Hereditary renal cancer syndromes account for approximately 5% to 8% of all renal cell carcinomas (RCCs) and are caused by germline alterations, mainly in tumor suppressor genes. Advances in molecular testing have led to the identification of new hereditary syndromes and expanded our understanding of the genetic landscape of renal neoplasia. This review summarizes both well-established and recently described hereditary renal cancer syndromes, highlighting their clinical, pathologic, and molecular features. Emphases are placed on genotype-phenotype correlations and the relationship between germline and somatic alterations in tumors. Understanding these correlations is critical for diagnosis, risk assessment, surveillance, and management and underscores the importance of a high index of clinical suspicion for early detection to optimize patient outcomes.

Over the last 2 to 3 decades, we have seen incremental movement from the "Rule of 10s" for pheochromocytomas, particularly those regarding tumor bilaterality, malignancy, and patterns of inheritance. The biology and prevalence of these tumors have not changed, but there has been a great deal of progress in terms of our understanding of tumor genetics, variable modes of acquiring of both pheochromocytomas and paragangliomas (PPGL), and our approach to clinical management of these unpredictable neoplasias. Although these non-epithelial neuroendocrine tumors are rare, they are clinically significant due to their hormonal activity, association with hereditary syndromes, and biological potential. Their detection has increased in recent decades with improved biochemical testing and advanced imaging modalities, yet predicting clinical behavior continues to be a major challenge. Histologically, PPGL typically shows classic neuroendocrine architecture but may display morphologic diversity, occasionally mimicking other adrenal or paraganglionic tumors. Immunohistochemistry remains essential for diagnostic confirmation and as a surrogate for genetic alterations, offering valuable genotype-phenotype correlations. With increasing knowledge of tumor genetics, additional emphasis has been placed on histology-based risk-stratification for these lesions, particularly those prone to metastasis or multifocality, and the 2022 WHO endorses no individual risk-stratification system, as none seems to be of definitive merit over another. Instead, it promotes a comprehensive approach integrating morphologic, molecular, and clinical factors. Approximately 40% of PPGL harbor germline mutations, whereas somatic alterations account for additional subsets. Mutations in SDH x, VHL , RET , NF1 , and other susceptibility genes define molecular clusters with distinct signaling pathways and clinical behavior, underscoring the importance of multidisciplinary, lifelong management.

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy requiring improved early diagnosis and prognostic assessment. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising biomarkers for ESCC. We conducted a comprehensive literature search in PubMed for studies published up to 2025. While miRNA profiles in ESCC tissues show significant associations with lymphatic dissemination, tumor progression, and patient survival, clinical translation remains limited by issues of sensitivity, specificity, and standardization. This review summarizes current knowledge on miRNA expression in ESCC, focusing on lymphatic dissemination and prognostic implications. We also explore circulating miRNAs as minimally invasive tools for early detection and treatment monitoring. By integrating recent findings, this article provides a critical overview of miRNA-based biomarkers to improve early diagnostic accuracy and therapeutic decision-making in ESCC.

Voltage-dependent anion channel 2 (VDAC2) is a pivotal β-barrel protein located in the mitochondrial outer membrane (MOM), playing a central role in metabolite transport, ion homeostasis, and the determination of cell fate. Compared to other isoforms in the same family, VDAC2 possesses unique structural features-including an N-terminal extension, an enrichment of cysteine residues, and a distinct β-barrel conformation-which underlie its non-redundant functional roles. Notably, VDAC2 acts as a "dual regulatory hub" in apoptosis: it suppresses apoptosis by directly binding and inhibiting BAK, while also being essential for BAX-mediated apoptosis, demonstrating marked context-dependency. Furthermore, VDAC2 is deeply involved in tumor progression through its regulation of metabolic reprogramming, reactive oxygen species (ROS) homeostasis, ferroptosis, and mitochondrial quality control. Dysregulation of VDAC2 expression is closely associated with prognosis in multiple cancers, highlighting its promise as a diagnostic and prognostic biomarker, as well as a therapeutic target. This review systematically consolidates current knowledge on VDAC2 in oncology, identifies limitations and challenges in existing research, and aims to offer strategic insights to guide future investigations.

