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.

RNA polymerase II (Pol II) is an essential eukaryotic enzyme that transcribes protein‑coding genes and various non‑coding RNAs. RNA polymerase II, I and III subunit L (POLR2L) is a highly conserved component shared by RNA polymerase subunits I, II, and III, which contributes to transcriptional regulation, enzymatic structural integrity, key cellular processes such as proliferation, differentiation, and stress responses. Recent research has shown that POLR2L is not merely a Pol II structural subunit but also plays key roles in disease progression, particularly cancer, where POLR2L dysregulation contributes to tumor growth, metastasis, and resistance to chemotherapy. Additionally, POLR2L is closely linked to major signaling pathways including the PI3K‑Akt, Wnt/β‑catenin, and TGF‑β pathways, highlighting the diverse roles played by POLR2L in cellular signaling. This review summarizes current knowledge on the structural and functional properties of POLR2L, its involvement in various diseases, and its potential as a therapeutic target. By outlining the diagnostic and therapeutic relevance of POLR2L, this review aims to provide a framework for understanding how POLR2L related research may inform transcriptional regulation and its impact on human health and disease.

Histone modification is an important mechanism of epigenetic regulation. New histone modifications play key roles in the regulation of gene expression and in the development and progression of various diseases. In addition to histone modifications, epigenetic regulation includes classic pathways such as DNA methylation, chromatin remodeling complexes and non‑coding RNAs, which interact with each other and jointly shape the occurrence and development of gastric cancer (GC). The present study systematically elaborated on the role of histone modification in GC and introduced several main types of histone modification, including acetylation, methylation, citrullination, ubiquitination and lactylation, focusing on histone lactylation modification and exploring its biochemical basis, interaction with other modifications and functions such as metabolic reprogramming, cell proliferation, migration and immune escape, covering non‑tumor and other cancer fields. On this basis, the specific application of histone modification (acetylation, methylation and other modifications) in GC is further explained and the effects of histone lactylation on metabolic reprogramming, proliferation, migration and immune escape of GC are analyzed in detail. Finally, the clinical significance of histone lactylation modifications in the diagnosis and prognosis of GC, biomarkers, therapeutic targets and drug resistance mechanisms provides a reference for an in‑depth understanding of the role of histone modifications, especially lactylation modifications, in the development of GC and clinical transformation applications.

ADP-ribosyltransferases (ARTs) regulate key processes in cancer, including DNA repair, transcription, immune responses, and treatment resistance. The clostridial toxin-like ADP-ribosyltransferase (ARTC) family and the diphtheria toxin-like ADP-ribosyltransferase (ARTD) family play a crucial role in genomic stability by modification of proteins either with mono(ADP-ribosyl)ation (MARylation) or poly(ADP-ribosyl)ation (PARylation). These ARTs are promising therapeutic targets and could serve as biomarkers in cancer management. This review explores the roles of these enzymes and current knowledge on specific inhibitors. A literature search was conducted in PubMed and Google Scholar to identify studies published between 1992 and 2025 on ADP-ribosyltransferases and their roles in cancer. Among ARTC family, ART1 and ART3 modulate the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, influencing angiogenesis, tumor growth, and immune evasion via cluster of differentiation 8+ (CD8+) T-cell apoptosis. Within the ARTD family, poly(ADP-ribose)polymerase (PARP)1 and PARP2 are activated by DNA single-strand breaks and are clinically validated targets in cancers with homologous recombination deficiency, such as breast cancer susceptibility genes 1/2 (BRCA1/2)-mutated breast cancer. Their inhibition exemplifies synthetic lethality and has shown clinical efficacy. Four PARP inhibitors, olaparib, niraparib, rucaparib, are approved by the Food and Drug Administration (FDA) approved. Despite these advances, selective inhibitors for ARTs remain underexplored. Ongoing research focuses on overcoming PARP inhibitor resistance, improving biomarker-driven patient selection, and expanding therapeutic strategies that target ART-related pathways.

-Synovial sarcoma is a rare soft tissue sarcoma. Treatment of synovial sarcoma includes surgery, radiation, pazopanib, and chemotherapy. Targeted therapies, such as B-Raf proto-oncogene, serine/threonine kinase (BRAF) inhibitors, are emerging as a potential treatment option. We describe the sixth case of a BRAFV600E synovial sarcoma, the first extra-thoracic case. This case is the first to show a complete pathological response to BRAF & mitogen-activated protein kinase kinase (MEK) inhibitors.

Malignant melanoma (MM) is a highly aggressive skin cancer known for its rapid progression, potential for metastasis, and resistance to treatment. Despite advances in targeted therapies and immunotherapy, the prognosis for metastatic melanoma remains unfavorable. Recent research has shed light on the significance of epigenetic modifications in the pathogenesis of melanoma, revealing critical mechanisms of melanoma development and progression. Epigenetic modifications, including DNA and RNA modifications, histone modifications, chromatin remodeling, and non-coding RNA regulation, disrupt normal gene expression without modifying the DNA sequence, leading to cellular transformation, invasion, immune evasion, and therapeutic resistance. The reversible nature of epigenetic modifications opens up new opportunities for melanoma recognition and classification, as well as therapeutic applications, including the development of diagnostic and prognostic biomarkers and innovative targeted therapies aimed at restoring normal gene function and enhancing the efficacy of existing treatments. This review will focus on the multifaceted role of epigenetic dysregulation in melanoma. The future integration of epigenetic data and genomic profiling with clinical outcomes, likely facilitated by artificial intelligence (AI) algorithms, holds promise for personalized treatment strategies that are informed by precise and combinatorial diagnostic tools, ultimately improving melanoma care. The study aims to deliver a comprehensive overview of the current state of epigenetics in melanoma.