-derived xenograft models to KRASG12C(OFF) and RAS(ON) G12C-selective inhibitors and interrogated resistance mechanisms using a multiomics strategy consisting of phosphoproteomics, whole-exome sequencing, and RNA sequencing combined with functional testing using small-molecule and CRISPR screens and RAS(ON) inhibitors being evaluated in clinical trials. Two models reactivated RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and were vulnerable to dual inhibition by RAS(ON) G12C-selective and RAS(ON) multiselective inhibitors, RMC-4998 and RMC-7977. Two models, which lacked any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity and were sensitive to RAS-GTP inhibition by RMC-7977. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS dependence, and acquired reliance on cell-cycle kinases and proteins associated with DNA damage response. This work highlights KRASG12C-selective inhibitor resistant states that parallel and complement clinical findings and demonstrate that a large subset could be overcome with a RAS(ON) multi-selective inhibitor as a stand-alone agent or in combination with other therapies. SIGNIFICANCE: Multi-omic characterization of resistance mechanisms to KRASG12C-selective inhibitors in non-small cell lung cancer provides insights that could inform precision medicine-based therapeutic approaches for improving the treatment of KRASG12C mutant tumors. See related article by Stern et al., p. 485.

Humans↗
PubMed2026

Integrated Genomic and Epigenomic Analysis Reveals Epigenetic Plasticity in Disease Progression and Multidrug Resistance in Multiple Myeloma.

UNLABELLED: Multiple myeloma is marked by recurrent cytogenetic abnormalities and mutations that accumulate as the disease progresses. In this study, we sought to elucidate the transitions driving tumorigenesis and therapy resistance in multiple myeloma using a unique cohort of nearly 900 patients spanning premalignant to late-stage refractory multiple myeloma, comprehensively characterized at molecular and clinical levels. Waves of epigenetic dysregulation drove these critical transitions. In this paradigm, genomic and cytogenetic events unlocked epigenetic plasticity, reshaping multiple myeloma cell biology to evade tumor microenvironment constraints and therapeutic pressures. Functional perturbation studies in an isogenic proteasome inhibitor-resistant cell line model demonstrated enhanced reliance on transcriptional cofactors, supporting a mechanistic link between chromatin plasticity and therapy adaptation. Collectively, these findings support a unifying framework in which genomic heterogeneity unlocks gene regulatory plasticity, enabling plasma cells (PC) to evade microenvironmental constraints and therapeutic pressure. These results provide a mechanistic explanation for sequential relapse without new genomic alterations and nominate epigenetic plasticity-mediated PC adaptation as a therapeutic vulnerability in the heterogeneous genetic background of multiple myeloma. SIGNIFICANCE: Assembly and analysis of a multiple myeloma cohort spanning the continuum from premalignant to late relapse that integrates bulk transcriptomics with single-cell multiomic data provides insights into disease progression and epigenetic plasticity.

Multiple Myeloma↗
PubMed2026

Intratumoral Sotigalimab with Pembrolizumab Induces Rapid Activation of Antigen-Presenting Cells and Drives Antitumor Responses in Non-injected Tumors in Metastatic Melanoma: A Phase I/II Study.

UNLABELLED: Immune checkpoint blockers (ICB) improve outcomes in metastatic melanoma (MM), but resistance limits benefit. This phase I/II (NCT02706353) study evaluated intratumoral sotigalimab (anti-CD40 agonist) with pembrolizumab in 32 patients with ICB-naïve MM. Primary endpoints were safety and objective response rate (ORR). Sotigalimab was well tolerated. At the recommended phase II dose, the ORR was 50%, and the disease control rate was 92%, with ORRs of 67% in injected and 50% in non-injected tumors. Multiomic analyses of tumor and blood showed that sotigalimab effectively engaged the CD40 pathway, boosting infiltration and activation of myeloid cells, including CD11c+DC-LAMP+ dendritic cells and macrophages. The combination therapy activated innate and adaptive immunity in injected tumors and cytotoxic responses in non-injected tumors. T-cell receptor sequencing showed increased T-cell clonality with expanded new clones shared across tumors. Clinical responses correlated with these immunologic changes but not with baseline features associated with response to anti-PD-1 monotherapy. SIGNIFICANCE: In this study, we provide compelling data that intratumoral sotigalimab combined with pembrolizumab is safe, activates antigen-presenting cells, and elicits broad innate and adaptive immune responses in both injected and non-injected tumors, supporting further randomized phase II trials to evaluate sotigalimab's potential to enhance anti-PD-1 therapy through "in situ" immunization.

