Angiogenesis, which is the formation of new blood vessels from existing vasculature, exhibits a pivotal role in breast cancer progression and promotes metastasis. This complex biological process is influenced by the dynamic balance of pro- and anti-angiogenic factors within the tumor microenvironment, such as vascular endothelial growth factor, fibroblast growth factors, and angiopoietins. Targeted therapeutic strategies have been developed to interfere with angiogenic signaling, aiming to normalize or inhibit the tumor vasculature. In recent years, miRNAs have arisen as crucial post-transcriptional regulators of gene expression implicated in angiogenic homeostasis. These microRNAs can function as either promoters or suppressors of angiogenesis by targeting mRNAs that encode angiogenic factors or other signaling molecules. Deregulated expressions of these miRNAs in BC are associated with perturbed angiogenesis, tumor progression, and therapeutic resistance. This review presents a thorough overview of the molecular processes controlling angiogenesis in BC and highlights the emerging roles of angioregulatory miRNAs. The article also discusses the therapeutic potential of targeting miRNAs to modulate tumor angiogenesis, providing novel insights for the development of miRNA-based diagnostics and therapeutics in BC management.

Pharmacovigilance has revealed an alarming correlation between certain medications and a higher risk of cancer. In this narrative review, included research from 2020 to 2025, along with a few seminal older studies, so that it provides a clear picture of which drugs actually set off cancer and mechanisms involved at the molecular level. An extensive literature review of the subject was designed on PubMed, Embase, Scopus, and Web of Science using systematic search. Search words and phrases included: "Carcinogenic drugs," "drug-induced cancer," "medication-induced carcinogenesis," "immunosuppressant cancer risk," "hormone therapy and cancer," "chemotherapy-induced secondary malignancies," and names of relevant drugs.

Brain metastases arise from the spread of cancer cells from tumors residing outside the brain. Immunotherapy and molecularly targeted therapeutics have improved outcomes for some patients with brain metastases, but many patients are still faced with a dismal prognosis. The inability to effectively treat these tumors and improve patient survival highlights the dire need for improved therapeutic strategies that ultimately depend on developing a greater understanding of the molecular underpinnings and inner wiring of these tumors. In this Review, we discuss current and emerging insights into the genetics and cellular signaling pathways that contribute to the spread of tumors to the brain. We also discuss potential therapeutic targets in the metabolic vulnerabilities of cells that metastasize to the brain and in the interactions between metastases and the microenvironment.

Spatial transcriptomics allows for the investigation of complex cellular ecosystems directly in their native tissues and enables the dissection of immune niches as spatially organized and functionally diverse microenvironments across homeostatic, inflammatory, and malignant settings. In this review, we examine how spatial transcriptomics tools have been applied to interrogate the cellular and molecular architecture of immune niches, including the emerging studies of B and T cell clonal niches. We focus on immune niches in intestinal and tumor tissues due to their importance to both health and pathology, discuss pressing immunological questions these technologies may help to address, and highlight future developments in the field.

Urological malignancies, primarily including renal cell carcinoma, bladder cancer and prostate cancer, underscore the critical importance of early screening, diagnosis and treatment in inhibiting disease progression and improving patient prognosis. Advancements in molecular biology have established urinary biomarkers as promising noninvasive tools with considerable potential for early tumour detection and screening high-risk populations, potentially overcoming limitations associated with traditional invasive procedures and imaging. This review systematically summarises urinary biomarkers related to renal cell carcinoma, bladder cancer and prostate cancer. It focuses on protein biomarkers (e.g., cytokeratin and nuclear matrix protein 22), epigenetic and transcriptional biomarkers (e.g., microRNAs and long noncoding RNAs), genetic biomarkers (e.g., telomerase reverse transcriptase and fibroblast growth factor receptor 3) and emerging biomarkers (metabolomic markers, circulating tumour DNA and mass spectrometry-based high-throughput proteomics). This review provides an in-depth exploration of the molecular mechanisms, diagnostic performance (sensitivity and specificity), current clinical applications and limitations of various biomarkers, placing a particular emphasis on comparing the differential expression of the same biomarker across different cancer types. By building on this foundation, this review further outlines future development pathways, including multibiomarker combination strategies, AI-assisted analysis and standardised testing protocols, to offer comprehensive references for the early, noninvasive and precise diagnosis of urological tumours.

