Risk-reducing mastectomy substantially reduces breast cancer risk in women at increased genetic or familial risk; however, it may have an impact on quality-of-life. The aim of this longitudinal study was to analyze differences in quality-of-life over time in women at increased risk of breast cancer who underwent risk-reducing mastectomy. A total of 55 cisgender women at increased risk of breast cancer, due to BRCA1/2 pathogenic variants or a significant family history, participated in the study. Some of them had a prior diagnosis of breast cancer. Quality-of-life was assessed using EORTC Quality-of-Life Questionnaire Core 30 (QLQ-C30) and the Breast Cancer-Specific Module (BR23). Assessments were conducted 15-30 days immediately before and 15-30 days immediately after the risk-reducing mastectomy, and at long-term follow-up. The follow-up assessment ranged from 1 to 15 years post-surgery (mean = 5.24 years). Changes over time were analyzed using repeated measures General Linear Models (GLM). Results indicated decreases in functional scales of quality-of-life and worsening of symptom scales following the risk-reducing mastectomy. However, quality-of-life scores returned to baseline levels at long-term follow-up. Worries regarding future perspective decreased following surgery and continued to improve over time. Although risk-reducing mastectomy was associated with short-term deterioration in selected domains, findings indicate recovery and long-term stabilization of quality-of-life. Additionally, risk-reducing mastectomy appears to alleviate future-oriented cancer concerns. This longitudinal evidence strengthens the basis for anticipatory guidance in genetic counseling and supports more balanced, evidence-informed decision-making.

We have previously defined the constitutive photomorphogenic protein 1 (COP1) gene as a therapeutic target in hepatocellular carcinoma (HCC). A recent study demonstrated that COP1 induces non-alcoholic fatty liver disease (NAFLD), a precursor to HCC, in normal hepatocytes and that reducing COP1 expression significantly improves high-fat diet-induced hepatic steatosis. Thus, in this study, we investigated if the function of COP1 was associated with HCC metabolism and evolution. Silencing of COP1 expression by a target siRNA significantly suppressed long-term colony formation in Huh7, HepG2, Huh1, and PLC/PRF/5 HCC cell lines. RNA sequencing of COP1-silenced Huh7 and HepG2 cells revealed the same directional regulation of 24 (14 up- and 10 down-regulated) genes. Notable molecular alterations were upregulation of AKR1D1 and downregulation of TMEM65, which involves negative regulation of lipid metabolism and promotion of metastasis, respectively. Correlation analysis using GEPIA2 supported inverse relationship between COP1 and AKR1D1 expression and positive relationship between COP1 and TMEM65 expression in HCC clinical samples. Targeting of COP1 reduced fat accumulation and metastatic potential in both HCC parental cells and CD133+ liver cancer stem cells. Overexpression of COP1 reversed the phenotypic changes. Collectively, our findings indicate that the COP1 is functionally correlated with HCC lipid metabolism and stemness.

We present a case of diffuse hemispheric glioma (DHG), H3 G34-mutant, NEC. Postoperative histological examination and DNA sequencing detected some features consistent with DHG, H3 G34-mutant; however, no canonical H3 alterations or ATRX variants were detected. The diagnosis could only be established based on the DNA methylation profiling result. In light of these distinctive molecular findings, we propose some insights into the current WHO diagnostic criteria for DHG H3-G34 and emphasise the value of comprehensive molecular diagnosis.

Kinesin family member 23 (KIF23) is recognised as an important tumour promoter involved in the pathogenesis of various cancers. However, its role and underlying molecular mechanisms in regulating cervical cancer (CC) growth and primary chemoresistance remain to be fully elucidated.

Accurate risk stratification and early detection of colorectal cancer (CRC) are critical for improving patient outcomes and optimizing the use of colonoscopy; however, the diagnostic performance of existing biomarkers remains suboptimal. This study aimed to develop and evaluate machine learning (ML)-based models to facilitate individualized risk assessment and clinical decision-making for colorectal lesions.