Humans↗
PubMed2025

Neoadjuvant Immunotherapy Promotes the Formation of Mature Tertiary Lymphoid Structures in a Remodeled Pancreatic Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. In this study, we report the generation of a spatial multiomic atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning-enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that are significantly associated with improved survival in patients with PDAC. We identified spatial features of pathologic immune responses, including intratumoral TLS-associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.

Humans↗
PubMed2025

Splice modulation of COL4A5 reinstates collagen IV assembly in an organoid model of Alport syndrome.

Kidney organoids are an emerging tool for disease modeling, especially genetic diseases. Among these diseases, X-linked Alport syndrome (XLAS) is a hematuric nephropathy affecting the glomerular basement membrane (GBM) secondary to pathogenic variations in the COL4A5 gene encoding the α5 subunit of type IV collagen [α5(IV)]. In patients carrying pathogenic variations affecting splicing, the use of antisense oligonucleotides (ASOs) offers immense therapeutic hope. In this study, we develop a framework combining the use of patient-derived cells and kidney organoids to provide evidence of the therapeutic efficacy of ASOs in XLAS patients. Using multiomics analysis, we describe the development of GBM in WT and mutated human kidney organoids. We show that GBM maturation is a dynamic process, which requires long organoid culture. Then, using semi-automated quantification of α5(IV) at basement membranes in organoids carrying the splicing variants identified in patients, we demonstrate the efficacy of ASO treatment for α5(IV) restoration. These data contribute to our understanding of the development of GBM in kidney organoids and pave the way for a therapeutic screening platform for patients.

Nephritis, Hereditary↗
PubMed2026

Druggable genome CRISPRi screen in hydrogels reveals regulators of cortactin-driven actin remodeling promoting glioblastoma invasion.

To identify therapeutic targets limiting glioblastoma invasion, we applied druggable genome CRISPRi screens and multiomic analysis to patient-derived glioblastoma cells in micro-dissectible biomimetic 3D hydrogels that permitted separation and analysis of core versus invasive fractions. Of 2,550 genes screened, 12 encoded druggable targets whose suppression limited invasion, of which AURKB (encoding aurora kinase B) and ACP1 (encoding low molecular weight protein tyrosine phosphatase, LMW-PTP) were validated in neurosphere assays and in vivo. Proximity labeling identified cortactin as a link between LMW-PTP and aurora B, and we observed that cortactin underwent serine phosphorylation by aurora B and tyrosine dephosphorylation by LMW-PTP. Targeting ACP1 or AURKB via CRISPRi or inhibitors in culture and in vivo shifted the cortactin phosphorylation balance in glioblastoma, reducing levels of cortactin and the actin-related protein 2/3 (Arp2/3) complex that mediates cortactin-induced actin stabilization, thereby reducing actin-cortactin-Arp2/3 colocalization and subsequent actin polymerization. AURKB or ACP1 targeting shifted actin from cytoplasm to the nucleus, reducing mesenchymal gene expression. Biophysical analysis implicated AURKB in glioblastoma cell adhesion and stiffness needed for initial migration and ACP1 in mechanical stress resistance required for later migration. These findings revealed a targetable axis balancing kinase and phosphatase activities to regulate actin polymerization during glioblastoma invasion.

Humans↗
PubMed2026

Tracing the molecular route to progression in miRNA-biogenesis-defective thyroid lesions.

Germline and somatic changes in DICER1 and DGCR8 microprocessors confer risk of developing benign and malignant thyroid lesions, yet the molecular events driving malignant transformation remain unclear. We trace the molecular trajectories from benignity to malignancy in DICER1- and DGCR8-mutated thyroid lesions using multiomic profiling on over 30 DICER1-/DGCR8-mutated samples. Our findings reveal a progressive, specific, and linear accumulation of genetic changes, which when combined with enhanced downregulation of miRNAs distinguished DICER1-/DGCR8-malignant lesions from their benign counterparts. Compensatory hypomethylation of miRNA-encoding genes characterized DICER1-/DGCR8-benign lesions, but as the tumors progressed to malignancy, methylation was partly reimposed, reversing the attempts to activate miRNA-encoded genes and further compromising miRNA production. Transcriptomic analyses revealed mutation-specific effects on the microenvironment, whereby DICER1 mutations activated canonical thyroid cancer progression pathways, whereas altered DGCR8 associated with immune-related changes. This work unveils specific molecular events underlying malignant progression of miRNA-biogenesis-related thyroid tumors and identifies potential biomarkers and disease etiology mechanisms.

MicroRNAs↗
PubMed2026

Genetic background influences developmental airway smooth muscle program and susceptibility to airway hyperresponsiveness in mice.

