High-grade serous ovarian carcinoma (HGSOC) is characterised by profound genomic instability and limited durable responses to standard therapy, leading to poor prognosis. The use of next-generation sequencing technologies has improved understanding of its molecular landscape, revealing consistent Tumour Protein p53 (TP53) mutations, homologous recombination defects, pathway alterations, and epigenetic dysregulation. Such genomic profiling now underpins the classification criteria between the ovarian cancer subtypes described by the Cancer Genome Atlas. Widespread chromosomal instability and pathogenic variants in multiple genes distinguish HGSOC from other subtypes of ovarian cancer and, further, from low-grade serous ovarian cancer. Importantly, the new-found understanding of the genomic landscape of HGSOC guides the use of platinum-based chemotherapies and Poly(ADP-ribose) Polymerase (PARP) inhibitors, with homologous recombination deficiency emerging as a cancer vulnerability that enhances treatment response. A combined multi-omics approach integrates transcriptomics, proteomics, metabolomics, and epigenomics to further the understanding of the characteristics, therapeutic targets and treatment resistance within HGSOC. Despite these advances, major challenges persist, including intratumoural heterogeneity and the poor diversity of genomic datasets. Artificial Intelligence (AI) technology, Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing, neoantigen-guided immunotherapy and ovarian cancer vaccination indicate a promising future for genomics-guided interventions and support the integration of genomics within multi-omic approaches to improve HGSOC outcomes.

Ampullary carcinoma (AC) is a rare gastrointestinal malignancy with dual intestinal and pancreatobiliary differentiation, complicating diagnosis, staging, and treatment. This review synthesizes current epidemiology, pathology, and multi-omic data to outline a pragmatic care pathway: lineage-first at presentation, mutation-fast at progression. Histology remains the primary classifier: the intestinal subtype generally aligns with colorectal regimens, whereas pancreatobiliary and mixed subtypes favor pancreaticobiliary therapy. In selected fit patients, modified FOLFIRINOX may address mixed phenotypes. Next-generation sequencing adds precision by identifying therapeutically relevant alterations, including ERBB2/HER2 amplifications, MSI-high/dMMR, BRAF V600E, and rare NTRK or RET fusions, while KRAS mutations are enriched in pancreatobiliary tumors. We recommend early application of a rapid-core panel (KRAS/BRAF, MSI/dMMR, ERBB2/HER2, RNA-based fusions) to capture high-impact targets, followed by comprehensive profiling at first progression. Liquid biopsy, plasma circulating tumor DNA (ctDNA), or bile-derived DNA may complement tissue and help identify the dominant lineage. Research priorities include ampulla-enriched umbrella trials, explicit AC subcohorts in tissue-agnostic studies, and ctDNA-informed endpoints. This lineage-first, mutation-fast paradigm supports precision care and evidence generation in AC.

Circulating tumor DNA (ctDNA) has gained increasing attention as a non-invasive biomarker with potential utility across multiple stages of melanoma. ctDNA reflects tumor-derived genetic alterations in real time and has shown value in detecting minimal residual disease, identifying early recurrence, estimating tumor burden, and monitoring response to systemic therapies. In early-stage melanoma, postoperative ctDNA positivity is strongly associated with higher recurrence risk and often precedes radiologic detection. In advanced disease, ctDNA correlates with tumor volume and can distinguish responders from non-responders during targeted therapy and immunotherapy, while also identifying emerging resistance mechanisms. Despite these advantages, clinical implementation remains limited by low shedding in early-stage disease, variation among detection platforms, and the absence of standardized clinical thresholds. Recent advances, including fragmentomics, methylation assays, and multi-target sequencing strategies, aim to improve sensitivity, particularly in low-tumor-burden settings. Integration of ctDNA with radiomics, artificial intelligence, and digital pathology represents an additional opportunity to enhance precision in risk stratification and treatment adaptation. This review summarizes current evidence on ctDNA biology, detection methods, and clinical applications in melanoma and outlines ongoing challenges and future directions required for translation into routine practice.