T cell-based immunotherapies have improved outcomes in lung adenocarcinoma (LUAD), yet many patients develop primary or acquired resistance. Tumor-intrinsic mechanisms that suppress CD8+ T cell function remain incompletely understood.

Gliomas are the most common primary malignant tumors of the adult central nervous system, characterized by rapid growth, high recurrence rates, and limited response to standard treatments, with median survival under 15 months. The SIX transcription factor family has been implicated in tumor development, but the role and regulatory mechanism of SIX5 in glioblastoma (GBM) remain unclear. This study systematically investigates the biological function of SIX5 and its regulatory network in GBM. Differential expression and weighted gene co-expression network analyses of GSE4290 and GSE50161 datasets, combined with machine learning algorithms including LASSO, identified SIX5 as a core candidate gene. Functional enrichment analyses and evaluation using TCGA and UALCAN databases revealed that SIX5 is highly expressed in GBM and associated with poor prognosis. Single-cell RNA sequencing and spatial transcriptomics showed enrichment of SIX5 in the tumor core and in astrocyte-like and stem cell-like subsets at the invasion front. In vitro, U87 and U251 cells with lentivirus-mediated SIX5 knockdown or overexpression were assessed for proliferation, migration, invasion, apoptosis, and colony formation. SIX5 knockdown significantly inhibited proliferation, migration, invasion, epithelial-mesenchymal transition, and tumorigenicity, while promoting apoptosis. Mechanistically, KDM5C positively regulates SIX5, which directly binds the UBE2C promoter to activate its transcription, enhancing AKT/mTOR signaling and promoting aerobic glycolysis via upregulation of GLUT1, HK2, PGK1, and LDHA. Rescue experiments showed that UBE2C overexpression partially restored malignant phenotypes under SIX5 downregulation. In vivo xenograft studies confirmed that the KDM5C-SIX5-UBE2C axis drives GBM growth. In conclusion, SIX5 functions as a critical oncogenic driver in GBM, regulated by KDM5C and promoting tumor progression through UBE2C-mediated activation of AKT/mTOR signaling and glycolytic reprogramming. The KDM5C-SIX5-UBE2C regulatory axis represents a potential prognostic biomarker and therapeutic target in glioblastoma.