Airway structural remodeling and hyperresponsiveness (AHR), hallmarks of asthma, are influenced by genetic variations and adverse exposures. While intrauterine perturbations in lung development have been linked to adult pulmonary disease, the developmental origins of these abnormalities remain poorly understood. Here, we provide evidence of genetic background playing a key role in this process. Using A/J and C57BL/6J mice known for their distinct susceptibility to AHR, we show that A/J embryos selectively develop an aberrant airway smooth muscle (SM) program and AHR in adulthood when exposed transiently to a vitamin A/retinoic acid (RA)-disrupted intrauterine environment in vivo by maternal BMS493 administration. Single-nucleus multiomics identified a mesenchymal cell population overactivating TGF-β targets in response to BMS493 selectively in A/J lungs. These cells, localized to sites of airway SM initiation and p-SMAD2- and -3, exhibited robust BMS493-mediated upregulation of SMAD2/3 targets, including regulators of SM program Pdgfra and Tnc. Functional analyses in vivo and cultured lungs showed aberrant SM formation in areas of overactive TGF-β of BMS493-exposed lungs. These abnormalities were prevented by inhibiting TGF-β signaling in utero in RA-deficient embryos. These findings underscore how distinct genetic backgrounds respond to intrauterine perturbations that program airway structure and function, with potential lasting consequences in postnatal pulmonary function.

Animals↗
PubMed2026

Prognostic value and immune landscape implications of using a novel homologous recombination repair pathway signature in prostate cancer: A retrospective cohort study.

ObjectiveAlthough the homologous recombination repair (HRR) pathway plays a critical role in the treatment of prostate cancer, its prognostic value remains incompletely understood. This study aimed to identify HRR pathway-related biomarkers with clinical utility for prognosis prediction and treatment guidance.MethodsWe analyzed genomic data from The Cancer Genome Atlas and Chinese patients with prostate cancer in a retrospective cohort study using a comprehensive multiomics approach to characterize a novel HRR-related prognostic signature and its immune implications.ResultsIn the Chinese cohort, 25.6% of the patients exhibited homologous recombination deficiency scores >42, whereas 27.3% carried ≥1 HRR gene mutation. We established a prognostic HRR signature (homologous recombination deficiency score >32, HRR gene mutations, and Signature 3) associated with poor outcomes. Compared with The Cancer Genome Atlas data, the Chinese cohort demonstrated a higher prevalence of HRR signature. Patients with HRR signatures demonstrated significantly increased genomic instability markers, including segment number, alteration burden, aneuploidy score, and intratumor heterogeneity. The HRR signature was associated with higher neoantigen load but reduced T cell receptor (TCR) evenness. Immunologically, HRR-positive tumors were associated with computationally inferred immune profiles suggestive of reduced immune activity, characterized by depletion of T-helper 17 cell; downregulation of TLR4/PDCD1LG2 expression; and upregulation of ARG1, IFNG, KIR2DL3, and CXCL9. However, these findings are descriptive and require experimental validation.ConclusionOur findings identify a clinically relevant HRR signature that warrants investigation as a potential predictive biomarker for prostate cancer prognosis and treatment response. This biomarker provides new insights for personalized therapy and may help optimize patient outcomes.

Humans↗
PubMed2026

Evolution of tumor subclones and T-cell dynamics underlie variable ibrutinib responses in Waldenström macroglobulinemia.

To elucidate the molecular basis underlying differential responses and resistance to ibrutinib in Waldenström macroglobulinemia (WM), we conducted a prospective phase 2 trial of ibrutinib monotherapy in treatment-naïve patients. A total of 74 sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multiomics. BM cells were segregated primarily into B-cell/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B cells/plasma cells identified 3 distinct evolutionary patterns: evolution (early clone contraction with late clone expansion and increasing genomic complexity), devolution (early clone expansion with late clone contraction and genomic simplification), and no evolution (stable clonal architecture). The evolution pattern was strongly associated with disease progression, whereas devolution correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenström ibrutinib prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combination strategy. In parallel, GZMB+ CD8+ effector-memory T cells expanded after treatment in patients with progressive disease and coexisted with tumor evolution. These cells exhibited persistently impaired cytotoxic programs (eg, GNLY), a dedifferentiated memory-like state, elevated PDCD1 expression, and reduced T-cell receptor diversity. Together, this study provides, to our knowledge, the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM, introduces the WIP score as a predictive biomarker for treatment response, and identifies actionable tumor-intrinsic and immune mechanisms driving resistance. This trial was registered at www.ClinicalTrials.gov as NCT02604511.