HER2 testing represents a cornerstone of the treatment algorithm in advanced gastric and gastroesophageal junction adenocarcinoma (GC), yet its evaluation remains complex due to tumor heterogeneity and methodological variability. Unlike breast cancer, HER2 expression in GC is often incomplete and heterogeneous, resulting in discordant results between biopsies, resections, and metastatic sites. Both spatial and temporal HER2 heterogeneity are key determinants of testing reproducibility, diagnostic accuracy, and treatment selection and response in GC. Optimizing sampling through multiple, well-targeted biopsies, standardizing IHC/ISH protocols, and reassessing HER2 status at progression may be crucial steps to ensure diagnostic accuracy. The recognition of HER2-low disease introduces a new pathological and clinical subgroup of GC with potential sensitivity to antibody-drug conjugates, while emerging techniques such as circulating tumor DNA analysis are increasingly applied to detect HER2 amplification and co-existing genetic alterations. Integrating molecular tools and standardized reassessment strategies can enhance HER2 testing reliability and enable more precise treatment strategies, with the potential to minimize HER2 resistance mechanisms. This review provides a practice-oriented guide on the interpretation and optimization of HER2 testing in gastric cancer, while providing insight into the underlying molecular mechanisms driving heterogeneity and resistance.

Cancer is a heterogeneous disease at the cellular level and analyzing the genetic and molecular profile is essential for targeted therapy. Cancer cells continue to mutate, often resulting in drug resistance. In addition, cancers such as triple-negative breast cancer (TNBC) lack the target proteins used in some of the most effective therapies. This necessitates the identification of novel target proteins and biomarkers for effective treatment strategies. Ubiquitin E3 ligases are often differentially expressed in cancer cells, and numerous anticancer agents have been developed to inhibit them. SMURF2 is an E3 ligase that is differentially expressed in multiple cancer types. Although inhibiting upregulated SMURF2 may be strategically straightforward, enhancing the downregulated gene is often difficult. In addition, because E3 ligases ubiquitinate a variety of substrate proteins, targeting SMURF2 requires detailed analysis to achieve anticancer effect. This review discusses the dual role of SMURF2 in carcinogenesis and addresses the complex context-dependent function of SMURF2 in the various cellular pathways. In addition, resistance to existing cancer therapy related to SMURF2 and sensitivity mechanisms is discussed. Lastly, theranostic strategies for anticancer agents and biomarker development are suggested.

Cellular senescence is a stress-induced cell-cycle arrest that constrains expansion of ultraviolet-damaged keratinocytes yet can remodel the microenvironment. This systematic review evaluated histological and genetic or epigenetic senescence markers in actinic keratosis (AK), cutaneous squamous cell carcinoma (cSCC), and basal cell carcinoma (BCC). PubMed, Scopus, and Web of Science were searched (January 2005-May 2025); 34 human studies were included. AK showed an early senescent signature with frequent cyclin-dependent kinase inhibitor p21 (p21CIP1) expression (82.1%) and DNA damage signaling, including phosphorylated histone H2AX (gamma-H2AX) positivity (77%). In invasive cSCC, p21CIP1 fell to 43.9% and tumor suppressor p53 immunoreactivity often declined, whereas cyclin-dependent kinase inhibitor p16 (p16INK4a) commonly accumulated without arrest, including cytoplasmic staining at invasion fronts. Reported escape pathways involved c-Jun N-terminal kinase 2 activity and long noncoding RNA PVT1-dependent repression of p21. Telomerase reverse transcriptase (TERT) promoter mutations were prevalent in cSCC (about 50%) and BCC (up to 78%) but uncommon in AK, consistent with late telomerase activation. Study heterogeneity, variable antibody scoring, and limited assessment of senescence-associated beta-galactosidase and secretory mediators restricted cross-study comparability. Standardized, spatially resolved profiling may refine risk stratification and support senescence-targeted prevention and therapy in keratinocyte cancers.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent B-cell type of non-Hodgkin's lymphoma. Recent genomic studies have highlighted the importance of genetic alterations in apoptotic pathways that help malignant DLBCL cells to evade apoptosis. Apoptosis evasion by DLBCL cells is known to mediate resistance to chemotherapy. Advances in the field of regulated cell death (RCD) research have identified novel therapeutic avenues in cancer. In particular, non-apoptotic RCDs can be targeted to overcome resistance to apoptosis in cancer and ensure cell death. In this review, we have highlighted the contribution of multiple RCDs, including apoptosis, necroptosis, ferroptosis, pyroptosis, PANoptosis, NETotic cell death, autophagy-dependent cell death, cuproptosis, methuosis, or mitotic death, to normal development of B lymphocytes and DLBCL pathogenesis. We have summarized molecular mechanisms governing distinct RCDs in DLBCL, differences in cell death pathways in activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL subtypes, prognostic values of RCD-related genes, and discussed the implication of RCD pathways for DLBCL treatment. Notably, the impact of RCDs goes far beyond just killing tumor cells. RCD modalities are important for orchestrating the immune response and modulating the tumor microenvironment. The current review also aims to reveal the effect of different RCDs on the tumor microenvironment in DLBCL. Most RCDs play a dual role in DLBCL, demonstrating both tumor-inducing and tumor-suppressing effects, which suggests that their targeting should be exploited with caution. Our analysis suggests that pharmacological ferroptosis induction may be the most promising RCD-targeting strategy in DLBCL.