Urological cancers, such as prostate, bladder and renal cell carcinoma, contribute substantially to the global cancer burden. Their management remains challenging due to extensive molecular and clinical heterogeneity. Conventional single-omics approaches (e.g., genomics and transcriptomics) have led to important discoveries but provided only partial views of tumour biology, which limit the robustness of biomarkers and therapeutic precision. Multi-omics integration offers a systems-level perspective that captures the complex regulatory networks underlying tumour initiation, progression and treatment resistance.

The tumor suppressor gene TP53 is the most frequently mutated gene in human cancers and has been a popular area of research in the field of oncology. The p53 protein, encoded by the TP53 gene, not only binds to many targeted genes but also regulates apoptosis, autophagy, cell cycle arrest, metabolism, senescence and the tumor immune microenvironment to suppress tumorigenesis. In recent years, an increasing number of new functions of p53 have been discovered, and p53-mediated tumor suppressor functions have been greatly expanded. Mutations in TP53 not only abolish its ability to suppress tumorigenesis but also confer carcinogenic properties to p53-mutant cells. Because of the prevalence of p53 dysfunction in various disease types, p53 has long been considered an attractive target for new anticancer drugs. However, drugs targeting p53 are still under investigation in early clinical trials and have not been approved for clinical use. This finding is consistent with the speculation that p53 is widely regarded as "undruggable." Surprisingly, several novel therapeutic approaches targeting p53, including MDM2/4 antagonists, compounds that target specific p53 mutants or restore the wild-type function of the mutated p53 protein, p53-based genetic therapies and p53-based tumor immunotherapy, have been developed in recent years. Here, we present a review of the structure, inactivation, and roles of p53 in diseases. In addition, this review discusses the efforts to target diseases associated with p53 dysfunction and the challenges encountered in the clinical development of these approaches.

Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, exhibits a 5-year survival rate below 10% and extremely poor clinical prognosis. Over 90% of PDAC patients harbor KRAS gene driver mutations, which promote tumor proliferation, invasion, and immunosuppression of the tumor microenvironment through constitutive activation of downstream RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways. Although the therapeutic potential of targeting KRAS has been recognized for decades, its smooth protein structure and lack of traditional drug-binding pockets led to its long-standing classification as an "undruggable" target, resulting in limited efficacy of early targeted agents. Recent breakthroughs with next-generation KRAS inhibitors have transformed the therapeutic landscape for pancreatic cancer. This review synthesizes evidence from basic research and clinical translation to provide a theoretical foundation and practical guidance for the precision treatment of KRAS-mutant pancreatic cancer.

The gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal tumors of the gastrointestinal tract. Between the 1990s and early 2000s, GIST was identified as a tumor characterized by KIT or PDGFRA mutations, resulting in imatinib being established as an effective targeted therapy. However, with advances in molecular diagnostics, approximately 10%-15% of GISTs have been reported to harbor alternative mutations, such as those in the succinate dehydrogenase subunit genes and BRAF, leading to the development of additional targeted therapies. GISTs exhibit a wide spectrum of clinical behaviors, ranging from indolent to highly aggressive, prompting the development of diverse risk classification systems. However, multiple systems remain in use, leading to inconsistent pathologic reports. Moreover, the mitotic counting method-a key factor in risk stratification-has become a major source of confusion among pathologists owing to the adoption of digital pathology and discrepancies between updated international guidelines and outdated reimbursement requirements. These inconsistencies have hindered pathologic reporting and communication between pathologists and clinicians. This review comprehensively overviews the historical background, molecular subtypes, and risk classification systems of GIST, focusing on evolving issues in mitotic rate evaluation and the application of risk classification systems in clinical practice.

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.

Hepatitis B virus (HBV) and hepatocellular carcinoma (HCC) are serious medical problems worldwide. Today, many researchers believe that genetic variations play a major role in how easily someone gets infected and how the disease progresses over time. Although many genetic association studies have suggested various susceptibility loci, lack of consistent results across studies has limited clinical utility. We performed a comprehensive meta-analysis primarily involving East Asian cohorts. We analysed eight SNPs related to HBV infection and 11 SNPs related to HCC across multiple etiologic subgroups. We found that CD40 rs1883832 and C2 rs9267665 exhibited the strongest associations with susceptibility to HBV infection, with no heterogeneity. We found that HLA-DPA1 rs3077 and HLA-DQB1 rs2856718 were significantly associated with HBV infection susceptibility, though with considerable heterogeneity. In our HCC analyses, we found that certain risk variants are linked to specific causes. These include HBV, HCV, alcohol-related disease, and non-alcoholic fatty liver disease (NAFLD). Each cause seems to have its own genetic factors. Based on these results, our meta-analysis brings together many studies to give a clearer picture of the genetic factors that influence HBV infection and HCC in different etiologic pathways. We found that immune-related genes and HLA class II variants seem to have roles in HBV persistence, while metabolic gene variants are major contributors to HCC risk.