Lung cancer is the leading cause of cancer-related deaths globally. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases, and drug resistance severely undermines treatment efficacy. This review summarizes recent advances in elucidating NSCLC drug-resistance mechanisms using multi-omics integration. Multi-omics integration systematically reveals the molecular networks of drug resistance, identifies key biomarkers and targets, and facilitates the screening of high-priority candidates for drug development through experimental validation. Small-molecule inhibitors targeting drug-resistant proteins and multi-omics-guided combination therapies offer strategies to reverse resistance. Future directions involve developing simultaneous multi-omics detection technologies, leveraging artificial intelligence for intelligent data analysis, establishing standardized frameworks for data sharing, and implementing personalized medicine based on multi-omics to improve patient prognosis.

Cancer arises and is resistant to therapy via intricate molecular networks that are poorly characterised. While individually, Cullin-3 (CUL3) and circular RNAs (circRNAs) have been reported to modulate cancer, their synergistic effect in the modulation of tyrosine kinase inhibitor (TKI) resistance is yet to be studied. An emerging circRNA-CUL3-TKI regulatory framework is highlighted as a potential contributor to oncogenesis and drug sensitivity in this review. We discuss how circRNA-associated networks may influence CUL3-dependent pathways implicated in tumour resistance to therapy by modulating autophagy, ferroptosis, stress-responses, and redox signalling. Exosomal circRNAs and circRNAs of the CUL3 gene itself are highlighted as dynamic mediators of resistance as well as biomarkers. How they interact with Kelch-like ECH-associated protein 1- Nuclear factor erythroid 2-related factor 2 (KEAP1-NRF2) signalling reveals that they enhance tumour survival under therapy pressure. By highlighting key processes of carcinogenesis and resistance, the circRNA-CUL3-TKI axis represents a testable therapeutic framework. Modeling circRNA networks, predicting TKI response, finding biomarkers, and developing personalised treatment plans are all made possible by applications of artificial intelligence and machine learning (AI/ML), as explored in this review. Antisense oligonucleotides, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based molecules, neddylation inhibitors or PROteolysis TArgeting Chimera (PROTACs) are examples of potential interventions that, when combined with AI/ML techniques, improve therapeutic efficacy and may inform future desensitisation strategies. These collectively emphasize the emerging applications for AI/ML in understanding the circRNA-CUL3-TKI crosstalk and developing methods to resensitize cancers that are resistant to therapy.

Epigenetic alterations are an important shared hallmark of ageing and cancer. The development of epigenetic markers of ageing using blood DNA methylation data has been an active area of research. These markers have been used to assess disease risk, with potential to shed light on the complex link between ageing and cancer. We comprehensively summarised the literature on the most widely used and recently developed epigenetic markers of ageing, and synthesised the findings from studies that assessed their associations with cancer risk. Using data from eight cancer case-control studies (Ncases = 3624) nested in the Melbourne Collaborative Cohort Study, we assessed and compared associations of these epigenetic ageing markers with cancer risk (including breast, colorectal, gastric, kidney, lung, blood, prostate, and urothelial cancers). While cancer is generally considered an ageing-related disease, the combined evidence suggested that epigenetic markers of ageing, including the most recently developed, showed generally weak associations with cancer risk and heterogeneous across markers and cancer types. The strongest associations were for lung cancer with GrimAge and its derivatives. Some associations, particularly those between mitotic clocks / stochastic epigenetic mutations and risk of blood cancer, were largely explained by underlying immune cell type heterogeneity, which was more prominent using finer cell type deconvolution. These findings indicate the potential for blood DNA methylation to help uncover the complex link between ageing and cancer and the need for new ageing markers to capture additional ageing features to improve disease risk prediction.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are widely available and inexpensive agents with proposed antitumor activity, particularly in tumors harboring PIK3CA mutations. This meta-analysis of randomized controlled trials (RCTs) evaluated whether adjuvant NSAID therapy improves outcomes in patients with resected PIK3CA-mutated colorectal cancer (CRC).