Multiple myeloma (MM) is the second most common hematological malignancy in the US and Europe-comprising approximately 10% of all hematologic cancer cases-and its incidence has increased over the last three decades by approximately 120% due to an aging world population. It remains an incurable cancer among diseases in modern medicine. This review outlines the relevant cancer biology of MM, with a special emphasis on the role of tumor protein p53. We provide the most up-to-date summary of the current drugs in clinical or pre-clinical trials targeting weaknesses in the MM apoptotic mechanism. In addition, we highlight the potential for new routes to strike and kill myeloma cells, possibly creating a vaccine-like effect that prevents relapse, using the principles of immunogenic cell death (ICD).

Pancreatic cancer (PC) is one of the most lethal malignancies worldwide, characterized by late diagnosis, aggressive progression, and limited responsiveness to current therapeutic strategies. Although extensive genomic analyses have identified key driver protein-coding genes (PCGs), therapeutic approaches targeting individual genes have shown limited clinical benefit. This limitation highlights the molecular complexity of PC, where tumor progression is governed by regulatory networks that extend beyond genetic alterations. Non-coding RNAs (ncRNAs), which constitute nearly 98% of the human genome, have emerged as regulators of gene expression in cancer. Among them, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate oncogenic processes, including aberrant signaling activation, tumor microenvironment remodeling, epithelial-mesenchymal transition, immune evasion, and resistance. Beyond their independent functions, lncRNAs, miRNAs, and mRNAs form an integrated regulatory network known as the lncRNA-miRNA-mRNA TRIAD, enabling control of gene expression. Such network-based regulation provides a framework for multi-target therapeutic strategies. Moreover, the rapid responsiveness and disease-specific expression patterns of ncRNAs suggest strong potential as diagnostic and prognostic biomarkers in PC, where early detection remains challenging. This review summarizes the regulatory roles of PCGs, miRNAs, and lncRNAs in PC and highlights the lncRNA-miRNA-mRNA TRIAD as a framework for understanding gene regulatory networks.

Endometrial cancer is the most common gynaecologic malignancy in high-income countries, with a rising incidence largely driven by reproductive factors, obesity, and prolonged exposure to unopposed oestrogens. Although most cases are sporadic, approximately 2-5% are associated with hereditary cancer syndromes, of which Lynch syndrome represents the most important contributor. Lynch syndrome results from germline mutations in DNA mismatch repair (MMR) genes and is associated with a substantially increased lifetime risk of endometrial cancer, reaching up to 71% in carriers of MutS homologue 6 (MSH6) mutations. Hereditary cancer predisposition typically follows an autosomal dominant inheritance pattern and may be suspected based on clinical warning signs such as early disease onset, multiple primary malignancies, a strong family history, or the presence of microsatellite instability in tumour tissue. In addition to Lynch syndrome, rarer genetic conditions-including Cowden syndrome (PTEN), Li-Fraumeni syndrome (TP53), polymerase proofreading-associated polyposis (POLE/POLD1), and hereditary breast and ovarian cancer syndromes (BRCA1/2)-also contribute to hereditary endometrial cancer risk. Recognition of these genetic backgrounds is essential for accurate diagnosis, personalised surveillance, and the implementation of targeted preventive and therapeutic strategies. Despite major advances in molecular diagnostics, hereditary endometrial cancer remains frequently underdiagnosed, leading to missed opportunities for cancer prevention among affected individuals and their families. This comprehensive review summarises current evidence on hereditary predispositions to endometrial cancer, with a particular emphasis on Lynch syndrome, and discusses underlying genetic mechanisms, inheritance patterns, diagnostic strategies, and clinical implications for screening, genetic counselling, and treatment optimisation.

