Epstein-Barr virus (EBV) infection is closely associated with the occurrence of nasopharyngeal carcinoma (NPC). The latent membrane protein 1 (LMP1) gene, known for its high heterogeneity, plays a crucial role in the oncogenic potential of EBV associated NPC (EBVaNPC). This study aimed to integrate algorithm with experimental validation to contribute valuable insights into the early detection and risk assessment of EBVaNPC, and investigate the functional significance of LMP1 key mutation. The LMP1 region in clinical EBV-positive subjects was sequenced with amplicon-based next-generation sequencing. An automatic viral sequence feature extraction (ViSFE) approach was developed. Biological implications of predicted key mutation on tumor cell biological behaviors were investigated through qRT-PCR, EdU analysis, transwell invasion assay, RNA sequencing and gene ontology fingerprint (GOF) method. Validation results demonstrate the feasibility of ViSFE applied to nucleotide data of varying lengths. Our study identified H101R mutation in LMP1 as a top feature, confirmed by proliferation and invasion experiments. By integrating EBVaNPC GOF and RNA sequencing data, the differentially expressed genes linked to the H101R mutation were primarily involved in immune regulation processes. Both approaches indicated a notable association between FOXP3-T cell anergy and WNT7A-stem cell population maintenance in HNE-1MUT-LMP1. This study offers a new strategy for high-risk NPC identification in EBV infected subjects. A tool for ViSFE is available at: http://www.biomedinfo.cn/ViSFE/index.html .

Gastric cancer (GC) ranks as the fifth most common cancer worldwide and is the third main cause of cancer-related mortality, posing a substantial burden to global public health. Research suggests that targeted therapy and immunotherapy may become more effective treatment options for advanced, unresectable, or metastatic gastric cancer. Ras-related C3 botulinum toxin substrate 1 (Rac1), a small GTP-binding protein within the Rac subfamily of the Rho GTPase family, is a critical molecule that promotes cancer cell invasion and metastasis by regulating signal transmission and promoting cell polarity. It has emerged as a key driver of tumor development and metastasis in several malignancies, including breast, lung, prostate, ovarian, gastric, and pancreatic cancers. This review summarizes the structure, regulatory dynamics, and signaling mechanisms of Rac1 in gastric cancer growth, epithelial-to-mesenchymal transition (EMT), and metastasis, as well as the roles of factors such as hypoxia, oxidative stress, and H. pylori infection. Additionally, it highlights small-molecule inhibitors targeting Rac1, miRNAs capable of suppressing Rac1, and ongoing research on Rac1-related immunotherapy. The potential of Rac1 as a therapeutic biomarker in gastric cancer and the remaining challenges in this area are also discussed. This review advances the understanding of Rac1's role in gastric cancer, provides a theoretical foundation for further studies, and supports the development of precision medicine for this disease.

Genome instability, tumour-promoting inflammation, and immune escape are three distinct hallmarks of cancer. However, accumulating scientific and clinical evidence over the past decade have uncovered a multifaceted interplay of complex dynamic network of interactions between genome instability, the DNA damage response (DDR), and tumour immunogenicity. Fuelled by the clinical successes of immune checkpoint blockers (ICB), growing interest for immuno-oncology and recent cancer biology discoveries have allowed a better understanding of the underlying biology and clinical opportunities brought by this interplay-which is yet, still only in its infancy. The cooperative nature of tumour cell-intrinsic and -extrinsic mechanisms involved suggests that harnessing genomic instability in cancer does not only hamper cancer cells fitness but also stimulate the anti-tumour immune response, thereby paving the way to the development of DDR-based immunomodulatory therapeutic strategies applicable to a variety of molecular and histological cancer types. Here, we review the various aspects of this crosstalk between genome instability and tumour immunogenicity, including feedforward and feedback mechanisms affecting either side of this interplay, as well as the specific consequences of chromosomal instability. We further discuss emerging DDR-based predictive biomarkers of response to ICB therapies, and finally examine the latest clinical developments of therapeutic combinations that exploit the DDR-immunity interplay in immuno-oncology.

