Search Results (187)

Background/Objectives: The base excision repair (BER) pathway repairs oxidative DNA damage, a common and detrimental form of damage to the genome. Although biochemical steps in BER have been well defined, little is understood about how the pathway is regulated. Such regulation is critical, as cells must respond rapidly to DNA damage while avoiding aberrant activation of repair proteins that can produce DNA damage as intermediates in the repair pathway. Indeed, overexpression of the human BER protein NTHL1, a DNA N-glycosylase, can cause genomic instability and early cellular hallmarks of cancer. Methods: We developed a Saccharomyces cerevisiae model to explore how overexpression of NTHL1 may impair cellular function. Results: Overexpression of Ntg1, the budding yeast orthologue of NTHL1, impairs cell growth. To dissect mechanisms underlying this growth defect, we overexpressed either wild-type Ntg1 or a catalytically inactive variant of Ntg1 (ntg1_catdead). Consistent with results obtained for NTHL1, both variants of Ntg1 impair cell growth, but only the wild-type protein causes accumulation of double-strand breaks and chromosome loss. We screened a panel of DNA repair mutants for resistance/sensitivity to overexpression of wild-type Ntg1 or ntg1_catdead. This analysis identified several cellular pathways that protect cells from Ntg1-induced damage, providing insight into the interplay between DNA repair pathways. Finally, we identified a link to SUMOylation and probed into how this post-translational modification could contribute to regulation of Ntg1 function. Conclusions: This study describes a budding yeast system to understand how cells regulate and respond to dysregulation of the BER pathway. Full article

Chromosomal instability (CIN) arising from mitotic errors is a hallmark of cancer progression, yet how specific spindle assembly factors are co-opted to support aggressive tumor phenotypes remains incompletely understood. Hepatoma Upregulated Protein (HURP/DLGAP5), a Ran-regulated microtubule-associated protein essential for kinetochore fiber stabilization and chromosome congression, is frequently overexpressed in aggressive cancers. Here, we investigated HURP’s role across a breast cancer metastatic gradient—immortalized MCF10A, the low-metastatic luminal T47D, and the highly metastatic triple-negative MDA-MB-231 cell lines—integrating quantitative spindle analysis, kinetochore tension measurements, spindle checkpoint profiling, migration dynamics, and three-dimensional spheroid modeling. We show that total HURP protein levels increase with metastatic potential, yet spindle-bound HURP is paradoxically reduced in MDA-MB-231 cells, indicating cytoplasmic mislocalization despite increased total protein levels. HURP silencing induced cell-line-specific defects: moderate disorganization and misorientation in MCF10A and T47D cells, but catastrophic spindle collapse, apoptosis, and G2/M arrest in MDA-MB-231 cells. Mechanistically, HURP depletion disrupted the spindle-associated levels and distributions of TPX2, Aurora-A, and NuMA in a subtype-dependent manner, implicating HURP as a context-dependent stabilizer of this mitotic regulatory axis. HURP loss reduced interkinetochore tension in all cell lines, but only MCF10A and T47D cells mounted a proportional BubR1-dependent checkpoint response; MDA-MB-231 cells showed reduced checkpoint signaling, consistent with constitutive spindle assembly checkpoint (SAC) attenuation in triple-negative breast cancer. Beyond mitosis, HURP depletion impaired collective migration and converted MDA-MB-231 cells from super-diffusive, amoeboid-like motility to sub-diffusive behavior, while minimally affecting the less aggressive cell lines. HURP-depleted MDA-MB-231 spheroids were significantly larger, less compact, and less spherical than controls, linking spindle regulation to tissue-level architectural coherence. These findings establish HURP as a multifunctional regulator coordinating mitotic fidelity, migration plasticity, and tumor architecture in breast cancer, with a selective dependency in highly metastatic cells, positioning it as a promising therapeutic target for aggressive breast cancers. Full article

