Search Results (1,306)

Background: Biallelic loss-of-function variants in LAMC3, encoding laminin gamma-3, cause occipital cortical malformation (OMIM#614115). White matter disease and intracranial neoplasia have not been reported in this spectrum. We report a novel homozygous LAMC3 frameshift variant, expanding its phenotypic and molecular spectrum. Methods: Two adolescent siblings from a consanguineous Turkish family underwent whole-exome sequencing, with segregation confirmed by NGS/IGV and classification per ACMG/AMP criteria. In silico analyses included multiple sequence alignment, AlphaFold modeling of wild-type and mutant proteins, and docking against nidogen-1 (NID1). Results: Both siblings had a novel homozygous LAMC3 variant frameshift variant (NM_006059.4: c.1852_1882del; p.(Pro618Serfs*5)), classified as pathogenic (PVS1, PM2, PP3, PP1) with full cosegregation. Proband II.III, a 17-year-old female, developed postoperative epilepsy after resection of a tectal low-grade glioneuronal tumor harboring a somatic KRAS (NM_004985.3) p.(Gln61Lys) variant (VAF 42.9%), with periventricular white matter gliosis. Proband II.IV, a 15-year-old male, presented with confluent leukoencephalopathy, occipital pachygyria, parietal polymicrogyria, and subcortical band heterotopia, illustrating striking intrafamilial discordance. Conclusions: Docking analysis revealed that the cleavage removes the C-terminal nidogen-binding region, eliminates the predicted wild-type interface (residues 906–1029), and shifts the binding to an unnatural N-terminal surface. This finding is a hypothesis-generating result consistent with loss of function. This study expands the LAMC3 phenotype to include leukoencephalopathy and reports a co-occurring low-grade tectal glioneuronal tumor as a novel, single-case observation, supporting inclusion of LAMC3 in the differential diagnosis of pediatric leukoencephalopathies, particularly with consanguinity. Full article

Background: S100A11, a calcium-binding S100 family protein, is increasingly implicated in carcinogenesis, yet its molecular regulation and clinical relevance across cancers remain unclear. Hepatocellular carcinoma (HCC) carries a dismal prognosis, in part due to a lack of reliable biomarkers for risk stratification of established disease. Methods: We conducted a pan-cancer analysis of S100A11 genomic alterations across 31 studies (10,767 samples) obtained from TCGA, encompassing copy number alterations, somatic mutations, and DNA methylation. HCC-specific analyses evaluated S100A11 expression, its potential as a diagnostic/prognostic marker, co-expression networks, and pathway enrichment using TCGA-LIHC data, with univariate and multivariate Cox regression to assess survival associations. Results: S100A11 alterations were predominantly driven by copy number amplification, with the highest frequencies in hepatobiliary cancers, lung and breast cancers. Copy number amplification showed a consistent inverse relationship with promoter methylation, indicating amplification-driven transcriptional activation. In HCC, S100A11 was markedly overexpressed compared with normal liver tissue, with strong diagnostic discriminatory capacity. High S100A11 expression was significantly associated with inferior overall survival (log-rank p = 0.032; HR = 1.46, 95% CI 1.03–2.06) and remained an independent predictor of overall survival after adjustment for age, sex, and AJCC pathologic stage (HR = 1.27, 95% CI 1.01–1.60, p = 0.038). Co-expression and pathway analyses demonstrated an association between S100A11 and metabolic reprogramming, extracellular matrix remodelling, and immune dysregulation. Conclusions: These findings identify S100A11 as a candidate diagnostic and prognostic biomarker in HCC whose overexpression is associated with metabolic reprogramming, ECM remodelling, and immune dysregulation, warranting experimental validation of a mechanistic role. Full article