The incidence of cancer in humans has been rising in association with extended life spans. Incidence rates of early onset cancers in humans <55 years of age have also been increasing for unclear reasons. One potential contributory factor is an antagonistic pleiotropy in which certain genes that appeared in mammals to increase fitness for reproduction contribute to cancer susceptibility later in life. A related concept is an evolutionary mismatch in which humans have adapted to certain environmental and dietary factors that change over time and thereby increase cancer incidence. The MUCIN 1 (MUC1) gene emerged in mammals and represents an example of antagonistic pleiotropy and evolutionary mismatch that is posited here as a contributing factor to the increasing incidence of cancer in humans. This Review focuses on the roles of MUC1 and the oncogenic M1C protein in reproductive fitness and barrier tissue protection that in settings of chronic inflammation promote pan-cancer progression and treatment resistance. Also highlighted are therapeutic approaches targeting MUC1 and M1C that are under clinical and pre-clinical development.

Renal cell carcinoma (RCC), the most common type of urogenital cancer, accounts for about 80 % of malignant renal tumors. Clear cell renal cell carcinoma (ccRCC), composed of cells filled with lipid droplets in cytoplasm, is the most common subtype of RCC. Mechanisms underlying ccRCC progression and metastasis are complicated and remain far from being clarified. Mitochondria, which serve as cellular energy supplier and central signal hubs, are involved in various physiological and pathological processes. Mounting evidence has revealed that mitochondrial changes, such as mutations, abnormal mitophagy and metabolisms and excessive reactive oxide species (ROS) are closely related with the progression, prognosis, metastasis and drug resistance of RCC and ccRCC. In this review, we'll provide an overview on mitochondrial changes in RCC, especially in ccRCC, and discuss their possible roles in the tumorigenesis and prognosis as well as their potential in serving as biomarkers and therapeutic targets.

Head and neck squamous cell carcinoma (HNSCC) represents a biologically diverse group of malignancies within the upper aerodigestive tract and oral cavity and remains a significant cause of global morbidity and mortality. Increasing evidence highlights that the tumour microenvironment (TME) plays a central role in disease progression and therapeutic response. Distinct immune and stromal profiles have been observed between HPV positive (HPV+) and HPV negative (HPV-) HNSCC, underpinning their differing natural history and responses to immunotherapy. Despite advances, only 15-20% of patients with recurrent or metastatic HNSCC (RMHNSCC) respond to immunotherapy, with no difference in response being seen between HPV+ and HPV- disease. This may reflect the complexity and heterogeneity of the TME. This review explores how emerging spatial omics technologies, combining molecular, and spatial context, are reshaping our understanding of the HNSCC microenvironment, with emphasis on recurrent and/or metastatic disease. By delineating the spatial organisation of immune, stromal, and metabolic features, these approaches provide new insights into mechanisms of treatment resistance, prognostic biomarkers, and therapeutic vulnerabilities. Understanding spatial TME dynamics across HPV-related subtypes may ultimately guide more precise and effective treatment strategies for HNSCC.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, with a 5 year survival rate of approximately 13%. Survival is extended for the few patients who undergo surgical resection with curative intent, whereas most patients succumb to distant disease recurrence. Neoadjuvant platinum-based chemotherapy has emerged as a promising strategy to improve resectability rates and survival outcomes for PDAC patients. However, treatment-related toxicities, unpredictable clinical responses, and associated risk of tumor progression during neoadjuvant therapy may delay or preclude curative resection.As a result, predictive biomarkers are needed to identify patients most likely to benefit from neoadjuvant platinum-based chemotherapy.

The evolution of serous high grade ovarian cancer management is characterized by a more regulated patients' journey on the one hand and the development of new therapeutic options on the other hand, the selection of which is guided by tumor molecular characteristics. Surgery remains the cornerstone of treatment. It can be performed only in authorized expert sites that can demonstrate sufficient experience from highly skilled surgical teams, and quality criteria including prehabilitation and rehabilitation programs. The diagnostic step is crucial; it comprises multiple biopsies that allow reliable pathological and molecular analyses, and a comprehensive surgical staging. Determination of BRCA1/2 mutation and homologous recombination deficiency statuses by validated methods guide maintenance therapy at advanced stages and referring to oncogenetic consultation if appropriate. For these advanced diseases, the two main questions for surgical strategy are the feasibility of complete resection (without residual disease, CC-0), assessed during surgical exploration of pelvis and abdomen, and the optimal timing of this surgery (upfront or after neoadjuvant chemotherapy). In recurrent diseases, surgery remains a main piece of treatment in case of late relapse and medical treatment depends on drugs used in the first line; in early platinum resistant relapse, a new therapeutic option is available with mirvétuximab soravtansine.