Aged↗
PubMed2024

Genomic landscape of hepatocellular carcinoma in Egyptian patients by whole exome sequencing.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Chronic hepatitis and liver cirrhosis lead to accumulation of genetic alterations driving HCC pathogenesis. This study is designed to explore genomic landscape of HCC in Egyptian patients by whole exome sequencing. METHODS: Whole exome sequencing using Ion Torrent was done on 13 HCC patients, who underwent surgical intervention (7 patients underwent living donor liver transplantation (LDLT) and 6 patients had surgical resection}. RESULTS: Mutational signature was mostly S1, S5, S6, and S12 in HCC. Analysis of highly mutated genes in both HCC and Non-HCC revealed the presence of highly mutated genes in HCC (AHNAK2, MUC6, MUC16, TTN, ZNF17, FLG, MUC12, OBSCN, PDE4DIP, MUC5b, and HYDIN). Among the 26 significantly mutated HCC genes-identified across 10 genome sequencing studies-in addition to TCGA, APOB and RP1L1 showed the highest number of mutations in both HCC and Non-HCC tissues. Tier 1, Tier 2 variants in TCGA SMGs in HCC and Non-HCC (TP53, PIK3CA, CDKN2A, and BAP1). Cancer Genome Landscape analysis revealed Tier 1 and Tier 2 variants in HCC (MSH2) and in Non-HCC (KMT2D and ATM). For KEGG analysis, the significantly annotated clusters in HCC were Notch signaling, Wnt signaling, PI3K-AKT pathway, Hippo signaling, Apelin signaling, Hedgehog (Hh) signaling, and MAPK signaling, in addition to ECM-receptor interaction, focal adhesion, and calcium signaling. Tier 1 and Tier 2 variants KIT, KMT2D, NOTCH1, KMT2C, PIK3CA, KIT, SMARCA4, ATM, PTEN, MSH2, and PTCH1 were low frequency variants in both HCC and Non-HCC. CONCLUSION: Our results are in accordance with previous studies in HCC regarding highly mutated genes, TCGA and specifically enriched pathways in HCC. Analysis for clinical interpretation of variants revealed the presence of Tier 1 and Tier 2 variants that represent potential clinically actionable targets. The use of sequencing techniques to detect structural variants and novel techniques as single cell sequencing together with multiomics transcriptomics, metagenomics will integrate the molecular pathogenesis of HCC in Egyptian patients.

Humans↗
PubMed2025

The application of AI-driven and engineered intratumoral microbes in cancer therapy.

BACKGROUND: Although investigations of the intratumoral microbiota date back thousands of years, breakthrough transformations have only recently been achieved through high-throughput sequencing and multiomic technologies. These advances have revealed diverse and tumor type-specific microbial communities that drive carcinogenesis via immunomodulation, metabolic reprogramming, and genomic instability. Current cornerstones of cancer therapies-including chemotherapy, radiotherapy, immunotherapy, and targeted therapy-are limited by systemic toxicity, localized tissue damage, drug resistance, and low patient response rates. These constraints underscore the urgent need for more effective and precise therapeutic strategies. MAIN BODY: This review comprehensively integrates artificial intelligence (AI) technologies into the characterization of the intratumoral microbiota, facilitating the development of novel computational pipelines for mapping microbe-host crosstalk. We systematically summarize recent advances in engineered microbial therapeutics, including bacteria designed for targeted antitumor activity and engineered microorganisms that enable the localized delivery of therapeutic agents. Furthermore, this review critically evaluates the safety profiles of microbiota-based interventions and discusses key challenges in clinical translation. CONCLUSIONS: By combining cutting-edge computational technologies, biological research, and clinical insights, this review aims to bridge the gap between microbiome science and oncological practice, pioneering innovative strategies for microbiota-guided diagnostics and personalized cancer therapy.

Humans↗
PubMed2026

The Landmark Series: Mutation-Based Therapy of Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited long-term survival despite advances in surgery and systemic therapy. PATIENTS: The population of interest comprises patients with PDAC characterized by targetable molecular alterations and biologically distinct transcriptomic subtypes. METHODS: We performed a narrative review of landmark and contemporary clinical trials, translational studies, and emerging molecular-classification platforms relevant to precision oncology in PDAC. RESULTS: Growing understanding of PDAC molecular biology has identified putative genetic mutations, including homologous recombination repair deficiency, mismatch repair deficiency, and mutated KRAS, enabling the development of targeted therapies and precision treatment strategies. Concurrently, transcriptomic profiling has revealed biologically distinct molecular subtypes associated with differences in prognosis and therapeutic response. Emerging tools such as molecular classifiers, deep learning models, and multiomic platforms may further refine patient selection and treatment personalization. CONCLUSIONS: This review highlights contemporary efforts of novel targeted therapies, ongoing advances in molecular subtyping, and the evolving role of precision oncology in improving outcomes for patients with PDAC.

Genomic alterations↗