Background and Clinical Significance: Cutaneous angiosarcoma frequently metastasizes to the lungs, where it may rarely present as diffuse cystic lung disease with recurrent pneumothorax, resulting in substantial diagnostic difficulty. We report a case of pulmonary metastatic cutaneous angiosarcoma in which paired whole-genome sequencing (WGS) of the primary and metastatic lesions was performed to clarify clonal origin and characterize metastatic evolution. Case Presentation: A 65-year-old man with recurrent right-sided pneumothorax and progressive bilateral cystic lung lesions underwent skin and lung biopsies. Histopathological examination and immunohistochemistry established the diagnosis of cutaneous angiosarcoma with pulmonary metastases. Paired WGS was performed on matched scalp and lung tumor specimens to evaluate shared and lesion-specific genomic alterations, pathway enrichment, and copy-number changes. Histopathology confirmed metastatic angiosarcoma involving the lungs. WGS identified 128 shared somatic alterations, supporting a common clonal origin, together with lung-specific and skin-specific mutations indicative of continued genomic divergence. Recurrent alterations involving POT1 and FLT4 were preserved in both lesions, whereas additional POT1 and TP53 alterations were detected only in the pulmonary metastasis. Pathway analysis demonstrated preferential enrichment of IGF1–mTOR, RAS, and WNT/LRP6 signaling in the metastatic lesion, while Gene Ontology analysis suggested functional divergence associated with metastatic progression. Conclusions: Pulmonary metastatic angiosarcoma should be considered in patients presenting with unexplained diffuse cystic lung disease and recurrent pneumothorax, particularly when pathological findings are inconclusive. Paired WGS complemented conventional histopathology by confirming the metastatic origin and providing insights into clonal evolution and lesion-specific molecular alterations, highlighting its potential value in the investigation of rare metastatic malignancies. Full article

Chronic hepatitis C virus (HCV) infection is an established risk factor for B-cell lymphoproliferative disorders and represents a paradigmatic model of infection-driven lymphomagenesis. Although direct-acting antivirals have markedly reduced the burden of HCV-related disease, HCV-associated lymphomas continue to occur. Moreover, HCV screening remains incomplete in some geographical areas and healthcare settings, leaving a substantial proportion of infected individuals unaware of their status. This narrative review integrates current evidence on the mechanisms linking chronic HCV infection to mixed cryoglobulinemia and overt B-cell non-Hodgkin lymphoma. HCV lymphotropism and persistent antigenic stimulation could initially promote the selection and expansion of autoreactive B-cell clones, while mixed cryoglobulinemia represents the most informative pre-lymphomatous risk condition. Cytokine-mediated survival signals, particularly those involving B-cell activating factor, reinforce clonal persistence and cooperate with host genetic susceptibility, impaired apoptotic control, and activation-induced cytidine deaminase-mediated genomic instability. The progressive acquisition of somatic driver mutations, copy-number alterations, and epigenetic and transcriptomic changes may enable selected clones to escape functional anergy and become increasingly independent of the original viral stimulus that, in turn, represents an initial trigger of the lymphoproliferative process. Recurrent abnormalities converge on NF-κB, NOTCH, chromatin-regulatory, apoptotic, and cell-cycle pathways, although HCV-associated lymphomas remain molecularly heterogeneous. Emerging microRNA profiles further contribute to the molecular characterization of the transition from chronic infection and cryoglobulinemia to lymphoma. Despite the availability of highly effective antiviral therapies, HCV-associated lymphomagenesis remains clinically relevant and continues to provide an especially informative model for understanding how chronic viral infection can drive human cancer development. Full article

We performed a focused review to better understand the pathogenesis of Agent Orange (AO)-associated myelodysplastic syndrome (MDS). We first examined the mechanisms underlying conventional (de novo) MDS, a clonal hematopoietic neoplasm that typically develops in later life, and integrated these findings with our recent analysis of obesity-associated carcinogenesis. Accordingly, we propose that genomic instability in de novo MDS results from selective inhibition of the DNA polymerase proofreading exonuclease. In obesity-associated carcinogenesis, impaired AMP-activated protein kinase (AMPK) activity disrupts mitochondrial ATP production, increasing intracellular AMP concentrations. Elevated AMP selectively inhibits the proofreading exonuclease while preserving polymerase activity, allowing replication errors to escape correction and become fixed as somatic mutations. Molecular studies demonstrate that AO-associated MDS exhibits essentially the same mutational profile as de novo disease despite arising after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in young, otherwise healthy military personnel. Because TCDD is highly lipophilic, it accumulates in adipose tissue and is released slowly over decades, producing sustained mitochondrial dysfunction, reduced ATP synthesis, and chronic elevation of intracellular AMP. We propose that this metabolic disturbance converges on the same endpoint—selective inhibition of the proofreading exonuclease—thereby promoting mutagenesis and clonal evolution. Recent studies further strengthen the central role of proofreading by demonstrating that many mutations, including many found in MDS, previously attributed to spontaneous cytosine deamination, instead arise from DNA polymerase misincorporation of thymidine opposite cytosine, particularly at CpG dinucleotides, emphasizing the critical importance of fully active proofreading in preventing such misincorporations from accumulating as mutations in the genome of the cell. Full article

