Search Results (600)

Background: Clear cell renal cell carcinoma (CCRCC) is the predominant subtype of renal cell carcinoma and is characterized by frequent chromosome 3 alterations, including 3p deletion, monosomy, and aneuploidy. However, the absence of standardized fluorescence in situ hybridization (FISH) cut-off values has led to inconsistent reported frequencies and limited clinical integration of this accessible assay. This study aimed to establish clinically applicable cut-off values, propose a practical three-tier classification, and evaluate its diagnostic accuracy and clinicomolecular correlation with tumor aggressiveness. Methods: FISH using VHL (3p25.3) and CEP3 probes was performed on 1748 RCC cases (1655 CCRCC, 48 papillary RCC, 45 chromophobe RCC). Cut-off values were determined by combining ROC analysis with Youden’s index and the mean + 3SD method from normal renal tubular cells. A paired cohort of 97 CCRCC cases with targeted next-generation sequencing was stratified into three subgroups (3p intact, isolated 3p loss, broad chr3 change) for clinicomolecular comparison, including 3D principal component analysis. Results: Clinically applicable thresholds of 30% for 3p deletion and 20% for monosomy identified chromosome 3 alterations in 76.9% of CCRCC cases. The combination of both markers achieved superior diagnostic accuracy (AUC = 0.82). Aneuploidy was significantly associated with higher WHO/ISUP grade (p < 0.001) and older age (p = 0.006). The three-tier classification showed stepwise progression of aggressive features (older age, higher grade, larger tumor size) and increasing PBRM1 mutation frequency from the 3p intact to the broad chr3 change group. Conclusions: This study establishes standardized FISH cut-offs and a practical three-tier classification that captures a continuous spectrum of genomic instability and tumor aggressiveness in CCRCC. Routine 3p FISH provides a simple, cost-effective, and reproducible tool with substantial diagnostic and stratification value that complements more complex genomic profiling. Full article

Fucosylation, the enzymatic addition of fucose residues to glycans, modulates receptor signalling and cellular identity in the intestinal epithelium. Its role as an integrative determinant of cancer cell fate in colorectal cancer (CRC) remains undefined. Transcriptomic and clinicopathological data from 976 CRC patients across three independent cohorts (TCGA-CRC, CPTAC2-CRC, Sidra-LUMC) were analysed. A curated fucosylation gene set was used to calculate tumour fucosylation scores. Associations with histogenetic status, genomic features, microenvironmental phenotypes, drug resistance programmes, and survival were evaluated using gene set enrichment analysis, multivariable Cox regression, and integrated molecular subtyping. High-fucosylation tumours exhibited elevated epithelial differentiation, MSI-H/BRAF-mutant enrichment, oxidative phosphorylation dominance, the complete absence of EMT and invasion programmes, and favourable prognosis (HR = 0.633, 95% CI: 0.470–0.853, p = 0.003). Low-fucosylation tumours demonstrated mesenchymal phenotypes, TP53 mutations, chromosomal instability, comprehensive multi-family RTK signalling, immune-excluded microenvironments, and poor outcomes. Distinct multidrug resistance programmes emerged: drug efflux in low-fucosylation tumours versus xenobiotic sensing, target bypass, and drug sequestration in high-fucosylation tumours. Tumour fucosylation status defines two fundamentally distinct CRC cell states with mutually exclusive engagement of invasion programmes, metabolic pathways, immune phenotypes, and resistance mechanisms. Fucosylation represents an independent prognostic biomarker and integrative determinant of cancer cell fate, with significant implications for risk stratification and personalised therapeutic strategies. Full article

Background and Clinical Significance: Chromothripsis represents a catastrophic genomic event in plasma cell myeloma (PCM) associated with poor prognosis. We report a case of newly diagnosed PCM with complex cytogenetic abnormalities indicative of genomic instability. Case Presentation: A 67-year-old man presented with acute dyspnea and was found to have severe acute kidney injury, anemia, hypercalcemia, and IgG lambda monoclonal gammopathy. Bone marrow biopsy revealed plasma cell infiltration. Comprehensive FISH analysis demonstrated a complex pattern with gain of 1q, monosomy 13, and multiple numeric and structural abnormalities affecting chromosomes 5, 9, and 15, suggestive of a chromothripsis-like pattern. Despite requiring hemodialysis, the patient achieved complete renal recovery and >99% reduction in serum-free light chains after one cycle of CyBorD plus daratumumab, which was continued for four cycles. Follow-up bone marrow evaluation at three months confirmed complete histologic, flow cytometric, and cytogenetic remission, allowing for preparation for autologous stem cell transplantation. Conclusions: This case demonstrates that exceptional clinical responses can be achieved in high-risk disease with contemporary quadruplet regimens. While the long-term durability of such responses in genomically unstable cases remains uncertain, this case highlights the importance of comprehensive cytogenetic characterization to identify and monitor genomic instability in PCM. Full article