Hepatocellular carcinoma (HCC) ranks as the fourth leading cause of cancer-related deaths globally, characterised by high incidence and extremely poor prognosis. In the context of cirrhosis, the hypoxic microenvironment resulting from HCC's intricate vascular network is closely associated with the poor therapeutic outcomes of targeted and immunotherapies in advanced HCC patients. In recent years, growing evidence indicates a profound intrinsic connection between the N6-methyladenine (m6A) epigenetic modification and tumor immune evasion, metabolic reprogramming, and ferroptosis resistance. As the cross-regulatory mechanisms of hypoxia-mediated m6A are progressively elucidated, the dynamic interplay of the hypoxia-m6A axis offers novel therapeutic perspectives and targets for clinical management of HCC. This review systematically elucidates the molecular mechanisms by which hypoxia-inducible factor (HIF-1α) and key m6A-modifying enzymes (METTL3, FTO, YTHDF2) jointly regulate HCC progression within the hypoxic microenvironment. From a clinical perspective, it demonstrates the potential of the hypoxia-m6A axis as a biomarker and a novel therapeutic target for overcoming treatment resistance in HCC. It critically discusses current limitations, including inconsistent research findings, challenges in translating clinical models, and off-target risks in combination therapies. Future research should focus on developing novel controllable targeted nanomedicines and immune checkpoint inhibitors, combined with multimodal image fusion, to enable real-time intraoperative monitoring and postoperative risk prediction, thereby advancing personalised treatment and precision medicine.

Drug synergy in cancer therapy has gained attention for its potential to enhance efficacy and minimize adverse effects. Synergy, where the combined effect of drugs exceeds the sum of their individual effects, is beneficial in addressing tumor heterogeneity and drug resistance in oncology. Esophageal squamous cell carcinoma (eSCC), accounting for over 85% of esophageal cancer cases, has a poor prognosis and limited therapeutic options. Targeted therapies have shown inefficiency in eSCC due to resistance mechanisms, making drug combination an interesting option.

Germline mutations in cancer-predisposition genes are critical for clinical risk assessment and therapeutic decisions in breast cancer, yet large-scale genomic studies and population-specific tools remain limited for Asian populations.

Multiple myeloma (MM) is a neoplasm of antibody-producing plasma cells and is the second most prevalent hematological malignancy worldwide. Development of drug resistance and disease relapse significantly impede the success of MM treatment, highlighting the critical need to discover novel therapeutic targets. In a custom CRISPR/Cas9 screen targeting 197 DNA damage response-related genes, Protein Arginine N-Methyltransferase 1 (PRMT1) emerged as a top hit, revealing it as a potential therapeutic vulnerability and survival dependency in MM cells. PRMT1, a major Type I PRMT enzyme, catalyzes the asymmetric transfer of methyl groups to arginine residues, influencing gene transcription and protein function through post-translational modification. Dysregulation or overexpression of PRMT1 has been observed in various malignancies including MM and is linked to chemoresistance. Treatment with the Type I PRMT inhibitor GSK3368715 resulted in a dose-dependent reduction in cell survival across a panel of MM cell lines. This was accompanied by reduced levels of asymmetric dimethylation of arginine (ADMA) and increased arginine monomethylation (MMA) in MM cells. Cell cycle analysis revealed an accumulation of cells in the G0/G1 phase and a reduction in the S phase upon GSK3368715 treatment. Additionally, PRMT1 inhibition led to a significant downregulation of genes involved in cell proliferation, DNA replication, and DNA damage response (DDR), likely inducing genomic instability and impairing tumor growth. This was supported by Reverse Phase Protein Array (RPPA) analyses, which revealed a significant reduction in levels of proteins associated with cell cycle regulation and DDR pathways. Overall, our findings indicate that MM cells critically depend on PRMT1 for survival, highlighting the therapeutic potential of PRMT1 inhibition in treating MM.

Despite significantPlease check if article title presented correctly. advances made by genome-wide association studies (GWAS) in the genetic exploration of tumors such as prostate cancer (PCa), the precise pathogenic genes and underlying biological mechanisms of PCa remain unclear.

Increasing evidence implicates the NF-κB/p65 signaling pathway in the progression of prostate cancer (PC) and the development of resistance to androgen deprivation therapy. This study aimed to investigate the potential role of UHRF1, a key epigenetic regulator, in modulating NF-κB activity, and to evaluate its association with clinicopathological features and clinical outcomes in PC patients.

Low-grade glioma (LGG) is a diverse group of primary brain tumors, whose molecular heterogeneity hinders classification by traditional pathological methods. Accurate phenotypic subtyping of LGG is essential for capturing tumor characteristics and optimizing clinical management. We intend to identify LGG phenotypic subtypes based on multimodal magnetic resonance imaging (MRI) data, enhancing prognosis evaluation and optimizing treatment strategy.

Osteosarcoma (OS) relies on the Warburg effect for aggressive growth and chemotherapy resistance, but strategies to disrupt this metabolic adaptation remain limited. This study aimed to identify novel noncoding RNA regulatory mechanisms governing the Warburg effect in OS and explore potential therapeutic targets.

The HOXB13 gene has been associated with hereditary prostate cancer (PCa), with rare germline variants linked to early-onset and aggressive forms of the disease. While the G84E variant has been well-characterized in Caucasian populations, the clinical relevance of the X285K variant-primarily found in individuals of African ancestry-remains unclear. This study aimed to determine the prevalence of HOXB13 X285K in a French Caribbean cohort and explore its association with adverse clinical features.