Liquid biopsy, the analysis of tumor-derived material in blood, saliva, and other body fluids, is increasingly explored for the diagnosis, surveillance, and molecular characterization of head and neck squamous cell carcinoma (HNSCC). Its performance, however, is not uniform across the disease, and the reason is fundamentally molecular. human papillomavirus (HPV)-positive oropharyngeal cancers carry viral oncogenes that are absent from the host genome and therefore provide a near ideal, tumor specific circulating marker, whereas HPV-negative tumors are driven by a heterogeneous somatic landscape that offers no single universal target. In this narrative review, we adopt a molecular perspective. We first examine the biological origin of circulating tumor DNA and of the other analytes that liquid biopsy can interrogate including circulating tumor HPV DNA, viral transcripts, microRNAs, extracellular vesicles, and methylation signatures. We then consider how analytical platforms, from droplet digital PCR to next generation and ultrasensitive whole-genome sequencing, translate these molecules into measurements. Only afterward do we discuss the clinical questions, organized by clinical objective rather than by individual study: diagnosis and early detection, prognosis and risk stratification, treatment response monitoring, minimal residual disease and surveillance, and biomarker guided de-escalation in HPV-positive disease. Twelve registered clinical trials, involving approximately 1183 patients, are presented as illustrations of these questions. We close on the biological and technical gaps that still separate promising signals from clinical practice, and on the multi analyte and dynamic strategies most likely to bridge them. At present, liquid biopsy should be regarded as a complementary tool rather than as a replacement for established clinicopathological assessment. Full article

Philadelphia-negative (Ph-negative) myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), which are clonal hematopoietic disorders caused by somatic gene mutations in the JAK2, CALR, or MPL genes. Mutations activate the JAK–STAT pathway and disrupt NF-κB signaling, leading to a chronic inflammatory state caused by pro-inflammatory cytokines and reactive oxygen species (ROS). This altered microenvironment causes serious clinical features of the disease, such as bone marrow fibrosis, splenomegaly, vascular niche remodeling, and a greater probability of thrombosis or secondary leukemic transformation. Concurrently, MPNs cause both severe immune dysregulation and tumor evasion, as evidenced by progressive lymphopenia, T and B cell exhaustion, Natural Killer cell maturation arrest, and the accumulation of myeloid-derived suppressor cells. Although FDA-approved JAK1/JAK2 inhibitors ruxolitinib, fedratinib pacritinib and momelotinib effectively reduce splenomegaly and symptom burden and have demonstrated survival benefits in clinical trials, their ability to eliminate malignant clones or induce durable disease modification remains limited, and disease progression continues to occur in most patients. Finally, this review assesses the complex immunological dysfunction and chronic inflammatory dysregulation that characterize Ph-negative MPNs, as well as emerging therapeutic strategies, emphasizing the importance of fully understanding these intricate microenvironmental mechanisms for the identification and development of novel precision treatment targets. Full article

Background: The growing awareness of breast cancer’s molecular diversity has not changed the technical foundations of surgery itself, but it has profoundly reshaped how surgeons think about surgery. Rather than molecular biology prescribing specific surgery, it is the surgeon’s interpretation of biological behavior—tumor subtype, genomic risk, treatment responsiveness—that influences surgical timing, extent, and feasibility. This is particularly important in the developing world, where mastectomy continues to be the default surgery, not always because it is required, but because biological nuance is underutilized in surgical planning. This review integrates existing evidence, guidelines, and real-world clinical experience to show how a surgeon who understands tumor biology can meaningfully expand safe breast conservation, de-escalate axillary surgery, and align operative choices with systemic therapy. In essence, molecular biology becomes a lens through which surgeons can practice more personalized, precise, and less invasive surgery, without compromising oncologic safety. Recent findings: We present evidence-based algorithms focusing on Luminal A, Luminal B, HER2-positive, and triple-negative subtypes, while discussing the nuances of multifocal and multicentric disease, metaplastic histologies, and discordant lesion management. The review addresses axillary management in the molecular era, specifying the appropriateness of sentinel lymph node biopsy, targeted axillary dissection, or completion axillary dissection, and how subtype-specific nodal responses to neoadjuvant therapy can guide de-escalation strategies. Through clinical vignettes, we exemplify how molecular integration into surgical planning can modify clinical courses, enabling oncoplastic conservation in downstaged tumors and justifying definitive resection in chemo-resistant cases. We examine the implications of germline and somatic genetic testing on surgical decision-making, particularly in relation to BRCA1/2 and PALB2 mutation carriers, alongside ethical and practical counseling considerations. Additionally, we review emerging biomarkers—such as circulating tumor DNA and immune and radiomic signatures—and propose research priorities for their incorporation into surgical trials. Conclusions: Effective implementation necessitates enhanced surgeon education, standardized assays, and multidisciplinary coordination to promote equitable access, consistent utilization of biology-driven algorithms, and rigorous quality oversight. This review furnishes breast surgeons with a pragmatic framework for translating molecular knowledge into multidisciplinary, patient-centered care pathways that optimize oncological safety, aesthetic outcomes, and overall quality of life. Full article