Chordoma is a rare malignant neoplasm of the axial skeleton, arising from notochordal remnants. No approved systemic therapies exist, and the 10-year overall survival is below 60%. Accurate molecular and pathological classification is a prerequisite for improved prognostication and the identification of actionable therapeutic targets; however, molecular classification of chordoma remains significantly less advanced than that of other neoplasms. This narrative review synthesizes proposed classification frameworks for chordoma across histological, radiological, surgical, genomic, epigenomic, transcriptomic, and proteomic domains. PubMed and CENTRAL were searched on 1 February 2026 using five queries: ‘chordoma classification’, ‘chordoma DNA sequencing’, ‘chordoma RNA sequencing’, ‘chordoma methylation’, and ‘chordoma copy number’. Original research articles describing more than one patient and reporting a classification or subtyping framework were included; review articles, case reports, and non-English publications were excluded. Sample size and the use of a validation dataset were identified for each study. Results were synthesized qualitatively. A total of 108 studies encompassing 6349 individuals were included. Across six domains, four cross-cutting themes with prognostic and potential theranostic value emerged: copy number alterations, particularly CDKN2A/B loss; SWI/SNF complex dysfunction; stroma–tumor ratio; and immune microenvironment heterogeneity. Full article

Background: Acute lymphoblastic leukemia (ALL) requires intensive induction, but implementation of pediatric-inspired regimens in low- and middle-income countries is constrained by diagnostic gaps, procurement instability, and limited supportive-care capacity. We evaluated the feasibility, safety, and affordability of a pragmatically adapted pediatric-inspired induction regimen for adults with Philadelphia chromosome-negative Ph(−) ALL in a Pakistani tertiary hospital. Methods: In this prospective single-center cohort study at the Pakistan Institute of Medical Sciences (December 2024–June 2025), consecutive adults aged 18–50 years with newly diagnosed Ph(−)ALL received an adapted pediatric-inspired induction regimen. The primary outcome was complete remission (CR) after induction, with or without extended induction. Secondary outcomes were early mortality, treatment abandonment, grade 3–4 toxicities, and service delivery feasibility indicators. Affordability was assessed against household income. Results: Among 200 adults (mean age 30.3 ± 8.8 years; 65.5% male), 39.5% presented with WBC ≥ 30 × 10⁹/L and 88.0% with platelets < 50 × 10³/µL. CR was achieved in 83.0% of patients. Early mortality was 2.0%, and treatment abandonment was 1.5%. Grade 3–4 toxicities included febrile neutropenia (15.0%) and sepsis (7.5%). The Day-30 evaluability was high (96.5%). Observed out-of-pocket diagnostic costs were USD 119, whereas a guideline-complete diagnostic package would cost USD 929, equivalent to 3–6 months of income for households in the poorest quintile. Conclusions: This adapted pediatric-inspired induction regimen was operationally deliverable in a resource-restricted hospital and produced favorable induction-phase outcomes. Limited diagnostic capacity and a lack of financial protection for testing remain barriers to risk-adapted care. Expanding subsidies for essential diagnostics and stabilizing the procurement of critical agents may yield the greatest implementation gains. Full article