Field cancerization is a fundamental paradigm in tumorigenesis, emphasizing that carcinogenesis begins long before the appearance of clinically detectable lesions and often precedes recognizable premalignant changes. A direct manifestation of this process is the molecular dysregulation observed in the peritumoral mucosa-histologically normal-appearing tissue that nonetheless exhibits genetic and epigenetic alterations similar to those of the adjacent tumor. This review summarizes current evidence on the molecular alterations shared between tumor tissue and peritumoral mucosa in HNSCC and evaluates their potential as biomarkers for defining molecular margins and improving surgical precision. A literature search was conducted in PubMed using combinations of the keywords "peritumor," "laryngeal", "HNSCC," and "field cancerization." Studies were included if they directly compared tumor tissue with peritumoral mucosa and, preferably, a third set of distant normal control samples. Only nine studies met the inclusion criteria, highlighting the scarcity of focused research in this area. Reported biomarkers exhibiting comparable dysregulation in both tumor and peritumor tissues include MDM2, E2F2, CDKN2A/p16, ETS-1, MGMT, and multiple microRNAs (e.g., miR-21, miR-96-5p, miR-145-5p). These molecular signatures demonstrate the presence of a biologically altered field extending beyond histologically defined tumor margins. Peritumoral mucosal dysregulation, as a consequence of field cancerization, underscores the need to redefine surgical margins at the molecular level. The identification and validation of biomarkers reflecting this continuum could enable the establishment of molecular margins-improving risk assessment, reducing local recurrence, and advancing personalized oncologic surgery in HNSCC. Standardizing definitions and sampling protocols for "normal adjacent tissue" remains essential for future translational research.

Pancreatic cancer (PC) remains a highly lethal malignancy with limited treatment options and poor survival. Targeting DNA damage response (DDR) pathways has emerged as a promising therapeutic strategy, particularly the ATR-CHK1 and ATM-CHK2 axes. Preclinical studies demonstrate that ATR inhibition disrupts replication stress tolerance, impairs homologous recombination, and disables checkpoint control, enhancing cytotoxicity from standard therapies including gemcitabine, FOLFIRINOX, fluoropyrimidines, and radiotherapy. Synergistic effects have also been observed with other DDR-targeted agents, such as PARP and WEE1 inhibitors. Genomic contexts, including ATM deficiency, ARID1A alterations, and oncogene-driven replication stress, refine therapeutic sensitivity, supporting precision patient stratification. Early-phase clinical trials of ATR inhibitors (ART0380, AZD6738, BBI-355) alone or in combination show promising safety, tolerability, and preliminary efficacy. In this review, we summarize current literature on targeting the ATM-CHK2 and ATR-CHK1 pathways in PC, highlighting preclinical evidence, clinical developments, and strategies for biomarker-driven, precision oncology approaches.

Gastric cancer is one of the most prevalent malignant tumors worldwide. Sporadic gastric cancer accounts for more than 80% of all gastric cancer cases, and its pronounced heterogeneity underlies the substantial variability in clinical outcomes and the complexity of treatment strategies. The breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2) are core regulators of the DNA damage homologous recombination repair (HRR) pathway, and their pathogenic mutations are closely associated with hereditary breast and ovarian cancer syndrome. Recent evidence has shown that BRCA1/2 mutations also exist in some sporadic gastric cancer patients and may profoundly affect tumor biological behavior, clinical prognosis, and treatment response. This article systematically reviews the latest research progress on BRCA1/2 mutations in sporadic gastric cancer, focusing on their incidence and molecular characteristics, their impact on patients' postoperative prognosis, and their potential value as novel biomarkers for guiding individualized therapy, thereby providing a theoretical basis for clinical risk stratification and tailored treatment strategies.

High-grade serous ovarian cancer (HGSOC) is often diagnosed at advanced stages (III/IV), with approximately 80% of patients experiencing relapse due to therapeutic resistance. The disease progression is largely influenced by a dynamic tumor microenvironment (TME), which is marked by sustained inflammation, immune evasion, and epigenetic reprogramming. This review investigates the dual role of inflammatory pathways and epigenetic alterations in driving HGSOC progression and chemo-resistance. A comprehensive literature search of articles from 2000 to 2025 was conducted across PubMed, Google Scholar, and Research Rabbit using search terms including "HGSOC," "epigenetics," "inflammation," and "chemoresistance." Of 1,166 identified publications, 593 peer-reviewed studies comprising original research, clinical trials, meta-analyses, and reviews were critically analyzed. Findings reveal that chronic inflammation in the TME enhances tumor proliferation, immune suppression, epithelial-mesenchymal transition, and metastasis through cytokines, interferons, and chemokines. Epigenetic mechanisms such as DNA methylation, histone modifications, miRNA and lncRNA contribute to tumor plasticity and treatment failure. Emerging therapies, including histone deacetylase inhibitors, DNA methyltransferase inhibitors, and immune checkpoint inhibitors, anti-inflammatory drugs demonstrate potential in overcoming resistance when used in combination. Integrative treatment strategies that target both inflammatory signaling and epigenetic dysregulation offer a promising avenue for improving patient outcomes. Further clinical exploration of such combination therapies is warranted to address the urgent need for effective interventions in HGSOC.