Background: South Korea reports one of the highest adolescent suicide rates among OECD countries. Both psychological factors (perceived stress, depression) and somatic/behavioral factors (atopic disease, obesity, diet, physical activity) have been proposed as correlates of adolescent suicidality, but the extent to which their co-occurring long-term national trends reflect genuine, independent associations—rather than a shared secular (time) trend—has rarely been tested at the population level. Methods: We compiled national annual prevalence estimates (2005–2025) from the Korea Youth Risk Behavior Survey (KYRBS), disseminated via the Korean Statistical Information Service (KOSIS), for eleven indicators. We computed (1) raw Pearson correlations, (2) year-detrended partial correlations, (3) multiple and hierarchical regression, and (4) an exploratory observed-variable path model on the year-adjusted series. Results: In raw correlations, nearly all indicators were significantly associated with the suicide attempt rate (|r| = 0.30–0.92). After removing the shared time trend, only perceived stress (partial r = 0.82, p < 0.001) and depressive mood (partial r = 0.81, p < 0.001) remained strongly and independently associated with suicide attempts. Detrended residuals were approximately normal (Shapiro–Wilk p > 0.26), and the two psychological associations were confirmed by Spearman rank-based partial correlations and permutation tests (both p ≤ 0.0002). A joint regression (suicide ~ stress + depression, year-adjusted) explained 93.5% of variance (adjusted R² = 0.923), and stress and depression added significant explanatory power beyond calendar year (ΔR² = 0.229, p < 0.001). Conclusions: Among the indicators examined, perceived stress and depressive mood show a robust population-level association with adolescent suicide attempts that is not attributable to a shared secular trend, whereas most somatic and behavioral correlates do not. The path model is exploratory and descriptive only and does not test causal mechanisms. Findings are ecological (population-level) and cannot establish—or exclude—individual-level causation. Full article

Background/Objectives: Juvenile myelomonocytic leukemia (JMML) is a rare, highly aggressive form of pediatric myelodysplastic/myeloproliferative neoplasm characterized by molecular heterogeneity and constitutive activation of the RAS signaling pathway. This study aimed to characterize the mutational landscape, driver genes, mutational signatures, functional pathways, and therapeutic potential of mutated epigenetic regulator genes in JMML. Methods: Tumor and matched buccal swab samples were collected from 35 JMML patients, and whole-exome sequencing was performed. Somatic variants were called with GATK-Mutect2 and annotated with ANNOVAR. maftools and OncodriveCLUST were used for mutational profiling, co-occurrence analysis, driver gene identification, and protein domain mapping. Drug–gene interactions were explored using DGIdb, mutational signatures for genes were characterized by MutationalPatterns, and functional enrichment analysis was performed by the clusterProfiler package. Results: A total of 28 variants were detected in epigenetic regulator genes, with missense mutations being the most common class of variants and a C>T nucleotide substitution pattern being the most frequent. EP300, SETD2, and DNMT3B were the genes most frequently altered, with 8.57% of cases each, followed by ASXL1, BCORL1, ATRX, KMT2A, and TET2 (5.71% each). Driver gene analysis identified ASXL1 as the top candidate driver gene, followed by BCORL1, EP300, and SETD2. Functional enrichment analysis revealed a high number of genes involved in chromatin organization, histone modification, transcriptional regulation, and oncogenic signaling pathways. The mutational signatures identified were SBS5-like, which are dominated by C>T and T>C transitions, indicating endogenous mutational processes. Analysis of drug–gene interactions revealed KMT2A, EP300, and ATRX as the most interconnected and potentially actionable therapeutic targets. Conclusions: This study provides a comprehensive characterization of epigenetic regulator gene alterations in JMML and highlights the importance of epigenetic dysregulation in disease pathogenesis. Full article