Liquid biopsy is a non-invasive molecular test that uses biofluid to detect cancer. This is a rapidly growing field that encompasses a diverse class of assays that rely on circulating nucleic acids, proteins, and cells to identify cancer. Recently, there is particular interest in using circulating tumor DNA (ctDNA) to screen for cancer, to monitor treatment response, and to help guide therapeutic decisions. Here, we will review the procedural aspects of ctDNA assays, as well as the various applications of ctDNA assays in cancer care. The utility of various biofluids to conduct ctDNA assays, the technical considerations for performing the assays, and several possible available assay formats that can be used for ctDNA analysis are reviewed. Several protocols that can be used for ctDNA isolation, detection, and quantification are presented, including targeted ctDNA qPCR.

Glutathione S-transferase P1 (GSTP1) is a crucial phase II metabolic enzyme in humans, playing an indispensable role in protein glutathionylation, antioxidant defense, and cellular metabolic detoxification. Additionally, GSTP1 exhibits multiple genetic polymorphisms that are closely associated with susceptibility to various cancers and diseases. Although the associations of GSTP1 with cancer drug resistance, signal transduction, metabolic and antioxidant functions, as well as GSTP1 methylation in disease diagnosis have been extensively reviewed, the genetic polymorphisms and transcriptional regulation mechanisms of GSTP1 in cancer and other diseases remain unreported. Extensive clinical data have demonstrated potential links between different GSTP1 genotypes and the development of various diseases, with particular attention given to the classic polymorphism Ile105Val. In this review, we systematically reviewed and categorized studies on GSTP1 genetic polymorphisms and transcriptional regulation across multiple cancers and common diseases, and provided a comprehensive summary. Furthermore, we thoroughly discussed emerging research on the physiological functions and mechanisms of GSTP1 in recent years. This review aims to summarize and explore the relationships between GSTP1 genetic polymorphisms and tumors/diseases, its transcriptional regulation, and to highlight other research directions and biological questions.

Circular RNAs (circRNAs) have emerged as pivotal regulators of tumor immune escape, acting through multilayered mechanisms that include miRNA sequestration, RNA-binding protein scaffolding, m⁶A-dependent stabilization, metabolic rewiring, and exosomal communication. These processes collectively sustain PD-L1 expression and stability, drive CD8⁺ T-cell exhaustion, promote Treg and MDSC expansion, skew macrophages toward immunosuppressive M2 phenotypes, and reshape glycolytic and lipid metabolic pathways to generate an immune-refractory microenvironment. In parallel, exosomal circRNAs disseminate long-range immunosuppressive signals, reinforcing therapy resistance and systemic immune dysfunction. Conversely, a newly recognized subset of "immune-activating circRNAs" induces ferroptosis, immunogenic cell death, and STING-mediated innate immune activation, highlighting the dual nature of circRNA immunoregulation. Recent advances in nanomedicine-spanning lipid nanoparticles, polymeric platforms, and biomimetic membrane-coated carriers-have enabled precise silencing of oncogenic circRNAs and efficient delivery of synthetic therapeutic circRNAs, demonstrating potent synergy with immune checkpoint inhibitors, NK-cell therapy, STING agonists, and ferroptosis inducers. Although challenges remain, including delivery specificity, biosafety, biomarker standardization, and off-target effects, the convergence of circRNA biology and advanced nanotechnology presents a transformative opportunity to develop next-generation RNA-guided cancer immunotherapies. Together, these findings position circRNAs as both key mechanistic drivers of immune escape and promising therapeutic targets for nanomedicine-enabled precision immunotherapy.

Males account for a small but clinically significant component of overall breast conditions, both benign and malignant. This review summarizes current evidence on epidemiology, male breast anatomy, clinical presentation, diagnosis, management, and identification of risk factors for male breast disease. Benign male breast disease, including gynecomastia, prompts clinical evaluation and requires understanding of hormonal and pharmacological causes to guide diagnostics and management. Although male breast cancer is rare, accounting for less than 1% of all breast cancers, it carries important hereditary and clinical implications. Pathogenic germline variants in BRCA2 are the predominant genetic contributor, conferring a lifetime risk of ~7%, while BRCA1, CHEK2 and PALB2 variants confer lower risk. Males with breast cancer typically present with subareolar masses, nipple changes, or pain, often at older ages and later stages compared with females. Imaging evaluation, including mammography and ultrasound, is central to diagnosis and management. Screening recommendations for high-risk men remain limited due to sparse prospective data, with multigene panel testing and family history assessment guiding individualized risk assessment. Management strategies for male breast cancer generally parallel female protocols, despite unique biological features. By integrating considerations of benign and malignant conditions, this review underscores the importance of tailored evaluation, risk assessment, and individualized care for males, while identifying knowledge gaps to inform future research and improve outcomes in this under-recognized population.