DNA mutations are the fundamental engines of cancer, driving its initiation and progression. The forces that fuel malignancy are also the architects of evolution, shaping life through genetic variations. Mutations, in fact, can emerge naturally from endogenous processes, such as oxidative DNA damage or errors in replication, as well as induced by external factors, including cosmic radiation and chemical carcinogens.

Melanin is no longer best understood as a passive UV filter. It is emerging as a programmable, redox-active pigment system that converts environmental energy and oxidative stress into lasting genomic and immunological consequences, placing pigment metabolism at the center of melanoma biology.

Nucleophagy is a crucial process by which cells selectively degrade nuclear components through autophagy mechanisms to maintain genomic stability. It occurs through two modes: macro-nucleophagy and micro-nucleophagy, relying on proteins such as Atg39 and Nvj1 to remove irreversibly damaged nuclear components (such as broken chromatin, micronuclei, and abnormal nuclear membrane components) caused by irreversible DNA damage, to degrade toxic nuclear protein aggregates, and to target abnormal nuclear structural components. The activity of nucleophagy is regulated at multiple levels. Transcription factors such as the MiT/TFE family and p53 can sense cellular stress signals to regulate the expression of autophagy genes. Epigenetic mechanisms such as DNA methylation, histone modification, and miRNA participate in the regulation by modifying genes or marking substrates, and these regulatory processes are modulated by signaling molecules and drugs such as mTOR inhibitors. The core function of nucleophagy is to eliminate irreparable damaged nuclear substances, toxic nuclear protein aggregates, and abnormal nuclear structural components, thereby preventing the accumulation of harmful substances. It also exerts a bidirectional regulatory role in pathological processes including cell differentiation, aging, cardiovascular diseases, neurodegenerative diseases, and cancer. Future research needs to further elucidate the regulatory mechanisms of nucleophagy, particularly the crosstalk between transcription factors and epigenetic modifications, as well as the complex connections between nucleophagy and other cellular processes. These studies will provide novel therapeutic targets and strategies for the development of treatments against cancer, neurodegenerative diseases, and cardiovascular diseases, and thus advance the progress of disease treatment and drug development.

Among the transcriptional regulators of cell fate, c-Myc is one of the most frequently deregulated oncogenes, exerting pleiotropic effects on cellular metabolism, survival, and stress adaptation. C-Myc occupies a pivotal position at the intersection of autophagy and senescence, two essential, yet paradoxical processes in cancer biology. Autophagy can both suppress tumor formation and support the survival of established tumors. In contrast, senescence acts as a barrier to malignant transformation but can also promote tumor progression through the senescence-associated secretory phenotype. C-Myc modulates both autophagy and senescence in a highly context-dependent manner. It acts as either an inducer or a suppressor depending on cellular state and microenvironmental conditions. This dual regulatory capacity underscores its role as a central hub in cell fate decisions. In this review, we first summarize how c-Myc, autophagy, and senescence contribute to tumor biology. We then highlight the molecular mechanisms through which c-Myc regulates autophagy and senescence. We examine how these interactions influence cancer progression. Finally, we discuss emerging therapeutic strategies and clinical trials targeting the c-Myc-mediated autophagy/senescence axis. We also address future challenges and opportunities for exploiting this network in precision oncology.

BRAF V600E-mutated colorectal cancer (CRC) is associated with poor prognosis and resistance to standard chemotherapy. Emerging evidence, including the BEACON trial and subsequent real-world studies, suggests that triple therapy targeting BRAF oncoprotein, epidermal growth factor receptor (EGFR), and MEK improves clinical outcomes.

Liquid biopsy (LB) offers a minimally invasive approach to characterizing and monitoring glioblastoma (GB), a tumor marked by extensive heterogeneity, limited surgical accessibility and rapid molecular evolution. By analyzing circulating tumor-derived components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), circulating RNA species and circulating tumor cells (CTC), LB provides dynamic molecular information that cannot be captured by neuroimaging or single-site tissue sampling. Cerebrospinal fluid (CSF) currently yields the highest sensitivity for detecting tumor-specific alterations, while plasma enables repeat monitoring despite lower biomarker abundance. EVs have gained particular prominence due to their ability to preserve DNA, RNA, and protein cargo that reflects key genomic changes, treatment resistance mechanisms, and immune evasion. Although advances are substantial, clinical implementation remains constrained by low analyte concentrations, methodological variability, limited standardization and the high cost of testing, which is rarely reimbursed by insurers. This review summarizes current evidence on circulating biomarkers in GB and highlights research priorities essential for integrating LB into future diagnostic and therapeutic workflows.