Background/Objectives: Chromosomal microarray analysis (CMA) is an essential tool in modern cytogenetics for detecting copy number alterations and copy-neutral loss of heterozygosity (CN-LOH). As optical genome mapping (OGM) emerges as a potential replacement for traditional cytogenetic methods, the extent to which CMA remains necessary in routine diagnostic workflows remains to be elucidated. Methods: We retrospectively reviewed 53 primary neoplastic cases, selected from a larger cohort of 327 hematologic malignancy specimens, in which CMA identified one or more CN-LOH events. Event size, genomic content, and correlation with next-generation sequencing (NGS) findings were assessed. A separate cohort of newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL) was analyzed to evaluate disease-specific CN-LOH frequency. Results: Nearly half of CN-LOH events detected were <25 Mb, below the current detection threshold of OGM inferred from published benchmarks and validated workflows. Many encompassed clinically relevant genes, including FLT3, JAK2, TET2, TP53, and RUNX1. Additionally, two-thirds of cases harbored pathogenic or likely pathogenic variants by NGS within the corresponding CN-LOH regions, further underscoring the clinical value of detecting these copy-neutral events. In contrast, CN-LOH was uncommon in B-ALL, and most alterations identified by CMA would be detectable by OGM. Many of these patients also harbored complex structural rearrangements that required multiple conventional assays for full characterization; these could be resolved by OGM in a single analysis. Conclusions: Our findings indicate that although OGM excels at resolving complex structural variants, CMA remains essential for detecting copy-neutral events. Until OGM achieves improved sensitivity for CN-LOH, an integrated approach utilizing conventional cytogenetics, CMA, NGS, and OGM provides the most reliable framework for comprehensive genomic assessment across cancer types. Full article

Radiotherapy is a highly effective, safe cancer treatment, and about half of all cancer treatments involve lifesaving radiotherapy. Despite huge advances in technology that have made it safer and more effective, it is still not without side effects. They differ from patient to patient and can include fatigue, nausea, skin reactions, and hair loss, but dysbiosis is the most common complication associated with radiotherapy. Probiotics aimed at restoring the microbiome have found widespread use, but the problem of their rapid inactivation in the gastrointestinal tract has not yet been solved. Our study aims to confirm the effectiveness of a novel biomineral complex, based on a powdered clinoptilolite containing a rock loaded with lactobacilli for restoring the intestinal microbiome of mice exposed to radiation. Based on the 16S rRNA gene analysis, alpha-diversity and dynamics of changes in the fecal metagenome, as well as the functional potential of mice exposed to radiation, were studied, and the prospects of administering the biomineral complex to achieve positive effects were assessed. NMR analysis of the mineral carrier was carried out, and its safety was confirmed. Moreover, per os administration of the complex following irradiation led to a reduction in the level of chromosomal aberrations induced by irradiation. Thus, the biomineral complex has a microbiome-restoring effect and reduces radiation-induced clastogenesis. Full article

Background: Non-invasive prenatal testing (NIPT) examines cell-free DNA (cfDNA) in maternal serum, which includes both maternal DNA and apoptotic placental DNA. The presence of multiple aneuploidies or widespread abnormal patterns of gains and losses across chromosomes in a structurally normal fetus has been linked to maternal cancer. Case Presentation: The patient was a 22-year-old G1P0 with a history of classical Hodgkin’s lymphoma in remission. Her NIPT collected at 14 weeks and 3 days was reported as a “no call”. A second NIPT at a different laboratory showed multiple chromosomal aneuploidies (trisomy 18, 21, and monosomy X) with normal fetal anatomy on ultrasound. The patient was asymptomatic and was referred to hematology–oncology specifically to address the concern that these NIPT results could be related to cancer recurrence. Imaging was deferred as she was already on an established surveillance protocol for her Hodgkin’s lymphoma. At 26 weeks of gestation, the patient presented with a cough and dyspnea. Chest x-ray raised concern for disease recurrence, and biopsy confirmed recurrent Hodgkin’s lymphoma. She received two cycles of ICE chemotherapy. Cesarean delivery at 34 weeks and 2 days was performed for non-reassuring fetal heart tones. She continued chemotherapy, followed by BEAM conditioning and autologous stem cell transplantation. Genetic testing of the neonate revealed a normal karyotype; the placenta karyotype yielded no interpretable results. Discussion and Conclusions: Certain patterns of abnormal NIPT results may be associated with maternal malignancy and warrant further investigation. The absence of standardized protocols for reporting such NIPT results can complicate timely interdisciplinary evaluation and treatment. However, diagnostic testing should be offered with a positive NIPT result, a no-call or test failure, and abnormal ultrasound results, even with a “low-risk” NIPT result. Full article