Neoadjuvant chemotherapy (NAC) combined with human epidermal growth factor receptor 2 (HER2)-targeted agents is the mainstay of treatment of HER2-positive (HER2 +) breast cancer (BC). We investigated intrinsic subtypes and clinicopathological features as predictors of outcomes of NAC in HER2 + early-stage BC patients.

Most cancers are diagnosed in people over 60 years of age, but little is known about how age impacts tumorigenesis. While aging is accompanied by mutation accumulation (widely understood to contribute to cancer risk) it is associated with numerous other cellular and molecular changes likely to impact tumorigenesis. Moreover, cancer incidence decreases in the oldest part of the population, suggesting that very old age may reduce carcinogenesis. Here we show that aging represses oncogenic KRAS-driven tumor initiation and growth in genetically engineered mouse models of human lung cancer. Moreover, aging dampens the impact of inactivating many tumor suppressor genes with the impact of inactivating PTEN, a negative regulator of the PI3K-AKT pathway, weakened disproportionately. Single-cell transcriptomic analysis revealed that neoplastic cells in aged mice retain age-related transcriptomic changes, showing that the impact of age persists through oncogenic transformation. Furthermore, the consequences of PTEN inactivation were strikingly age-dependent, with PTEN deficiency reducing signatures of aging in cancer cells and the tumor microenvironment. Our findings underscore the interconnectedness of the pathways involved in aging and tumorigenesis and document tumor-suppressive effects of aging that may contribute to the deceleration in cancer incidence with age.

Polycystic ovary syndrome (PCOS), the leading endocrine disorder in women of reproductive age, is highly heritable, yet its polygenic architecture remains poorly understood. Here we conducted a genome-wide association study on 12,419 Chinese women with PCOS and 34,235 controls, followed by a multi-ancestry meta-analysis with up to 13,773 European cases and 411,088 controls, identifying 94 independent loci, 73 of which were previously unreported. Despite different evolutionary pressures, Chinese and European ancestries showed substantial genetic overlap. Integrative functional analyses prioritized regulatory variants controlling gene activity in specific tissues, disease-causing genes including anti-Müllerian hormone (AMH), and biological pathways involving ligand-binding domain interactions and peroxisome proliferator-activated receptor gamma (PPARG) signaling. We identified granulosa cells as particularly important in PCOS development. Our genetics-driven drug discovery approach revealed multiple drug targets and repurposing opportunities, enabling personalized treatment strategies. These results enhance our understanding of the molecular basis of PCOS, paving the way for precision medicine.

Lysine (K)-specific demethylase (KDM) 6A, a histone modifier with inhibitory roles in many types of cancers, is frequently mutated in clear cell renal cell carcinoma (ccRCC). Here, we investigated the role of KDM6A in ccRCC progression, including its effect on resistance to tyrosine kinase inhibitors (TKIs). The clinical impact of KDM6A expression was examined by immunohistochemical analysis of nephrectomized tissues from patients with ccRCC. Upon generation of KDM6A-deficient RCC cells by CRISPR/Cas9-mediated gene editing, in vitro cancer cell property analysis, RNA sequencing, and in vivo murine xenograft model examination were performed. The relationship between KDM6A expression and efficacy of TKIs was analyzed using data from public databases and in vitro pharmacological assessments. Patients with KDM6A-low ccRCC had poor prognoses. Promoted invasion, migration, cancer stemness, epithelial-mesenchymal transition (EMT), and in vivo tumor progression were observed in KDM6A-deficient RCC cells. A reanalysis of previous clinical trial data revealed lower efficacy of sunitinib in patients with KDM6A-low ccRCC. Consistently, KDM6A-deficient cells showed resistance to cabozantinib and decreased expression of target molecules of TKIs. KDM6A deficiency contributes to ccRCC progression and TKI resistance, suggesting that targeting KDM6A-related pathways may offer new therapeutic strategies for patients with KDM6A-deficient ccRCC.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive, heterogeneous non-Hodgkin lymphoma with high relapse rates and drug resistance, which necessitates novel biomarkers. This study aimed to fill a research gap by investigating the function of ferroptosis-an iron-dependent form of programmed cell death-in DLBCL, an area that remains inadequately explored. Employing a comprehensive bioinformatics framework, we analyzed ferroptosis-related genes in The Cancer Genome Atlas-DLBCL dataset using consensus clustering and differential expression, somatic mutation, copy number variation (CNV), gene ontology and pathway enrichment, and immune infiltration analyses. Our analysis identified two DLBCL subtypes, revealing 912 differentially expressed genes, including 24 ferroptosis-related differentially expressed genes (FRDEGs). Enrichment analyses indicated that these genes are involved in crucial biological pathways, including the lipoxygenase pathway and inflammatory regulation, while immune infiltration assessment highlighted significant correlations with specific immune cell types, particularly the positive correlation of IDO1 with M1 macrophages and the negative correlation of IFNG with memory B cells. Further, we established a prognostic risk model incorporating CDKN1A, KLF2, and IFNG that holds promise for predicting patient outcomes. These findings demonstrate that ferroptosis regulates DLBCL progression and identify potential biomarkers/therapeutic targets requiring validation to develop new therapies.