Endotoxin tolerance (ET) is an immunological state in which repeated exposure to endotoxins such as lipopolysaccharide (LPS) leads to reprogramming of the immune system and a diminished inflammatory response. In this study, we used a murine model to explore the role of ET in breast cancer progression, hypothesizing that ET may foster a tumor-permissive immune environment. We compared endotoxin tolerant breast cancer-bearing mice (ETBC group) with non-endotoxin tolerant breast cancer-bearing controls (BC group). ETBC mice exhibit significantly faster tumor progression and earlier disease onset. Hematological analysis revealed reduced leukocyte counts in the ETBC group, indicating compromised immune cell recruitment. Additionally, ETBC mice showed decreased spleen weight relative to that in the BC group, further supporting systemic immune suppression. Gene expression profiling in both spleen and tumor tissues revealed marked immunological alterations in ETBC mice. In the spleen, there was notable downregulation of key pro-inflammatory cytokines, including interleukin (IL) 6 and interferon (IFN) γ. Conversely, genes associated with immune modulation and tumor progression such as IL-1β, inducible nitric oxide synthase (NOS2), cyclooxygenase (COX) 2, vascular endothelial growth factor (VEGF), and colony stimulating factor 1 (CSF-1) were upregulated. Notably, IL-1β, NOS2, COX-2, IL-10, and VEGF were consistently upregulated in tumor tissues of ETBC mice. We conclude that ET not only impairs immune surveillance but also reshapes the tumor microenvironment in favor of cancer growth. This highlights the potential role of ET in oncology and suggests that its modulation could represent a novel avenue for therapeutic intervention.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, with its pathogenesis primarily linked to activating mutations in the KIT or platelet derived growth factor receptor alpha (PDGFRA) genes. Surgical resection remains the standard curative treatment for localized GIST; however, ~50% of patients eventually develop recurrence or metastasis. Since the introduction of imatinib in the early 21st century, the management of metastatic GIST has shifted from solely surgical intervention to a systemic, chronic disease management model centered on tyrosine kinase inhibitors (TKIs). However, during the course of treatment, most patients develop drug resistance. Despite the transformative impact of TKIs, some critical clinical challenges remain unresolved. Intratumoral heterogeneity, in particular, poses a significant obstacle, as tumors often comprise diverse populations of cells with varying genetic and molecular profiles. This diversity means that while some subclones may initially respond well to TKI therapy, others harboring inherent or acquired resistance mutations can continue to proliferate, ultimately leading to treatment failure. Additionally, the limited durability of TKIs responses, even in tumors initially sensitive to treatment, remains a pressing concern. Moreover, the lack of curative systemic options for advanced GIST, along with adverse drug reactions, underscores the unmet needs within this patient population. These challenges underscore the necessity of this review, which discusses current standard drug treatment strategies for advanced GIST, including sequential TKIs therapy and investigations into mechanisms of drug resistance. Finally, the review explores precise and actionable future directions for GIST drug development and clinical management, including mutation-stratified therapeutic sequencing, rational TKI-based combination regimens, and circulating tumor DNA (ctDNA)-guided real-time treatment monitoring and resistance surveillance.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide. Although the transcription-export (TREX) complex plays a central role in RNA maturation and nuclear export, the clinical and biological relevance of individual THO Complex Subunit (including THOC1, THOC2, THOC3, THOC5, THOC6, and THOC7) in LUAD is not well defined. We performed integrative analyses combining bulk transcriptomics from TCGA/GTEx and independent GEO cohorts, survival modeling, DNA methylation profiling, protein-level annotation from public resources, protein-protein interaction network analysis, immune infiltration estimation (TIMER), and single-cell RNA sequencing (scRNA-seq) to evaluate the relevance of THOC3 and THOC7 in LUAD. Across TCGA and external GEO validation datasets, THOC3 and THOC7 were consistently upregulated in LUAD and associated with poorer overall and disease-free survival, whereas other THO complex members showed weaker or inconsistent associations. Given these comparatively consistent and reproducible signals, we therefore prioritized THOC3 and THOC7 for downstream multi-layer analyses. Epigenetic profiling and interaction network analyses placed both genes within conserved RNA processing and export programs linked to genome maintenance pathways. Single-cell transcriptomic analysis provided additional resolution, demonstrating predominant enrichment of THOC3 and THOC7 in malignant epithelial clusters, with THOC3 aligning with transcriptional programs associated with DNA replication and repair, and THOC7 with proliferative and checkpoint-related states. Notably, expression of both genes was also detectable in myeloid and neutrophil subsets, and THOC7 expression remained elevated in recurrent LUAD samples, indicating association with aggressive and treatment-resistant disease states. Collectively, by integrating bulk, single-cell, epigenetic, and immune profiling across multiple independent cohorts, this study identifies THOC3 and THOC7 as reproducible molecular correlates of aggressive LUAD phenotypes. These highlight dysregulated RNA export programs as potential biomarkers of poor prognosis and motivate future functional studies to assess RNA export dependencies in LUAD.

Increasing evidence indicates that tumor cellular senescence can impair antitumor immunity and promote skin cutaneous melanoma (SKCM) progression. However, effective methods for assessing tumor cellular senescent status and tumor immune microenvironment (TIME) status remain lacking. This study intends to establish a novel Senescence-TIME Risk Score (STIRS) based on senescence and TIME related genes to predict prognosis and immunotherapy responsiveness in SKCM patients, thereby providing new strategies for current clinical personalized treatment.

Efferocytosis plays a critical role in clearing apoptotic tumor cells and suppressing inflammation in hepatocellular carcinoma (HCC). This study aimed to identify efferocytosis-related genes (ERGs) with prognostic value and develop a predictive model for HCC outcomes.

