The epigenetic landscape of cancer reveals how microRNAs (miRNAs) regulate gene expression through epigenetic mechanisms, alongside advancements in miRNA-based biosensor technology for early detection. Epigenetics, which studies heritable gene function changes without altering DNA sequences, has transformed our understanding of cancer by highlighting the complex interaction between genetics and environment. Key mechanisms such as DNA methylation, histone modification, and chromatin remodelling shape gene expression and cellular identity, with dysregulation in these processes often marking cancer development. Within this framework, miRNAs act as crucial epigenetic regulators, influencing gene expression post-transcriptionally and functioning as either oncogenes (oncomiRs) or tumour suppressors. miRNAs interact with epigenetic modifiers like histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), creating regulatory networks that affect cancer cell behaviours such as proliferation, differentiation, and apoptosis. To apply these molecular insights, the chapter reviews innovations in miRNA-targeting biosensors. Electrochemical and photoelectrochemical biosensors, enhanced with nanotechnology, are designed to detect miRNAs at ultra-low concentrations in biological fluids, addressing limitations of conventional cancer diagnostics. These biosensors offer high sensitivity, specificity, and point-of-care potential, with benefits such as rapid response, cost-efficiency, and miniaturization. Case studies showcase miRNA-based biosensors targeting cancer-related miRNAs, underscoring their promise in early cancer detection and monitoring. By bridging epigenetics, miRNA regulation, and biosensor technology, these emerging diagnostic tools offer new possibilities for improving cancer diagnosis and patient outcomes.

The dysregulation at the epigenetic level, such as DNA methylation, histone modifications, and changes in noncoding RNA, plays an important role in many serious human pathologies, including cancers. Epigenetics modulates the expression of tumor-related genes without any changes in the DNA sequences, thus understanding the epigenetic profile is a promising way to clarify the underlying mechanism of cancers as well as other diseases. Specific techniques like chromatin immunoprecipitation followed by sequencing (ChIP-seq), whole-genome bisulfite sequencing (WGBS), or mass spectrometry (MS) were developed to obtain epigenetic data. This leads to the need for robust tools to analyze and interpret these high-throughput data. With the development of bioinformatics tools, several complex interactions between DNA methylation and chromatin modification were clarified to help researchers control gene expression. Moreover, data science, and information technology, especially machine learning and deep learning, have revolutionized the study of epigenetics in cancer, providing powerful tools to integrate both genetic and epigenetic data, as well as clinical/para-clinical characteristics to enhance the accuracy of cancer diagnosis and treatment strategies. In this study, we will provide an overview of epigenetics' role in cancer, and more importantly, an update on the application of bioinformatics and data science in the epigenetic field for cancers. Integrating epigenetic data with other data like omics and clinical data with the help of bioinformatics and data science is an emerging direction for deciphering the epigenetic landscape of cancer and identifying potential therapeutic targets.

One of the three most common cancers in the world today is breast cancer. In recent years, molecular biology studies have highlighted the role of gene mutations. Epigenetic modifications have also been studied and have been shown to be one of the main contributors to the development and progression of breast cancer. Targeting these epigenetic regulatory mechanisms is considered a potential therapeutic strategy with the goal of inhibiting tumor progression and restoring normal gene activity. Epigenetic research has shed light on the important role of epigenetics in various aspects of breast cancer development, the underlying mechanisms of breast cancer, and its potential applications in improving diagnosis, prognosis, and treatment. These findings highlight the transformative potential of epigenetics in advancing the understanding and management of breast cancer. From there, it opens opportunities to detect breast cancer early even in a non-invasive way.