NOL1/NOP2/SUN domain family member 2 (NSUN2), a member of the RNA methyltransferase family responsible for catalysing 5-methylcytosine (m5 C) modifications, has been increasingly recognized as a key regulatory factor in the initiation and progression of cancer. A growing body of evidence indicates that NSUN2 is aberrantly expressed in multiple malignancies, such as hepatocellular carcinoma, breast cancer, and gastric cancer, where its overexpression is frequently associated with unfavourable clinical outcomes, increased tumour aggressiveness, and resistance to therapy. Through its m5C modification activity, NSUN2 influences RNA stability, translational efficiency, and molecular interaction networks, thereby modulating critical oncogenic signalling pathways, including Wnt/β-catenin, PI3K/AKT, and epithelial-mesenchymal transition (EMT). Moreover, NSUN2 has been shown to interact with non-coding RNAs and epigenetic regulatory factors, contributing to the remodelling of the tumour microenvironment and facilitating immune evasion. Although NSUN2 is predominantly characterized by its tumour-promoting functions, emerging studies also suggest context-specific tumour-suppressive roles, highlighting its functional complexity in cancer biology. This review aims to summarize recent advances in understanding the molecular mechanisms underlying NSUN2 function, its clinical significance, and its potential as a biomarker or therapeutic target, while also discussing the challenges in translating these findings into clinical practice. A deeper understanding of NSUN2's diverse roles in carcinogenesis may provide novel insights into RNA epigenetics and inform the development of innovative strategies for cancer diagnosis and treatment.

Retinoblastoma (RB) is typically associated with highly penetrant pathogenic sequence variants (PSVs) in the RB1 gene; however, some families exhibit low penetrance RB (LPRB). We aimed to determine the penetrance rate and identify genetic and clinical characteristics of LPRB. To that end two cohorts were analyzed: 250 genetically confirmed LPRB cases identified through systematic literature review and 78 classical germline RB (CGRB) from three international centers- Thailand, Korea, and Israel. Penetrance rate was estimated as the proportion of affected individuals among RB1 PSV carriers. Multivariate models assessed parent-of-origin effects and predictors of penetrance. PSVs were annotated with Combined Annotation Dependent Depletion (CADD) scores and mapped to pRB structural domains. LPRB penetrance ranged from 50% (125/250, non-age-adjusted, CI [43.8%-56.2%]) to 64% (125/196, age-adjusted, CI [56.8%-70.2%]). Paternal inheritance of RB1 PSV was associated with a significantly increased risk of LPRB in offspring (OR = 6.24; P < 0.0001). Clinically, LPRB were significantly more likely than CGRB to present with unilateral disease (OR = 9.3, P < 0.0001), diagnosed at an older age (13 Vs 6.5 months, P = 0.01), and affect males (OR = 2.4, P = 0.03). LPRB-associated PSVs showed lower CADD scores (OR = 1.5; P = 0.0008), indicating lower predicted pathogenicity, and were enriched in pRB's N- or C-terminal domains (OR = 3.2; P = 0.007), consistent with hypomorphic effects. In conclusion, LPRB shows a 50-64% penetrance rate, more likely to be paternally inherited, have unilateral presentation, and associated with hypomorphic RB1 PSVs in the terminal pRB regions. These findings support retitling 'low penetrance RB' to 'medium penetrance RB'.