Colorectal cancer (CRC) is one of the most prevalent and deadly gastrointestinal malignancies worldwide. Lenvatinib, a multi-tyrosine kinase inhibitor, has shown limited clinical benefit as a monotherapy for CRC. Therefore, combining lenvatinib with N-butylidenephthalide (BP), a known anticancer and adjuvant agent, has been explored to enhance therapeutic outcomes. This study investigates the effects of lenvatinib and BP, individually and in combination, on HCT15 and HCT116 CRC cell lines.

The ZZ-type zinc-finger family has emerged as an important regulator of tumorigenesis; however, its roles in renal cell carcinoma (RCC) susceptibility and prognosis are largely unexplored. This study aimed to systematically evaluate the genetic variants within this gene family to identify novel risk drivers and elucidate their downstream pathogenic networks. A total of 148 single-nucleotide polymorphisms (SNPs) were genotyped across 17 ZZ-type zinc finger genes in a cohort of 630 Taiwanese participants (312 patients with RCC and 318 healthy controls). The results were validated using pooled transcriptomic analysis of 18 independent datasets. Weighted gene co-expression network analysis (WGCNA) was used to construct tumor-specific networks and identify key driver genes. The Asian-specific variant of KCMF1 rs146409312 emerged as a significant susceptibility locus. The minor A allele conferred a 3.38-fold increased risk of RCC (adjusted odds ratio = 3.22, 95% confidence interval = 1.57-6.58, p = 0.001). KCMF1 was consistently upregulated in tumor tissues and was associated with poor patient survival. WGCNA identified a clinically relevant KCMF1-associated gene module enriched in ribosomal biogenesis and MYC target signaling. Within this network, SNRPD2 was identified as a critical hub gene, and its overexpression was strongly correlated with advanced tumor grade, stage, and reduced overall survival (p < 0.001). In conclusion, KCMF1 rs146409312 was identified as a potent, population-specific risk factor for RCC. A pathogenic KCMF1-driven network converging on SNRPD2 was delineated, offering novel insights into RCC etiology and highlighting potential biomarkers for prognostic stratification.

Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed malignancies and exhibits a high mortality rate. Patchouli alcohol (PA) is a tricyclic sesquiterpene derived from Pogostemon cablin, and the present study evaluated the antihepatoma capacity of PA and described a potential strategy for its combination with sorafenib (SOR) in vitro and in vivo. The anticancer potential of PA against HCC was evaluated using the MTT assay, flow cytometry, western blotting, DCF-DA and JC-1 staining, TUNEL assay, immunofluorescence and immunohistochemistry staining, and migration and invasion assays. The results indicated that PA suppressed HCC growth by inducing reactive oxygen species (ROS) generation, mitochondrial membrane potential imbalance, and DNA damage, ultimately resulting in cell cycle arrest and apoptosis via the activation of p53/p21 and also extrinsic (Fas/FasL/caspase-8), intrinsic (Bax/Bcl2/caspase-9), and caspase-independent pathways. The combination of PA with SOR exhibited synergistic effects, exerted survival benefits, and improved the lifespan of mice at well-tolerated doses. Furthermore, PA targets the androgen receptor (AR) to inhibit dihydrotestosterone-induced (DHT)-induced cell proliferation, AR translocation to the nucleus, and downstream gene expression during HCC growth. On the whole, PA alone or in combination with SOR exhibited markedly improved therapeutic efficacy in HCC by blocking AR-mediated and multiple other signaling pathways. Therefore, this study provides an experimental basis for the evaluation of PA as an alternative drug (alone or in combination) for the treatment of HCC.