Ovarian cancer is a highly heterogeneous and lethal gynecological malignancy, with its progression tightly regulated by both genetic and epigenetic mechanisms. Among the epigenetic regulators, histone modifications-including acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation-have emerged as pivotal modulators of chromatin architecture and gene transcription. These post-translational modifications, governed by specific histone-modifying enzymes, shape the transcriptional landscape of tumor cells and influence key oncogenic processes such as cellular proliferation, invasion, stemness, DNA repair, and chemotherapy resistance. Dysregulation of enzymes such as histone acetyltransferases (HATs), deacetylases (HDACs), methyltransferases (HMTs), demethylases (HDMs), ubiquitin ligases, and SUMO ligases has been implicated in the pathogenesis of ovarian cancer and is associated with adverse clinical outcomes. Importantly, these modifications are reversible, rendering them tractable therapeutic targets. This review provides a comprehensive synthesis of the major classes of histone modifications and their biological functions in ovarian cancer, highlights recent insights into the interplay between different modifications (crosstalk), and evaluates ongoing therapeutic strategies that aim to reverse epigenetic dysregulation. By elucidating the complex epigenetic landscape, this review supports the development of next-generation diagnostic, prognostic, and therapeutic approaches in ovarian cancer.

Malignant melanoma is the most aggressive and lethal type of skin cancer associated with increased mortality rates. Moreover, beyond the genetic background, the altered epigenetic landscape (e.g., abnormal patterns of DNA methylation, aberrant histone modifications and de-regulated expression levels of ncRNAs) further contributes to the pathophysiology of the disease. In addition, despite the improvement of current anti-melanoma strategies and the development of new therapeutic approaches, the 5-year survival among melanoma patients is still high, mainly due to acquired-drug resistance. On the other hand, phytochemicals have been associated with various health-promoting properties through pleiotropic mechanisms including acting as potent epigenetic regulators restoring back a normal phenotype in various experimental cancer models. In this review article, we discuss the general characteristics of malignant melanoma and current therapeutic approaches while we report the epigenetic basis of the disease along with the main compounds capable of restoring a normal epigenetic landscape. Finally, we describe the role of various phytochemicals in targeting the epigenome of malignant melanoma thereby potentially acting as an alternative therapeutic approach.

Spontaneous pneumothorax (SP) is defined by the presence of air in the pleural space arising from neither trauma nor iatrogenic causes. It can develop secondary to various etiologies. The familial clustering observed in some patients with SP supports the view that genetic factors play a role in the pathogenesis of SP. Several recognizable pneumothorax-associated genetic syndromes exist, including Birt-Hogg-Dubé syndrome (BHD), tuberous sclerosis complex-associated lymphangioleiomyomatosis (TSC-LAM), Marfan syndrome (MFS), cystic fibrosis (CF), alpha-1 antitrypsin deficiency (AATD), vascular Ehlers-Danlos syndrome (vEDS), Loeys-Dietz syndrome (LDS), and a few others. Recognition of these syndromes underlying SP facilitates optimal management and counseling regarding prognosis and potential comorbidities. In this review, we systematically summarize several genetic syndromes associated with pneumothorax, in which SP may manifest either as an initial presenting symptom or as a potential complication that adversely affects the prognosis.

Liquid biopsies offer a promising, noninvasive approach for monitoring and predicting responses to immunotherapy across multiple solid tumors. For the most part these are circulating tumor DNA (ctDNA) based assays. Here, we discuss the biological basis, clinical evidence, and potential applications of different types of ctDNA assays in tracking tumor dynamics, distinguishing pseudoprogression, and assessing minimal residual disease. We explore the current limitations, assay variability, and future directions, including integration with other biomarkers and real-world clinical trials aimed at validating ctDNA as a routine tool in precision immuno-oncology.