Fibromyalgia (FM) causes widespread pain, poor sleep, fatigue, and reduced quality of life. Exercise is the best supported non-pharmacological treatment, yet many patients report that it is insufficient on its own. Somatic tracking is a component of pain reprocessing therapy. It is promising in chronic back pain but untested as a stand-alone intervention in FM. The Fibromyalgia Somatic Tracking and Exercise Program Study (FIBROSTEPS) is a single-center 2 × 2 factorial randomized controlled superiority trial estimating the separate and combined effects of group exercise and somatic tracking on the impact of FM. Two hundred adults aged 18–65 years, of either sex, with FM diagnosed by the 2016 criteria, are randomized 1:1:1:1 after an 8-week baseline period to general activity recommendations plus usual care (control), supervised group exercise, somatic tracking, or both. Both interventions run for 16 weeks with one session per week (45 min physiotherapist-led group exercise; 40 min guided somatic tracking with a certified therapist). The primary outcome is change in total original Fibromyalgia Impact Questionnaire score (0–100) from week 8 to week 24, analyzed by intention-to-treat. Secondary outcomes include insomnia severity, daily pain intensity, and Fitbit-measured activity and sleep. The trial has 80% power for the two main effects; the exercise × somatic-tracking interaction is prespecified as exploratory. No results are reported; the trial will provide randomized evidence on somatic tracking in FM, alone and combined with exercise, informing multi-component FM rehabilitation. Trial Registration: ClinicalTrials.gov (NCT06922747). Ethics Approval: Regional Committee for Medical and Health Research Ethics (REK), reference 2025/853403. Full article

Moringa oleifera leaf extract (MOLE), including polysaccharides, polyphenols, amino acids and other extracts, are increasingly being used as feed additives in ruminant nutrition due to their high profiles of bioactive compounds. This comprehensive narrative review aims to review current research on their use in ruminant production regarding their productive performance, immune status, rumen microbiota and fermentation. Dietary supplementation with MOLE enhances growth rates and feed conversion efficiency, as well as immune status, milk yield and rumen microbiology, in ruminants by improving nutrient digestibility and metabolic efficiency. Additionally, MOLE exerts significant immunomodulatory effects, and studies indicate that immunoglobulins, antioxidants, cytokines, and enzymes reduce oxidative stress markers and incidence of subclinical diseases in dairy animals. Furthermore, supplementation with MOLE often increases milk fat and protein content while reducing somatic cell counts (SCCs) in milk. MOLE enhance the function of the rumen fermentation profile by increasing volatile fatty acid (VFA) production, especially propionate, and also regulating the stability of rumen pH. Additionally, it also selectively promotes microbial community diversity, enhances the population of cellulolytic bacteria and has a suppression function in protozoa and methanogens. Moreover, MOLE also contributes to improving fiber degradation and reducing the emissions of methane. In conclusion, MOLE is considered as a viable natural strategy to promote productivity, immune function, health, and environmental sustainability while decreasing methane production in ruminant production. Full article

Background/Objectives: Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders driven by somatic mutations, most commonly those in JAK2, CALR, and MPL. While conventional molecular testing often focuses on these canonical mutations, emerging data suggest that additional mutations and low-variant-allele-frequency (VAF) subclones may contribute to disease progression and prognosis. Methods: We applied ultra-deep targeted sequencing with an error-correction algorithm to analyze bone marrow and peripheral blood samples from 134 patients with essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), secondary myelofibrosis (MF), or post-MPN acute leukemia. Targeted sequencing panels were used to detect disease-associated and clonal driver mutations. Matched germline controls were not systematically available. Results: Low-VAF variants (<5%) were identified in 4/16 (25%) CALR, 3/7 (43%) MPL, and 9/11 (82%) TP53 mutations. In contrast, all TP53 mutations identified at leukemic transformation had VAFs > 5%, suggesting clonal expansion during progression. Paired sequencing at initial MPN diagnosis and leukemic transformation was available for three patients. JAK2 p.V617F VAFs differed according to treatment timing (Kruskal–Wallis test, p = 0.0138), with lower VAFs observed in untreated patients; however, this association may be influenced by treatment-selection confounding. Mutations in ASXL1 and SRSF2 were occasionally observed in ET and secondary MF, although their prognostic significance remains uncertain. Progression analyses were exploratory because of the limited number of events and longitudinally sampled patients, and formal survival or prognostic modeling was not performed. Conclusions: Ultra-deep error-corrected sequencing enables sensitive detection of low-VAF mutations in MPNs, including subclonal events potentially missed by less sensitive assays. These findings demonstrate the potential utility of high-sensitivity panel-based sequencing for molecular characterization of MPN, while larger longitudinal studies are required to establish the prognostic and clinical significance of these findings. Full article