Background/Objectives: Accurate ploidy determination is essential for understanding population structure and evolutionary history for breeding and domestication. The Chrysanthemum arcticum (Arctic daisy) complex, comprising C. arcticum and subspecies arcticum and polaré, exhibits variability in ploidy variation with reports ranging from diploid (2n = 2x = 18) to octoploid (2n = 8x = 72). Methods: The objective of this study was to assess ploidy levels in n = 225 genotypes from n = 46 wild, native populations of the three taxa collected across mainland Alaska, Attu Island (Alaska), and Hudson Bay (Canada) using flow cytometry, and using C. nankingense (2n = 2x = 18) as the diploid reference. Results: Genome sizes were from 5.27 to 20.69 pg (2C), corresponding to diploid through hexaploid. Triploids were the most frequent (64%) before, as well as after, applying the reference standard bias (10% correction). All ploidy levels were present in multiple geographic regions, with no clear spatial, taxonomic, or latitudinal segregation. The high incidence of triploids, most of which were self-compatible and highly fertile, may reflect genetic instability, underlying aneuploidy (which is common in several Chrysanthemum polyploids), or systematic bias from reference standard differences. Inconsistencies between flow cytometry estimates and observed reproductive compatibility, such as successful crossings with known diploids, suggest additional genomic complexity. Potential historical influences creating genomic instability, including environmental disturbances (chemical, radiation warfare remnants) from World War II military activities at Attu Island and Hudson Bay, are discussed. Conclusions: This study shows the challenges of accurately determining ploidy levels in the C. arcticum trifecta complex and highlights the need for other approaches, including high-density SNP genotyping and chromosome imaging, to resolve ploidy questions and guide future breeding strategies. Full article

Recombinogenic DNA damage can initiate chromosomal rearrangements that can alter gene expression or accelerate cancer progression in higher eukaryotes. Thus, there is a critical need to identify genes that suppress chromosomal rearrangements and environmental exposures that promote genetic instability. Cell cycle checkpoints modulate the cell cycle so that DNA repair occurs before the replication or segregation of damaged chromosomes. Saccharomyces cerevisiae (budding yeast) RAD9 was the first cell cycle checkpoint gene identified, which initiated intensive research studies into the mechanisms of checkpoint activation and the phenotypes of checkpoint mutants. The budding yeast Rad9 protein serves as both an adaptor and scaffold that facilitates downstream effector activation to orchestrate a DNA damage response at multiple stages of the cell cycle, which facilitates double-strand break (DSB) repair by sister chromatid recombination. However, the role of RAD9 in homologous recombination and in suppressing gross chromosomal rearrangements (GCRs) is not completely understood. In this review we discuss how RAD9 can promote genome instability resulting from aberrant DNA replication intermediates, while suppressing DSB-associated rearrangements. We also discuss possible mechanisms accounting for the synergistic increase in genomic instability in double mutants defective in both RAD9 and recombinational repair. We emphasize that while there is an overlap between checkpoint and recombinational repair pathways, RAD9 and checkpoint pathways can function independently to suppress chromosomal instability. These studies thus elucidate checkpoint mechanisms that control homologous recombination between repeated sequences. Full article

The retinoblastoma (RB) protein was the first tumor suppressor discovered and has been extensively studied for its canonical role in cell-cycle regulation. However, RB has broader noncanonical roles in DNA damage repair, chromosomal stability, apoptosis control, lineage commitment, cell differentiation and broad transcriptional regulation. Historically, RB inactivation has been associated with tumorigenesis, as well as resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), leading to its investigation as a potential predictive biomarker. However, clinical data have not demonstrated that RB function reliably predicts response to CDK4/6i consistently. These discrepancies highlight the need to reconsider RB’s role in therapeutic response, as RB loss can promote replication stress, induce chromosomal instability, and lead to transcriptional reprograming, potentially generating context-specific therapeutic vulnerabilities. In this review, we examine the multifaceted biology of RB and evaluate how its loss influences responses to chemotherapy and targeted therapies. We highlight emerging strategies that exploit RB-deficient states using rational monotherapy and combination approaches. Reframing RB dysfunction from a binary biomarker to a driver of exploitable cellular vulnerabilities may inform and expand precision oncology strategies for aggressive and treatment-resistant cancers. Full article

Early-onset colorectal cancer (EOCRC), defined as diagnosis before the age of 50 years, is increasing globally and is frequently characterized by aggressive biology and a disproportionate burden of liver metastases. This review synthesizes emerging evidence on the distinct molecular, immunologic and clinical features that differentiate EOCRC liver metastases from those arising in older adults. Genomic studies revealed increased chromosomal instability, increased copy number variation burden and unique amplification patterns involving MYC, RAD21, GNAS and MAPK1, alongside altered frequencies of classical driver mutations and increased germline predisposition. EOCRC liver metastases also exhibit a progenitor-like transcriptional state and an immune-cold microenvironment marked by reduced myeloid infiltration, impaired antigen presentation and profound resistance to immunotherapy, particularly in microsatellite-stable disease. Mechanistic insights into ferroptosis highlight therapeutic vulnerabilities, especially in PIK3CA-mutant tumors, where aspirin and ferroptosis inducers show synergistic potential. Clinically, high-risk EOCRC patients often present with left-sided primary tumors, synchronous metastases, adverse histology, elevated CEA levels and a hereditary predisposition, with prognostic models incorporating these variables outperforming traditional staging. Collectively, accumulating evidence suggests that EOCRC liver metastases may represent a biologically and clinically distinct entity, although ongoing debates regarding the extent of this distinction underscore the need for age-specific molecular profiling and prospectively validated therapeutic strategies. Full article