Inflammatory and nested testicular sex cord tumor (IN-TSCT) is a recently characterized malignant neoplasm within the spectrum of testicular sex cord-stromal tumors. Previously misclassified as Sertoli cell tumor, not otherwise specified, or as seminoma, this entity has emerged as a distinct clinicopathologic and molecular subtype defined by recurrent EWSR1::ATF1 gene fusions and a potentially aggressive clinical course. Patients most commonly present with unilateral painless testicular enlargement, and radiologic findings are typically nonspecific. Histologically, tumors demonstrate solid and nested growth patterns, epithelioid cytology with eosinophilic to clear cytoplasm, prominent hyalinized stroma, and a conspicuous inflammatory infiltrate. Immunophenotypically, tumors express sex cord-stromal markers, including steroidogenic factor-1 (SF-1) and inhibin, and frequently co-express epithelial membrane antigen and CD30 while lacking germ cell tumor markers. Molecular studies indicate fusion-driven oncogenesis associated with low tumor mutational burden. Published cases suggest that IN-TSCT may exhibit aggressive clinical behavior, including metastatic spread in a subset of patients; however, the total number of reported cases remains very limited, and the true metastatic risk and prognostic spectrum have not yet been clearly defined. This review synthesizes the available literature to provide a comprehensive clinicopathologic and molecular overview of this emerging tumor entity.

Background/Objective: Although most melanocytic lesions are diagnosed as benign or malignant by histopathologic evaluation, with or without the aid of immunohistochemistry, diagnosis may remain uncertain in a minority of cases. Assessment of copy number abnormalities (CNAs) may provide sufficient additional evidence to favor either a benign or malignant diagnosis in both pediatric and adult cases and in melanocytic lesions of various subtypes, including Spitzoid, mucosal, and acral. CNAs are common in melanomas, while they are rare, with few exceptions, in benign lesions. Detection of CNAs by fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA) has been well established for melanocytic lesions, with advantages and disadvantages for each. The objective of this meta-analysis was to evaluate the utility of CNA testing for the diagnosis of melanoma, across subtypes, when a lesion remains ambiguous after histopathologic and immunohistochemical assessment. In addition, the utility of CNAs to determine prognosis in established diagnoses of melanoma was also evaluated. Methods: The Cancer Genomics Consortium Working Group for Melanocytic Lesions reviewed published data from January 1998 through September 2022 of CNAs in melanocytic lesions detected by either FISH or CMA and conducted a meta-analysis of the findings. Results: Specific abnormalities common in primary cutaneous melanomas of various subtypes and uveal melanomas were enumerated. Differences in CNAs found in primary versus metastatic lesions were also determined, and published evidence for prognosis was summarized. Conclusions: The working group established evidence-based recommendations for the use of CNA testing for evaluation of ambiguous melanocytic lesions.

Soft-tissue sarcomas (STSs) comprise a rare, heterogeneous group of mesenchymal malignancies in which histologic grade remains the strongest determinant of outcome, metastatic risk, and therapeutic strategy. Intermediate/high-grade STSs exhibit a pronounced propensity for early distant relapse, yet growing evidence indicates that metastatic behaviour is not uniform. Within this spectrum, an oligometastatic phenotype, characterised by a limited number of metastases, often confined to the lung, has emerged as a clinically and biologically distinct state associated with more indolent metastatic kinetics and improved survival when treated with aggressive local interventions. However, the criteria that define true oligometastatic STSs remain unsettled, and prospective evidence is lacking. Emerging molecular and immunological correlates provide a potential framework for biological triage. Low genomic complexity (low-risk CINSARC), a B-cell/TLS-rich tumour microenvironment, high immune-cytotoxic signatures, and persistently low or undetectable circulating tumour DNA (ctDNA) are each linked to reduced metastatic competence and may underpin oligometastatic trajectories. Conversely, high chromosomal instability, immunosuppressive microenvironments, and elevated ctDNA levels align with covertly polymetastatic biology despite limited radiographic disease. In this context, artificial intelligence and machinelearning approaches applied to computational genomics, immune profiling, imaging, and liquid-biopsy data offer a powerful strategy to integrate these multi-dimensional features and refine predictions of metastatic behaviour in STS. Oligometastatic STS therefore represents a biologically definable subset amenable to multimodal management integrating local ablative therapies, systemic agents, and immune-based strategies. Prospective, biomarker-stratified trials are needed to validate selection frameworks and optimise treatment sequencing in this evolving therapeutic space.