Germline EGFR pathogenic variants (PVs) are rare and define a distinct hereditary subset of NSCLC with unique clinical characteristics. Germline EGFR p.T790M is the most frequent and best characterized, with reported sensitivity to first- and second-generation EGFR-TKIs. Yet, the response of germline EGFR variants, especially the rarer ones such as p.V843I, to osimertinib remains poorly characterized. Given the very low frequency of germline non-p.T790M variants, their clinical relevance can only be investigated via case reports. Herein, we report what is, to the best of our knowledge, the first case of advanced lung adenocarcinoma harboring a germline EGFR p.V843I variant coexisting in cis with the unusual somatic EGFR exon 19 C-helix deletion, p.S752_I759del. Additionally, a somatic TP53 variant was detected. Treatment with afatinib induced a partial response lasting only six months, as rapid disease progression occurred without identifiable acquired resistance mechanisms. Subsequently, no objective response to osimertinib or afatinib rechallenge was observed. Acquired EGFR and MET amplification were detected in corresponding rebiopsies. Overall survival was 29 months. Our findings suggest that, despite the presence of the previously reported EGFR-TKI-sensitive, EGFR p.S752_I759del, the co-occurrence of germline p.V843I may have contributed to reduced sensitivity to afatinib and osimertinib. This case expands the molecular spectrum of hereditary EGFR-mutated NSCLC and, together with our narrative review of the literature, supports an emerging model in which germline EGFR PVs may act both as tumor-predisposing events and as potential mechanisms of early resistance to EGFR-TKIs. Full article

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated premalignant state defined by somatic mutations in hematopoietic cells at a variant allele frequency (VAF) ≥2% in the absence of overt hematologic malignancy. Among CHIP-associated mutations, JAK2 V617F is of particular interest because it occupies a dual biological and clinical role: it is both the principal driver of BCR::ABL1-negative myeloproliferative neoplasms (MPNs) and a clonal hematopoiesis variant conferring approximately 12-fold cardiovascular risk in selected cohorts, exceeding that reported for common DTA CHIP variants. Quantitative assessment of JAK2 V617F allele burden is therefore clinically relevant across the full disease continuum—from subclinical clonal expansion to MPN diagnosis, prognostic stratification, and therapeutic monitoring—as VAF thresholds correlate with disease phenotype, thrombotic risk, molecular response, and fibrotic progression. Digital PCR platforms, including droplet digital PCR (ddPCR) and chip-based digital PCR, have emerged as highly sensitive and reproducible methods for absolute JAK2 V617F quantification without the need for standard curves, with reported limits of detection as low as 0.01%. In this review, we synthesize current evidence on the molecular biology of JAK2-driven clonal hematopoiesis, the clinical significance of allele burden quantification, and the analytical performance of digital PCR compared with quantitative PCR and next-generation sequencing. We interpret these findings through a systems biology lens that draws together JAK-STAT signaling networks and thrombo-inflammatory pathways including inflammasome-dependent IL-1 signaling, clonal architecture, and bone marrow microenvironmental remodeling. We also discuss published quantitative models in which JAK2 V617F allele burden is treated as a dynamic state variable, while emphasizing that the present review offers a conceptual synthesis rather than a new computational model. We provide a structured comparative synthesis of published digital PCR analytical performance data, a stage-adapted proposal for clinical monitoring, and schematic models to guide future implementation. Overall, the evidence supports digital PCR as a precision tool for monitoring JAK2 V617F clonal dynamics across the CHIP–MPN spectrum, and points to several priorities: assay standardization, harmonized reporting, external quality assessment, and prospective clinical validation. Full article