The ubiquitously transcribed tetratricopeptide repeat Y-linked gene (UTY/KDM6C), a catalytically impaired histone demethylase encoded on the Y chromosome, has garnered increasing attention for its emerging roles in tumorigenesis and cancer progression. Despite high sequence homology with its X-linked paralog UTX/KDM6A, UTY exhibits markedly reduced or absent H3K27me3 demethylase activity due to critical amino acid substitutions in its Jumonji C domain. Consequently, UTY primarily functions through non-enzymatic mechanisms, acting as a scaffold in chromatin-remodelling complexes like COMPASS and SWI/SNF, or mediating protein–protein interactions that regulate transcriptional programs independent of demethylation. This aligns with epigenetic dysregulation in cancers, where imbalances in repressive H3K27me3 and active H3K4me either drive tumour suppressor silencing or oncogene activation. Unlike frequently mutated UTX in cancers such as breast, renal cell carcinoma, and acute myeloid leukaemia, UTY’s contributions in cancer are less defined, constrained by male-specific expression. Emerging evidence suggests UTY as a context-dependent tumour suppressor in AML and squamous-like pancreatic ductal adenocarcinoma. While direct functional validation remains limited in several cancer types, UTY is increasingly implicated as a potential tumour suppressor in haematological malignancies and prostate cancer. Therapeutically targeting UTY’s scaffold functions shows promise for male-specific cancers and merits future investigation. Full article

The taxane family of compounds, including paclitaxel, docetaxel (Taxotere), and cabazitaxel (Jevtana), are common drugs used in chemotherapy for the frontline treatment of most major types of cancer. Alopecia, the dramatic loss of hair, is a common side effect that became a symbol of the suffering of many cancer patients. Concerted efforts have been made to understand the mechanism of taxane toxicity to hair follicles and, thus, prevention methods. Taxanes act by stabilizing cellular microtubules, which consequently cause mitotic arrest and then failure, as microtubules play critical functions in chromosome segregation. Hair follicle matrix cells are highly proliferative and thus are exceedingly sensitive to taxanes. We review the cellular mechanism-based strategies under investigation to counter taxane-induced hair follicle damage. These include the application of cyclin kinase inhibitors to block mitotic entry, the practical method using scalp cooling to reduce exposure of scalp hair follicles to drugs during infusion, the requirement of p53 action for hair follicle damage, and the recently discovered method of using low-intensity ultrasound to break taxane-stabilized microtubules and thus reverse taxane toxicity in hair follicle matrix cells. The concept of low-intensity ultrasound as an antidote to taxanes may have the potential to provide a practical and compelling strategy to counter alopecia in cancer treatment using taxanes. Tweet: Taxanes (paclitaxel/docetaxel) are powerful microtubule-stabilizing cancer drugs, but they also cause adverse effects, including alopecia. New research discoveries of temporary microtubule disruption by low-intensity ultrasound may counteract taxane toxicity and prevent alopecia during cancer chemotherapy. “Mechanistic-based strategies for the prevention of taxane-induced hair follicle damage in cancer chemotherapy” OUTLINE: 1. Taxane/paclitaxel mechanism of action in cancer therapy. 2. Taxane side effects: Alopecia (hair loss). 3. p53 dependence of taxane-induced hair follicle damage. 4. Research efforts to counter taxane -induced alopecia by CDK4/6i. 5. Prevention of taxane chemotherapy side effects using scalp cooling. 6. Discovery of low-intensity ultrasound as an antidote for taxane cytotoxicity, and potential prevention of alopecia in chemotherapy using taxanes. 7. Summary and prospective. 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

Background: Deletion of the MTAP gene at chromosome 9p21.3 defines a therapeutically actionable molecular subset of cancers due to synthetic lethal vulnerability to PRMT5 and MAT2A inhibition. The real-world prevalence and genomic context of MTAP deletion in diverse solid tumors remain incompletely characterized. Methods: We retrospectively analyzed 579 solid tumor specimens subjected to next-generation sequencing-based copy-number profiling. The prevalence of MTAP deletion and its co-occurrence with CDKN2A and CDKN2B were evaluated, and genomic deletion patterns across chromosome 9 were systematically assessed. Results: MTAP deletion was detected in 14 cases (2.4%, 95% confidence interval [CI], 1.45–4.02%), with enrichment in sarcoma, pancreatic cancer, and urothelial carcinoma. Concurrent CDKN2A loss was observed in 92.9% of MTAP-deleted tumors, and 64.3% showed additional CDKN2B loss, indicating a coordinated focal deletion event at 9p21.3. Statistical analyses confirmed strong genomic associations between MTAP and neighboring tumor suppressor genes. Across the full cohort, deletion frequency peaked at the 9p21 locus, and among MTAP-deleted tumors, co-deletion frequency decreased with increasing genomic distance. All MTAP-deleted tumors were microsatellite stable and low tumor mutational burden (TMB-low). Conclusions: Our findings demonstrate that MTAP deletion is an infrequent but genomically coherent event in solid tumors, characterized by a canonical 9p21 co-deletion pattern. This real-world analysis underscores the importance of comprehensive genomic profiling to identify patients who may benefit from emerging MTAP-directed therapies. Full article