Non-coding RNAs (ncRNAs) are conserved in the genome of cells across the three domains of life. They comprise a diverse group that are particularly prominent in metazoans where they provide a crucial interface between genes and proteins, participating in key cellular processes at different levels: from control of DNA transcription to modulation of messenger RNA stability to modification of protein activity. The interactions of ncRNAs with one another as well as with other RNAs, DNA and proteins form the basis of a genome-wide regulatory network (GRN). Because of the mutual influence of its components on each other, the GRN is a dynamic system. Further, the GRN imposes constraints on which genes are expressed and when, leading to specific gene-expression patterns or transcriptomes. The configurations of the activities of all gene loci represent self-stabilizing cell states, referred to as "attractor" states, each of which corresponds to a distinct cell type. The cancer cell is also an attractor state that arises from a change in the topography of the epigenetic landscape caused by dysregulation of the GRN. It is proposed that the transition to a neoplastic attractor state is caused by ncRNA alterations, while subsequent somatic mutations of oncogenes and tumor suppressor genes drive cell proliferation and clonal expansion.

Acute myeloid leukemia (AML) is a biologically heterogeneous hematologic malignancy arising from the oncogenic transformation of hematopoietic stem and progenitor cells, resulting in clonal expansion and progressive subclonal diversification. Although considerable advances have deepened our understanding of AML pathogenesis, major challenges persist, particularly regarding relapses and therapeutic resistance. In recent years, exosomes-extracellular vesicles of 30-150 nm in diameter of endosomal origin-have emerged as critical mediators of intercellular communication within the AML tumor microenvironment. These vesicles transport a diverse cargo of proteins, metabolites, and nucleic acids, including mRNA, non-coding RNA species, and DNA, which is selectively packaged during their biogenesis. Circulating exosomes have garnered attention as promising liquid biomarkers for diagnosis, prognosis, and monitoring minimal residual disease, while also representing potential therapeutic targets or delivery platforms. Nonetheless, significant knowledge gaps remain regarding the mechanisms governing exosome biogenesis, cargo selection, and the functional impact on leukemia progression and immune modulation. This review focuses on the role of exosomes in acute myeloid leukemia, with an emphasis on the molecular mechanisms underlying their involvement in pathogenesis, tumor communication, and resistance to therapies, as well as their potential as diagnostic biomarkers.

Vitamin B6 is an essential micronutrient whose biologically active form, pyridoxal 5'-phosphate (PLP), acts as a cofactor in metabolic reactions linked to tumorigenesis and also functions as an antioxidant. Low plasma PLP levels are consistently associated with cancer, but studies on dietary intake have yielded conflicting results. Overall, evidence suggests that the effects of vitamin B6 deficiency on cancer are context-dependent, varying with cell type and tumor stage. Accordingly, high expression of PDXK and PNPO, two key genes involved in PLP biosynthesis, is associated with tumor progression in some malignancies, whereas it correlates with improved outcomes in others. This review explores Drosophila melanogaster as a useful model to investigate underlying mechanisms, bypassing the limitations of human studies. Research in Drosophila demonstrates that PLP deficiency promotes cancer by triggering genomic instability. Furthermore, a critical PLP-SHMT gene-nutrient interaction impacting oncogenesis has been established in flies, offering significant therapeutic implications. Finally, studies in Drosophila have shown that PLP deficiency can promote tumor development by also triggering the loss of heterozygosity (LOH). These findings highlight Drosophila as a powerful tool to elucidate the molecular pathways linking vitamin B6 deficiency to cancer.

Neurofibromatosis type 1 (NF1) and NF2-related schwannomatosis (NF2-SWN) are major genetic tumor predisposition syndromes characterized by progressive, often debilitating neoplasms of the peripheral and central nervous systems. Over the past five years, substantial advances in molecular genetics, signaling biology, and targeted therapeutic development have reshaped diagnostic and management paradigms for both disorders. This Perspective synthesizes recent developments, including gene-based reclassification, emergence of MEK inhibitor therapy in NF1, renewed evaluation of bevacizumab and kinase-pathway inhibitor brigatinib, the discovery of a novel TβR1-RKIP pathogenic axis, and a brain-penetrant HDAC inhibitor in NF2-SWN. These insights highlight a shift toward precision-medicine strategies and mechanistically driven therapies poised to redefine future clinical care.