Background and objectives Diffuse large B-cell lymphoma presents a significant challenge due to its high rate of treatment failure in 40% of patients. In this study we screened microRNAs as biomarkers in chemotherapy non-responding patients, to allow their early prognostication. Methods In the exploratory phase, whole transcriptome microRNA profiling was conducted on 10 diffuse large B-cell lymphoma cases. Three patients achieved complete remission, while seven had refractory or relapsed disease. The differentially expressed miRNAs were validated in 41 retrospective, treatment-naive diffuse large B-cell lymphoma biopsies, including the original 10 cases. Additionally, 33 cases with paired biopsy and plasma samples were prospectively evaluated using qRT-PCR to correlate miRNA expression with clinical outcomes. Functional validation to identify downstream pathways was done by knocking down identified miRNAs in JM-1 cells by semi-quantitative proteomics. Results miR-193b-5p, miR-1307-5p, and miR-671-5p expression were downregulated in refractory/relapsed diffuse large B-cell lymphoma biopsies. Plasma miRNA levels did not reflect prognosis. In vitro proteomics showed their impact on key oncogenic pathways, revealing significant enrichment of replication and transcription-related proteins. Interpretation and conclusions The expression of miR-193b-5p, miR-1307-5p, and miR-671-5p miRNAs in diffuse large B-cell lymphoma tissues may serve as predictive biomarkers.

Background and objectives Genomic studies are essential for identifying mutations that may influence key aspects of breast tumours, such as susceptibility, aggressiveness, and response to treatment. There are deficient molecular and genomic data from Indian breast cancer patients. Methods mRNA from primary breast cancer samples were subjected to next-generation transcriptome (mRNA) sequencing on an Illumina platform, in duplicates and triplicates to generate 30-60 M reads/sample. PAM50, and absolute intrinsic molecular subtyping (AIMS) gene expression-based classifiers were used for intrinsic subtyping. Variants were called using, GATK, MuTect2, VarScan2, and VarDict, followed by filtering for somatic and non-synonymous changes. Germline variants were excluded using public databases. ClinVar annotations prioritised pathogenic variants, and the STRING algorithm was used for network analysis. Results A total of 207 RNA-Seq datasets from 97 breast cancer patients were analysed. There was good concordance between the immunohistochemical receptor and AIMS classification for all subtypes, but there was discordance between immunohistochemical and PAM50 subtypes within the ER-positive/HER2-positive subgroup, wherein only 38.5% (n= 5) were classified as HER2-like by gene expression classification. Variant analysis identified 145 high-confidence somatic mutations, with TP53 (n=46, 47%) and PIK3CA (n=33, 34%) being the most frequent. Additional actionable mutations in BRCA1, BRCA2, FGFR2, PTEN, AKT1, and mTOR pathways were identified. At least one actionable mutation was found in 52% of patients. Fusion transcript analysis identified 91 recurrent fusions, including novel partners with ERBB2, MED1, and CDK12, suggesting the possibility of unique molecular events. Interpretation and conclusions This study demonstrates that Indian breast cancer patients exhibit molecular subtypes and actionable mutations comparable to Caucasian cohorts.

Tumor-agnostic therapies represent a transformative shift in oncology, targeting molecular alterations irrespective of cancer histology. These therapies offer new hope for patients with rare and difficult-to-treat malignancies, yet their integration into clinical practice remains inconsistent because of the absence of guidelines. Traditional organ-based classifications hinder timely access to precision treatments, despite evidence supporting molecular-driven approaches. Living guidelines, continuously updated frameworks based on emerging data, are essential to bridge this gap. They enable just-in-time incorporation of new therapies, streamline biomarker-driven care, and address the unique needs of rare and ultrarare cancers. Regulatory approvals for tumor-agnostic agents, such as NTRK inhibitors and immunotherapies for microsatellite instability-high/mismatch repair-deficient tumors, underscore the urgency for unified guidance. Trials like TAPUR, TRACK, and NCI-MATCH demonstrate the feasibility and benefit of molecular profiling across diverse cancer types. Tools like ESMO's ETAC-S provide structured criteria for evaluating tumor-agnostic potential, yet real-world implementation lags. Living guidelines can harmonize testing practices, improve access, and educate clinicians on cross-tumor applicability. They also facilitate proactive biomarker testing, reduce treatment delays, and enhance patient safety through tailored toxicity management. As oncology evolves toward molecular precision, living tumor-agnostic guidelines are critical for ensuring equitable, evidence-informed care for all patients, particularly those with rare cancers. National organizations must prioritize their development to fully realize the promise of precision medicine.