Triple-negative breast cancer (TNBC), particularly the androgen receptor-low (AR-low) subtype, is one of the most aggressive and hard-to-treat forms of BC, characterized by a high index of proliferation, chromosomal instability (CIN), and high prevalence of TP53 mutations. These features fuel therapy resistance, metastases, and poor clinical outcomes. An integrated framework describing the dysregulated molecular networks that support the pathobiology of AR-low TNBC is lacking. Multiple published studies in breast cancer have previously proposed mechanistic links between TP53 loss, AR-low states, and heightened FOXM1-driven G2/M transcriptional programs, potentially via deregulation of E2F activity, chromatin-associated co-regulators (e.g., ATAD2), and disruption of repressive networks involving p53–p21–DREAM and SPDEF. Additional reports suggest that FOXM1-associated circuitry may be reinforced by chromatin regulators such as WDR5 and by mitotic/spindle factors such as ASPM, including through feedback interactions and condensate-associated transcriptional organization. We previously showed that FOXM1, a master regulator transcription factor, is upregulated and is a biomarker of poor prognosis in AR-low TNBC. In this study, we filtered a set of “TNBC core genes” known to promote transcriptional chaos downstream of FoxM1. We identified a set of 15 cell cycle regulators—including mitotic kinesin motors (KIF14, KIF11, KIF4A, KIF2C, and KIF20A), centromeric proteins (CENPA, CENPO, CENPL, CENPF, and OIP5), and regulators of proteolysis (UBE2C, UBE2S, UBE2T, PSMD14, and TUBA1B). These 15 genes, which were ranked highly among genes overexpressed in TNBC featured prominently in gene signatures of chromosomal instability and were also overexpressed among AR-low TNBCs and TP53-mutant breast tumors. We show that expression of each of these 15 genes correlates positively with proliferation markers (Ki67, PCNA, and MCM2) in TNBC, and that the overexpression of this gene set is associated with shorter relapse-free survival and distinct immune/stromal infiltration patterns. In light of prior work, our findings point to a FOXM1-associated 15-gene signature enriched in AR-low TNBC and associated with the high-proliferation and high-CIN phenotypes of this clinically challenging tumor type. This 15-gene set represents an actionable vulnerability with therapeutic potential for AR-low TNBC and provides a framework for rethinking how to manage highly proliferative, genomically unstable BCs. Full article

Xeroderma Pigmentosum group C (XP-C) is an autosomal recessive disorder caused by mutations in the XPC gene, leading to defective nucleotide excision repair. This defect leads to genomic instability and a profound cancer predisposition. To model this disease, we generated induced pluripotent stem cells (iPSCs) from an XP-C patient carrying a novel homozygous nonsense mutation in the XPC gene (c.1830C>A). The resulting iPSCs demonstrated typical pluripotent characteristics, including expression of key markers and trilineage differentiation capability. However, genomic assessment revealed progressive karyotypic instability during extended culture. While initial whole-genome sequencing detected no major chromosomal abnormalities, subsequent G-banding analysis identified acquired trisomy 12 in two lines (CL12 and CL27) and a derivative X chromosome in a third line (CL30). These abnormalities were absent in early-passage analyses, indicating that they were acquired and selected for during extended culture. The acquisition of a derivative X chromosome in CL30, alongside recurrent trisomy 12, represents a unique cytogenetic signature likely attributable to the underlying XPC defect. We hypothesize that the loss of GG-NER creates a permissive genomic environment, accelerating the accumulation of DNA damage and chromosomal missegregation under replicative stress. This temporal divergence in genomic integrity highlights how culture pressures drive chromosomal evolution in XP-C iPSCs independently of initial reprogramming. Our findings emphasize that XP-C iPSCs require continuous genomic surveillance and provide a model for investigating how DNA repair deficiencies interact with in vitro culture stress. Full article

The MTAP (methylthioadenosine phosphorylase) gene, located on chromosome 9p21, plays a crucial role in the methionine salvage pathway and is frequently co-deleted with CDKN2A in various malignancies. Loss of MTAP expression leads to the accumulation of methylthioadenosine (MTA), which selectively inhibits protein arginine methyltransferase 5 (PRMT5) and creates a unique metabolic vulnerability in MTAP-deficient tumors. These alterations have emerged as promising therapeutic targets in precision oncology. Recent advances highlight the potential of exploiting MTAP loss through synthetic lethality approaches using PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibitors. Preclinical and early clinical data indicate that targeting these pathways can selectively impair tumor growth while sparing MTAP-proficient cells. Moreover, MTAP deletion has been associated with specific molecular and immunologic profiles that may influence treatment response and tumor microenvironment characteristics. This review summarizes current knowledge on the biological functions of MTAP, the mechanisms linking its loss to oncogenesis, and the evolving landscape of therapeutic strategies targeting MTAP-deficient cancers. Understanding these molecular dependencies offers novel opportunities for the development of precision-based therapies across diverse tumor types. Full article