Understanding and accurate diagnosis of lymph node metastasis (LNM) for patients with colorectal cancer (CRC) is essential to determine treatment and follow-up strategies. Therefore, in this study, we aimed to elucidate the biological process and identify the potential biomarker for LNM in CRC.A total of 30 patients who received a histologically confirmed diagnosis of CRC with Stage I to III and a curative surgery between November 2020 and July 2021 at Kyung Hee university hospital at Gangdong were included. We performed multi-omics approach integrating the data on somatic mutation, transcriptomic expression, DNA methylation, and microbiome with tumor and adjacent matched normal tissues of each patient. In total, 12 significant DEGs between the patients with and without LNM were identified, consisting of significantly upregulated S100A8 gene, a proinflammatory gene. The GSEA revealed that gene sets involving "MULTI CANCER INVASIVENESS" in terms related to epithelial-mesenchymal transition was significantly upregulated in the patients with LNM. Integrated functional analysis of DNA methylation with transcriptome profile shows that significantly hypomethylated promoters of the genes are enriched for LNM. The phylum Proteobacteria, unassigned (p_PU) presented significantly higher proportions in cancer tissues from the adjacent normal tissues. Notably, when compared to the patients without LNM, the gut microbiota of those with LNM appears to exhibit a significantly lower abundance of the p_PU, indicating its potential as promising biomarker for LNM in CRC. We explained the mechanism of tumor spreading using multi-omics analysis and identified the relevant metagenomic biomarker to predict the LNM in CRC by the recognition of host-microbial interaction, thereby can make the cancer surveillance of the patients more individualized and convincing.

Limited success has been achieved in the development of patient-derived xenografts (PDX) models of hormone receptor-positive (HR+), Human Epidermal growth factor Receptor 2-negative (HER2-negative) metastatic breast cancers that are resistant to hormone therapy (HT). We aimed to establish and characterize PDX models from HR+/HER2-negative breast cancer. A total of 28 tumors were orthotopically implanted in the fourth mammary fat pad of female NOD-SCID mice. Seven PDXs were developed, five from heavily pretreated HT-resistant patients and two from treatment-naïve patients. Three of the seven PDXs (two from HT-resistant and one from treatment-naive) converted into lymphoma by generation 2 (G1). The median time for developing palpable G0 PDX was 100 (45-150) days for five HT-resistant tumors, and the mean time was 178 (160-196) days for two treatment-naïve tumors. Successful PDXs were developed from three HT-resistant tumors (two up to G4, one up to G0), including one of solid papillary morphology, and one treatment-naïve tumor (up to G2). Histopathological analyses showed complete concordance for all 14 PDX generations (11 resistant, 3 treatment-naïve) with their corresponding patient's tumor for estrogen receptor (ER), progesterone receptor (PR) and HER2. Short tandem repeat (STR) profiling using 18 markers was done in 8/11 HT-resistant generations and 3/3 treatment-naïve generations and showed good concordance of 51-100% and 91-100%, respectively, with patient tumors. We successfully established PDXs of HT-resistant and treatment-naïve HR+/HER2-negative breast cancer, which will be valuable tools for understanding molecular resistance mechanisms and for exploring novel treatment strategies.

Older adults with HER2-positive early breast cancer are underrepresented in clinical trials, and the benefit of chemotherapy in this population remains uncertain. We evaluated the HER2DX genomic assay within the randomized RESPECT trial (NCT01104935), which compared adjuvant trastuzumab with or without chemotherapy in patients aged 70-80 years. In this prespecified translational analysis (Trans-RESPECT), HER2DX scores were available for 154 patients. The HER2DX risk score classified 74.0% as low risk and 26.0% as high risk. Ten-year relapse-free and overall survival were higher in the low-risk group. HER2DX remained independently associated with overall survival in multivariable analysis. The HER2DX immune, luminal, and proliferation signatures that compose the risk score were also prognostic. While the HER2DX pCR score was not prognostic overall, exploratory subgroup analyses suggested a potential survival benefit from chemotherapy in the pCR-high group. HER2DX offers prognostic value and may guide chemotherapy use in older patients with HER2-positive early breast cancer. Clinical Trial Information NCT01104935.