Single-cell RNA sequencing (scRNA-seq) has transformed the resolution of cellular heterogeneity, offering insights into dynamic biological processes from tumor evolution to immune regulation. However, its clinical translation is limited by challenges such as data sparsity, batch effects (differences caused by technical variation rather than biology), and the absence of standardized benchmarks for core pipelines like Seurat and Scanpy. This review outlines emerging computational strategies that address these limitations: (A) robust preprocessing, including SCTransform for zero-inflation(an excess of zero counts in gene-expression data) correction and Harmony for batch integration-achieving 30% faster alignment than BBKNN in cohorts exceeding 100,000 cells; (B) transformer-based annotation tools such as scGPT and CellTypist, which reach >95% accuracy in immune profiling using models pretrained on 33 million cells; and (C) multimodal integration with spatial transcriptomics (e.g., 10x Visium, cell2location v2), which delineate microenvironmental niches and rare CX3CR1+ T-cell subsets in disease contexts like glioblastoma and severe COVID-19. We further assess how scANVI bridges scRNA-seq and ATAC-seq to uncover epigenetic mechanisms underlying therapy resistance, and how spatial methods elucidate tumor-immune crosstalk at subcellular resolution. Despite these advances, ethical risks remain, particularly around re-identification of rare patient-derived clones such as pre-metastatic cells. To promote clinical adoption, we propose a roadmap that prioritizes benchmarked workflows (e.g., scverse ecosystem), privacy-aware data sharing via federated learning, and causal AI approaches to disentangle biological signal from technical artifact. By synthesizing computational innovations with translational case studies, this review equips researchers to navigate both the analytical and ethical complexities of scRNA-seq in pursuit of actionable diagnostics.

The therapeutic landscape for non-small-cell lung cancer (NSCLC) harbouring epidermal growth factor (EGFR) gene mutations is undergoing significant transformation. For classical EGFR mutations such as exon 19 deletion and exon 21 L858R mutation, combination strategies in the first-line setting, based on the results of the MARIPOSA (lazertinib and amivantamab) and FLAURA 2 (platinum-based doublet chemotherapy and osimertinib) trials, provide promising outcomes. Compared to osimertinib monotherapy, they potentially delay both the onset of molecular resistance to treatment and the intracranial progression of the disease. Selecting the best first-line option should take into consideration patient and genome-related factors as well as the burden of the disease including the presence of central nervous system metastases. Beyond first-line therapy, novel agents-including antibody-drug conjugates, bispecific antibodies, and T-cell engagers-have emerged as innovative options for pretreated patients with EGFR-mutated disease. Optimising the treatment sequence in advanced EGFR-mutated NSCLC is crucial to ensure the best survival outcomes along with the best treatment tolerance and quality of life. Predictive biomarkers are strongly needed as well as biomarker-based escalation and de-escalation clinical trials.

In humans, circadian rhythm regulates the expression of numerous protein-coding genes across nearly all cell types, playing a central role in maintaining health. However, circadian rhythm components interact with a wide variety of intracellular signaling pathways. Through these interactions, the circadian system interfaces with various pathologies by governing different molecular mechanisms. Evidence suggests that the interaction between circadian rhythms and apoptosis plays a pivotal role in both health and disease, warranting careful investigation. Apoptosis, one of the main mechanisms of programmed cell death, is essential for establishing maintaining cellular homeostasis in the human body. Alterations in apoptotic activity occur during the progression of cancer, as well as in various autoimmune and neurodegenerative diseases. Conversely, bidirectional interactions between circadian components and apoptotic factors offer new insights into disease development. Therefore, this review highlights the links between circadian rhythms and apoptosis across health and disease states, aiming to identify potential therapeutic interventions based on this connection.