Background/Objectives: Insect-derived lipids are emerging as circular-economy feed ingredients, but their implementation in ruminant diets requires robust safety assessment beyond productive endpoints. This study evaluated genome integrity in 26 lactating Valdostana Red Pied cows fed concentrates containing either hydrogenated palm fat (HPF; n = 13) or black soldier fly oil (Hermetia illucens oil, HIO; n = 13) for 50 days. Methods: Peripheral blood lymphocytes were analyzed using Sister Chromatid Exchanges (SCE), reflecting replication-associated chromosomal instability, and the alkaline Comet assay, quantifying primary DNA damage at the single-cell level (Tail DNA and Olive tail moment) at T0 (the day before the start of the two experimental diets), T1 (30 d) and T2 (50 d). Results: Baseline SCE frequencies were comparable between groups. Over time, SCE values decreased in both groups, but a significant reduction occurred only in HIO at day 50, with lower SCE frequency than HPF (5.73 ± 0.11 vs. 6.29 ± 0.13; p = 0.002). Comet tail DNA showed a significant time effect (T0 vs. T1: mean difference = 179,846.6; p < 0.001; T0 vs. T2: mean difference = 138,395.2; p = 0.012), with diet-dependent modulation. In fact, in HIO, tail DNA decreased from 387,886 ± 94,606 (T0) to 147,006 ± 30,592 (T1; p < 0.001), remained lower at day 50 (155,723 ± 29,357; p = 0.024), and was lower than HPF at both T1 (p = 0.006) and T2 (p = 0.009). Olive tail moment also decreased over time (T0 vs. T1: mean difference = 1.925 × 10¹⁵; p = 0.008; T0 vs. T2: mean difference = 1.676 × 10¹⁵; p = 0.025), and it differed between diets at day 50 in favor of HIO (5.99 × 10¹⁵ ± 5.45 × 10¹⁴ vs. 7.26 × 10¹⁵ ± 5.98 × 10¹⁴; p = 0.017). Conclusions: Overall, no evidence of genotoxicity was observed in cows fed HIO; conversely, the results support compatibility with genome stability and suggest a modest time-dependent improvement detectable mainly after prolonged supplementation. Full article

Background/Objectives: Early embryonic arrest during the cleavage stage (days 2–4) accounts for a substantial proportion of developmental failure in in vitro fertilization. This phenomenon remains poorly understood at the molecular level, even in chromosomally normal embryos identified by preimplantation genetic testing. This review aims to redefine cleavage-stage arrest from a passive energy deficit to a checkpoint-regulated endpoint caused by inadequate coordination among metabolism, transcriptome integrity, and stress-response pathways. Methods: We integrate evidence from long-read transcriptomics, metabolomics, epigenetics, and immunobiology relevant to pre-blastocyst development. These data are assembled into a unifying mechanistic framework and a clinically oriented stratification model, together with candidate multimodal readouts for early classification. Results: We propose a three-axis model linking: (i) metabolic–epigenetic insufficiency, including defective histone lactylation and impaired alpha-ketoglutarate-dependent DNA demethylation; (ii) isoform-level abnormalities, including intron retention and retrotransposon activation within a hidden transcriptomic landscape better resolved by long-read sequencing; and (iii) stress-related immune signaling, in which NLRP7 links alternative splicing and DNA-damage-response dysfunction with mitochondrial stress and p53-associated arrest. Within this framework, we distinguish three molecular arrest states: an early transition failure marked by defective maternal-to-embryonic reprogramming and severe splicing disruption; a metabolically quiescent state that may retain a limited rescue window; and a later stress-associated state characterized by senescence-like features, oxidative stress, and broad transcriptomic and genomic instability. Conclusions: Early embryo arrest should no longer be viewed as a nonspecific developmental failure, but as a mechanistically stratifiable condition with distinct metabolic, transcriptomic, and stress-associated trajectories. A diagnostic platform combining fluorescence lifetime imaging microscopy, long-read sequencing, and digital polymerase chain reaction may improve early mechanistic classification, help identify embryos with possible reversibility, and reduce uncertainty in embryo selection during in vitro fertilization. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide and is characterized by high aggressiveness and therapeutic resistance, partly driven by mitotic dysregulation. Key mitotic regulators, including kinases such as PLK1, AURKA, AURKB, and MPS1 and kinesins such as CENPE and Eg5, are frequently overexpressed in NSCLC and SCLC, contributing to chromosomal instability, aneuploidy, and highly proliferative tumor phenotypes. Although multiple inhibitors targeting these proteins have been developed, their clinical efficacy as monotherapies has been limited. This is largely due to insufficient target dependency, adaptive resistance mechanisms, mitotic slippage, activation of compensatory pathways, and dose-limiting toxicity. This review integrates current knowledge on the physiological roles of major mitotic regulators, their dysregulation in lung tumorigenesis, and the biological and pharmacological barriers that underlie the limited success of antimitotic drugs. We further highlight preclinical and clinical evidence supporting rational combination strategies designed to enhance the antitumor activity of mitotic inhibitors while minimizing toxicity. Together, these insights underscore the need for refined therapeutic approaches that better exploit vulnerabilities in mitotic control to improve outcomes for patients with lung cancer. Full article