Head and neck squamous cell carcinoma (HNSCC) is biologically and clinically dichotomous according to HPV status, a distinction that fundamentally dictates the design, implementation, and interpretation of liquid biopsy strategies. Conventional anatomical imaging lacks sufficient sensitivity for minimal residual disease (MRD) detection, contributing significantly to treatment failure and suboptimal clinical outcomes. This review provides a critical, evidence-based synthesis of the three principal circulating analytes, circulating tumor DNA (ctDNA), exosomes, and circulating tumor cells (CTCs), and their evolving roles in real-time, non-invasive molecular monitoring. Critically, the clinical readiness of these analytes differs substantially: while ctDNA, particularly HPV-related ctDNA, is approaching clinical validation for MRD detection and recurrence surveillance in HPV-positive HNSCC, exosomes and CTCs remain investigational tools hindered by ongoing technical challenges including lack of standardized assays, limited reproducibility across platforms, and insufficient prospective validation. We review how the presence of a clonal, virally derived DNA target in HPV-positive HNSCC contrasts with the heterogeneous somatic mutational landscape of HPV-negative tumors, necessitating divergent analytical platforms and yielding distinct clinical utility profiles for MRD detection and recurrence surveillance. We further outline a pragmatic translational pathway focused on assay standardization, particularly for exosomes and CTCs where this foundational work is most urgently needed, integration of complementary multimodal liquid biopsy approaches, and rigorously designed prospective interventional clinical trials to establish clinical utility. Collectively, these efforts aim to transition HNSCC management from reactive, anatomy-based surveillance to proactive, molecularly guided precision oncology, with the potential to improve therapeutic decision-making and patient outcomes.

Lung cancer is the leading cause of cancer-related mortality worldwide, accounting for more deaths than any other malignancy. Despite advances in treatment, it remains highly lethal, with 5-year survival rates showing minimal improvement over the past several decades, highlighting a critical unmet clinical need. Macrophage Migration Inhibitory Factor (MIF) is a multifunctional cytokine that contributes to inflammation and cancer, promoting tumor growth, progression, and metastasis through modulation of the tumor microenvironment, stimulation of angiogenesis, and regulation of immune responses. Polymorphisms in the promoter region of MIF, such as high-expression CATT repeats, influence MIF expression and susceptibility to a range of inflammatory, autoimmune, and malignant disorders, yet their role in lung cancer remains largely unexplored. Therapeutic strategies targeting MIF, including small-molecule inhibitors, antibodies, and peptide-based agents, have shown promise in preclinical models, although their clinical translation is still limited. This review discusses the dual role of MIF in inflammation and oncology, summarizes current therapeutic developments, and emphasizes the potential of MIF-targeted interventions in lung cancer. It discusses the significance of genetic predisposition, particularly high-expression MIF alleles, in guiding personalized treatment strategies for lung cancer and identifying patients who may derive benefit from MIF inhibition.

Dedifferentiation-the acquisition of an early developmental state-is a hallmark of cancer. However, the underlying mechanisms that lead to cancer-associated dedifferentiation are not fully understood. Transposable elements (TEs) are becoming increasingly recognised as important regulators of development and disease. The recruitment of TE sequences has played an important role in placental evolution, and TE-derived genes play critical roles in placental development. Although important biological differences exist between tumours and the placenta, the placenta shares certain features with tumours, including the capacity to invade surrounding tissue and modulate the maternal immune response. In this regard, TEs have been implicated in cancer development, and are documented to contribute to oncogenesis through multiple different mechanisms. Moreover, cancers reacquire an epigenetic landscape, which is reflective of early development, and which corresponds to increased phenotypic plasticity, including facilitating the activation of early developmental genes. Many cancers can repurpose developmental genes, including TE-associated genes, which may contribute to pathways involved in invasion and metastasis. Determining whether TE activation is a consequence of broader epigenetic reprogramming or actively contributes to dedifferentiation will be important for understanding cancer biology and may facilitate improvements in cancer diagnosis and treatment.

PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNAs initially identified in germline cells as genome guardians that silence transposable elements. Recent studies have expanded this view, revealing that piRNAs and PIWI proteins are broadly expressed in somatic tissues and participate in epigenetic and post-transcriptional gene regulation. This review systematically summarizes piRNA biogenesis and molecular mechanisms, with a focus on their functional diversification from germline to somatic cells. We detail piRNA dysregulation and its association with various human diseases, including cancer, cardiovascular disorders, neurodegenerative diseases, immune dysfunction, and reproductive disorders. By integrating recent findings, this review provides a comprehensive overview of piRNA-mediated regulatory networks and highlights their potential as novel biomarkers and therapeutic targets.

Oligoprogressive disease (OPD) in non-small-cell lung cancer (NSCLC) is a clinical entity with peculiar behavior and treatment. OPD patients, during systemic therapy, may receive local ablative treatment (LAT) with survival benefit. The importance of OPD and the role of LAT has been comprehensively assessed in the setting of EGFR mutant and ALK-rearranged NSCLC during tyrosine kinase inhibitor (TKI) treatment, but it is still almost unexplored in the context of NSCLC harboring actionable oncogenic drivers other than EGFR and ALK. The aim of our review is to collect and discuss the available data about standard treatment in this latter setting, with special consideration given to the role of LAT in case of OPD in systemic treatment. Through a comprehensive PubMed and ClinicalTrials.gov search, we identified the available data and ongoing clinical trials addressing these aims. To date, only limited evidence supports the use of LAT in OPD involving NSCLC driven by these molecular alterations, mainly deriving from case reports and retrospective series. This highlights an unmet clinical need that warrants systematic and multicentric data collection to generate more robust evidence.

Nuclear mechanics and mechanotransduction are involved in the migration and invasion process, such as those in which the cells need to deform themselves to pass through constrictions. Specifically, properties like nuclear softness, viscoelasticity, plasticity (like nuclear pore complexes) and deformability are critical in cancer and its malignant progression. The nucleus represents a physical barrier for the migration and invasion in dense 3D extracellular matrix (ECM) scaffolds. Therefore, the deformability of the nucleus seems to determine the migration limit in circumstances where the enzymatic remodeling of the surroundings is impaired. There are still significant knowledge gaps regarding effects of nuclear deformation during cancer dissemination. It seems that nuclear deformation can alter gene transcription, induce alternative splicing processes, impact nuclear envelope rupture, nuclear pore complex dilatation, damage the DNA, and increase the genomic instability. These mechanically induced alterations can in turn impact the migratory behavior of the cancer cells. The stiffness of the nucleus relies on the condensation of chromatin, and the nuclear lamina, which consists of a network of intermediate filaments underneath the nuclear envelope. All of this is discussed in the review and it is argued that nuclear deformability is universally found in various cancer types. Another focus is placed on the nuclear envelope proteins like emerin, and the SUN-KASH complex and how they contribute to the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which consequently couples the nucleus and the cytoskeleton. It is argued that this connection is crucial for force transmission, which governs nuclear stiffness dynamically, depending on the force applied. In this review, recent findings are described that couple ECM-induced nuclear mechanosensing and mechanotransduction with the migration and invasion of cancer cells. Moreover, it is suspected that changes in the mechanosensory characteristics of the cell nucleus could play a pivotal part in the malignancy of cancer cells and the heterogeneity of tumors. Finally, it is discussed what impact the individual elements of the nucleus offer to mechanically alter cellular migration and invasion in cancer and its malignant progression.