BackgroundSERPINE1 has attracted considerable attention in tumor biology, but its clinical importance in head and neck squamous cell carcinoma (HNSCC) is not yet clear. We therefore examined whether SERPINE1 expression is related to survival in patients with HNSCC.MethodsWe searched three major databases (PubMed, EMBASE, and the Cochrane Library) and identified observational studies reporting survival outcomes in relation to SERPINE1 expression through November 11, 2024. From eligible reports we extracted data on progression-free survival (PFS), overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS), and calculated pooled hazard ratios (HRs) using random-effects models.ResultsEleven studies including 733 individuals with HNSCC met the inclusion criteria. Across these cohorts, higher SERPINE1 expression was consistently linked with shorter OS (HR 2.81, P = 0.003) and shorter DFS (HR 1.57, P = 0.004). In contrast, no clear associations were observed for PFS or DSS (P ≥ 0.05).ConclusionCurrent evidence suggests that increased SERPINE1 expression is associated with an unfavorable prognosis in HNSCC, particularly for OS and DFS. Larger prospective studies are needed to confirm these findings and to determine how SERPINE1 assessment might be incorporated into risk stratification and treatment planning for patients with HNSCC.

High mobility group box 3 (HMGB3) acts as an essential participator in fundamental biological processes, including transcriptional regulation, chromatin remodeling and DNA repair. HMGB3 is highly expressed and functionally essential during embryonic development, particularly in the hematopoietic and nervous systems, but it is significantly downregulated or silenced in most normal adult tissues. Its aberrant upregulation has been revealed in numerous human malignancies, such as leukemia, as well as breast, bladder, colorectal and gastric cancer, and its expression levels have been established to be closely associated with poor prognosis of specific patients. Accordingly, the present review systematically explores the central roles of HMGB3 in mediating resistance to cancer therapy. This review focuses on its multifaceted mechanisms of maintaining cancer stemness, enhancing DNA damage repair, modulating cell death pathways and remodeling the tumor microenvironment, thereby contributing to the resistance to chemotherapy, radiotherapy, targeted therapy and immunotherapy collectively. HMGB3 can be accepted as a key target in the development of highly promising therapeutic strategies, given its pivotal involvement in multidrug resistance, which may offer novel avenues for overcoming clinical treatment resistance and improving patient outcomes.

Chromodomain helicase DNA‑binding protein 4 (CHD4) is a core adenosine triphosphate (ATP)‑dependent chromatin‑remodeling factor of the nucleosome‑remodeling and deacetylase (NuRD) complex. It plays a crucial role in chromatin structure regulation, gene expression regulation, and DNA damage response. It has been demonstrated that CHD4 has context‑dependent functions in tumor development and progression. It can influence tumor progression via such mechanisms as regulating tumor‑related signaling pathways, maintaining the silencing of tumor suppressor genes, and promoting metabolic adaptation; it can also exert tumor‑suppressive effects in specific transcriptional regulatory environments. Additionally, during DNA damage response, CHD4 participates in chromatin remodeling at damage sites, in cell cycle recovery, and in repair pathway selection. It is also involved in the development of tumor treatment resistance through mechanisms that include regulation of DNA repair, cell cycle progression, drug efflux, the tumor immune microenvironment, and replication fork stability. It has also been shown that various non‑coding RNAs participate in the functional regulation of CHD4 by modulating its expression, localization, and protein stability. In summary, as a key node connecting chromatin regulation, genome stability, and tumor treatment response, CHD4 holds significant importance in tumor progression and treatment.

The global incidence of thyroid cancer (TC) has markedly increased in recent years, making it the most prevalent endocrine‑related cancer worldwide. TC primarily originates from follicular and parafollicular cells of the thyroid gland, and includes four main pathological types: Papillary TC (PTC), follicular TC, medullary TC (MTC) and anaplastic TC. Notably, characteristic oncogenes and tumor suppressor genes are associated with TC, which are considered targets for the development of treatment strategies. The rearranged during transfection (RET) gene serves a pivotal role in the development of TC, and mutations and fusions of this gene are closely associated with the onset of MTC and PTC. The structure of RET includes four cadherin‑like domains and 16 cysteine residues in its extracellular domain, which confer unique functionalities and contribute to its intracellular role. RET activation is a complex process involving multiple intracellular events, including calcium ion binding, glial cell line‑derived neurotrophic factor family ligand binding, and RET receptor aggregation, dimerization and autophosphorylation. The present study reviews the structure and function of the RET proto‑oncogene and its pathogenic roles in various TC subtypes.