Hexavalent chromium [Cr(VI)] is a lung carcinogen. Central to its carcinogenic mechanism are Cr(VI)-induced DNA double strand breaks and chromosome instability. While breaks are usually repaired in healthy cells, Cr(VI) inhibits homologous recombination repair by targeting RAD51. RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) are responsible for RAD51 loading and the stabilization of nucleoprotein filaments necessary for DNA strand exchange and repair. This study aimed to investigate the effects of Cr(VI) exposure on RAD51 paralogs. WTHBF-6 cells, a human lung cell line, were exposed to various environmentally and occupationally relevant concentrations of zinc chromate for acute (24 h) and prolonged (120 h) exposure times. After exposure to Cr(VI), we collected RNA for sequencing and assessed the ability of DNA repair proteins to form foci using immunofluorescence. Protein levels were measured with western blotting, RNA-Seq was validated with RT-qPCR, and protein–protein interactions were assessed with the Proximity Ligation Assay (PLA) assay. Cr(VI) transcriptionally repressed all RAD51 paralogs. Further functional analyses showed that Cr(VI) inhibited the foci formation of RAD51D after acute and prolonged exposures and of XRCC2 and XRCC3 after prolonged exposure. Cr(VI) also inhibited overall RAD51D protein expression, as well as its interaction with RAD51. These findings suggest that Cr(VI) inhibits all RAD51 paralogs, but RAD51D might be an early target of Cr(VI), leading to the loss of RAD51 filament formation and function and the overall inhibition of homologous recombination repair. Full article

Background: Polyploid and chromosomal copy number gains (CNGs) cells may serve as key mediators of tumor plasticity, therapeutic resistance, and clonal evolution. Despite growing interest, their biological and clinical relevance in colorectal cancer, particularly in the metastatic setting, remains poorly defined. Methods: We performed an integrated morphological, cytogenetic, and genomic analysis of metastatic colon cancer. A tissue microarray comprising 100 tumors was evaluated, of which 47 cases were fully assessable for morphology and fluorescence in situ hybridization (FISH). Polyploid nuclei and chromosomal CNGs were assessed morphologically and cytogenetically. High-resolution targeted sequencing (TruSight Oncology 500) was conducted to characterize genomic alterations. Bioinformatic analyses included Gene Ontology enrichment and Phenolyzer network modeling. Associations with clinicopathological variables and survival outcomes were explored. Results: Polyploid nuclei and/or chromosomal CNGs were identified in approximately 25% of evaluable cases. These alterations were enriched in right-sided CRCs and in older patients, suggesting a link with age-related genomic instability. Polyploid/CNG tumors did not show significant enrichment for canonical CRC driver mutations (RAS, TP53, SMAD4), although trends toward co-occurrence with BRAF mutation and mutual exclusivity with HER2 amplification were observed. Integrative bioinformatic analyses highlighted dysregulation of pathways involved in mitotic control, centrosome organization, and DNA replication stress. Conclusions: In metastatic colon cancer, the presence of genome-wide copy number gain may delineate a tumor subset with distinctive clinicopathological and molecular characteristics. Further studies are warranted to elucidate the biological significance of these features and to explore their potential implications for tumor evolution, treatment response, and clinical stratification. Full article

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. Full article