Acute myeloid leukemia (AML) harboring IDH1 mutations presents unique metabolic vulnerabilities that remain incompletely addressed by current targeted therapies. In this study, we demonstrate that IDH1-mutant AML cells are markedly more sensitive to cuproptosis induced by the copper ionophore elesclomol (ES), compared to their wild-type counterparts. While ES impairs mitochondrial function in both cell types, transcriptomic profiling reveals that ES treatment induces a global downregulation of lipid metabolism pathways. Functional assays further show that IDH1-mutant cells rely more heavily on exogenous fatty acids and exhibit impaired de novo lipogenesis. Under lipid-deprived conditions, ES-induced cytotoxicity is significantly enhanced, suggesting a synthetic-lethal interaction between cuproptosis and fatty acid metabolic deficiency. In vivo experiments confirm that ES more effectively suppresses tumor growth in IDH1-mutant xenografts. These findings uncover a copper-dependent metabolic vulnerability and provide a rationale for exploiting cuproptosis as a therapeutic strategy in IDH1-mutant AML.

Oral cancer ranks as the fourth most common cancer among men in Taiwan and the ninth most common cancer among men worldwide. Nesfatin-1, an adipokine derived from the precursor NUCB2 gene, was originally discovered in hypothalamic neurons. The connections among lifestyle factors that promote cancer, NUCB2 polymorphisms, and oral cancer are still not well understood. We examined the association of four NUCB2 gene polymorphisms (rs1330, rs214101, rs757081, and rs10766383) and clinicopathological characteristics with oral cancer in Taiwanese men compared with healthy controls. According to our data, in patients aged ≥60 years, specific NUCB2 genotypes were significantly associated with more aggressive disease features. Compared with the wild-type C/C genotype, carriage of at least one polymorphic allele (T allele at rs1330 or G allele at rs757081) was correlated with an elevated risk of progression to stage III/IV disease. Furthermore, the GA/AA genotypes at rs214101 and the TG/GG genotypes at rs10766383 were associated with elevated risks of both advanced-stage (III/IV) disease and lymph node metastasis. Our findings suggest that NUCB2 SNPs may play a pivotal role in oral cancer progression and metastatic potential, particularly in older patients.

Background/Aims: Globally, colorectal cancer ranks third in causing 900,000 deaths annually. Some patients undergoing chemotherapy develop resistance, leading to metastasis. We investigated CHGA and UCHL1 proteins correlate with lymph node metastasis (J Cell Mol Med. 2023;27:2004-2020). This study aimed to analyze the relationship of CHGA and UCHL1 with the epithelial-mesenchymal transition (EMT) and the Rho/ERK/NFκB signaling pathway in OXA-resistant CRC cells.

Oral tongue cancer is an aggressive malignancy and represents the most common subsite of head and neck cancer. The long non-coding RNA myocardial infarction associated transcript (MIAT) has been implicated in the development and progression of several cancers. This study aimed to investigate the association between MIAT single-nucleotide polymorphisms (SNPs) and oral cancer susceptibility as well as related clinicopathological characteristics. In this study, MIAT SNPs (rs4274, rs1061540, and rs1894720) were genotyped using real-time polymerase chain reaction in 1,194 controls and 397 male patients with tongue cancer. A significant association was observed between the MIAT rs4274 AA genotype and the occurrence of tongue cancer compared with controls (p = 0.018). Among the patients, carriers of the rs4274 A allele exhibited a higher likelihood of developing moderately or poorly differentiated tumors [OR (95% CI) = 2.246 (1.217-4.147); p = 0.001]. Betel-quid chewers and smokers carrying the A allele showed similarly elevated risks for poor tumor differentiation. Bioinformatic analyses further indicated that the rs4274 A allele is associated with increased MIAT expression, and higher MIAT levels correlated with higher tumor grade. In conclusion, the MIAT rs4274 A allele is linked to poorer tumor differentiation, particularly among betel-quid chewers and smokers, and elevated MIAT expression supports its potential as a biomarker of tumor aggressiveness.

Epstein-Barr virus (EBV) is a widespread gamma-herpesvirus associated with a number of malignancies, including nasopharyngeal carcinoma and gastric cancer (GC/EBV+). The primary oncogenic protein of EBV is latent membrane protein 1 (LMP1). Genetic variability of the LMP1 protein affects its oncogenic activity and clinical manifestations.