Vasculogenic mimicry is the capacity of growing cancer cells to overcome the lack of normal capillaries and hypoxia by forming networks of sinuses lacking endothelial cells. The formation of vasculogenic mimicry by melanoma cells is coupled with the upregulation of the genes involved in ribosome biogenesis, the downregulation of hundreds of developmental genes, and strong changes in the inter-chromosomal contacts of developmental genes with rDNA clusters. The epigenetic mechanism driving the regulatory role of inter-chromosomal contacts of genes with nucleoli is not yet known. This study aimed to determine whether these contacts are associated with either the silencing or the activation of the expression of developmental genes. Here, two different sets of developmental genes are subjected to silencing either by increasing or decreasing their contacts with nucleoli. Our data indicate that one set of developmental genes mainly associated with system development is silenced by the contacts, while another set of genes involved mainly in the generation of neurons is silenced by the loss of contacts with the nucleoli. We conclude that mechanisms of silencing of these sets of developmental genes lead to the loss of the established differentiated state of melanoma cells and to the formation of more aggressive cancer cells. The data also indicate the important role of the nucleoli in the global regulation of gene expression during differentiation and cancer. Full article

Colorectal cancer (CRC) remains one of the most prevalent and lethal malignancies. Accumulating genetic evidence supports a multistep model of tumor progression, in which early APC loss leads to chromosomal instability and adenoma formation, followed by activating mutations in KRAS that synergize with β-catenin signaling to promote tumor growth and invasion. Among the downstream effectors of these pathways, the Notch ligand Jagged1 has emerged as a critical mediator of CRC progression and chemoresistance. Jagged1 is not only a transcriptional target of the Wnt/β-catenin axis but also undergoes proteolytic cleavage via the KRAS/ERK/ADAM17 signaling cascade, generating a nuclear Jagged1 intracellular domain (Jag1-ICD) that drives reverse signaling. This dual functionality, activating canonical Notch signaling and initiating reverse nuclear signaling, positions Jagged1 as a key oncogenic driver in CRC. In this review, we first summarize the role of Jagged1 as an integral part of canonical Notch signaling. We then focus on the non-canonical Jagged1 reverse signaling function in cancer, with a particular emphasis on CRC. We underscore the dual role of Jagged1 in tumor biology and propose that it functions as a novel oncogene within the adenoma-to-carcinoma sequence, supporting CRC development and drug resistance via non-canonical mechanisms. Full article

Telomere maintenance enables unlimited cell proliferation by counteracting telomere erosion. While the majority of tumors activate telomerase, a significant subset—approximately 10–15%—utilizes alternative lengthening of telomeres (ALT), a recombination-based mechanism. ALT-positive cancers are classically associated with genomic instability, anaphase bridges, chromosomal rearrangements, and resistance to DNA-damaging therapies. This process is closely associated with genetic instability, which contributes to chromosomal rearrangements and tumor evolution. Consequently, ALT has traditionally been considered an adverse prognostic marker in aggressive malignancies such as osteosarcoma, pancreatic neuroendocrine tumors, and high-grade sarcomas. Paradoxically, recent evidence demonstrates that ALT positivity correlates with improved survival in glioblastoma (GBM) and chondrosarcoma, two tumor types that have historically been regarded as immune-cold and therapeutically intractable. This favorable outcome likely reflects a convergence of factors, including replication stress and DNA damage that impose a fitness cost in slow-growing or metabolically constrained tumors. Loss of ATRX/DAXX, while enabling ALT, further amplifies chromatin fragility, and ALT-mediated instability may paradoxically enhance immunogenicity within immune-quiescent microenvironments. Moreover, ALT-positive cells exhibit unique therapeutic vulnerabilities, particularly to ATR and PARP inhibitors. Together, these observations support a context-dependent model in which ALT functions as a double-edged sword, acting as a driver of malignant aggressiveness in rapidly proliferating cancers while serving as a relative liability in slower-growing, immune-cold tumors. Understanding this duality not only refines prognostic stratification but also opens opportunities for precision oncology. By integrating ALT-specific biomarkers into clinical workflows and exploiting ALT-related DNA repair dependencies, clinicians may transform a once uniformly negative prognostic factor into an actionable therapeutic target. Full article