The subventricular zone (SVZ) is a region surrounding the lateral ventricles that contains neural stem cells and neural progenitor cells, which can proliferate and differentiate into various neural and glial cells. SVZ cells play important roles in neurological diseases like neurodegeneration, neural injury, and glioblastoma multiforme. Investigating the anatomy, structure, composition, physiology, disease associations, and related mechanisms of SVZ is significant for neural stem cell therapy and treatment/prevention of neurological disorders. However, challenges remain regarding the mechanisms regulating SVZ cell proliferation, differentiation, and migration, delivering cells to damaged areas, and immune responses. In-depth studies of SVZ functions and related therapeutic developments may provide new insights and approaches for treating brain injuries and degenerative diseases, as well as a scientific basis for neural stem cell therapy. This review summarizes research findings on SVZ and neurological diseases to provide references for relevant therapies.

Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis. Recent advancements in bioinformatics have contributed to uncovering the genetic alterations that underlie the development and progression of GBM. Analysis of extensive genomic data led to the identification of significant pathways involved in GBM, such as the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling pathways, alongside key genes such as EGFR, TP53 and TERT. These findings have enhanced our understanding of GBM biology and led to the identification of new therapeutic targets. Bioinformatics has become an indispensable tool in pinpointing the genetic modifications that drive GBM, paving the way for innovative treatment strategies. This approach not only aids in comprehending the complexities of GBM but also holds promise for improving outcomes in patients suffering from this devastating disease. The ongoing integration of bioinformatics in GBM research continues to be vital for advancing therapeutic options.

Marred by a median survival of only around 12-15 months coupled with poor prognosis and effective therapeutic deprived drug armory, treatment/management of glioblastoma has proved to be a daunting task. Surgical resection, flanked by radiotherapy and chemotherapy with temozolomide, stands as the standard of care; however, this trimodal therapy often manifests limited efficacy due to the heterogeneous and highly infiltrative nature of GBM cells. In addition, the existence of the blood-brain barrier, tumor microenvironment, and the immunosuppressive nature of GBM, along with the encountered resistance of GBM cells towards conventional therapy, also hinders the therapeutic applications of chemotherapeutics in GBM. This review presents key insights into the molecular pathology of GBM, including genetic mutations, signaling pathways, and tumor microenvironment characteristics. Recent innovations such as immunotherapy, oncolytic viral therapies, vaccines, nanotechnology, electric field, and cancer neuroscience, as well as their clinical progress, have been covered. In addition, this compilation also encompasses a discussion on the role of personalized medicine in tailoring treatments based on individual tumor profiles, an approach that is gradually shifting the paradigm in GBM management. Endowed with the learnings imbibed from past failures coupled with the zeal to embrace novel/multidisciplinary approaches, researchers appear to be on the right track to pinpoint more effective and durable solutions in the context of GBM treatment.

This study aimed to determine the feasibility of preoperative multi-sequence magnetic resonance texture analysis (MRTA) for predicting TERT promoter mutation status in IDH-wildtype glioblastoma (IDHwt GB).

The clinical and imaging data of 111 patients with IDHwt GB at our hospital between November 2018 and June 2023 were retrospectively analyzed as the training set, and those of 23 patients with IDHwt GB between July 2023 and November 2023 were interpreted as the validation set. We used molecular sequencing results to classify the training set into TERT promoter mutation and wildtype groups. Textural features of the whole-tumor volume were extracted, including T2-weighted imaging (T2WI), T2-fluid-attenuated inversion recovery, apparent diffusion coefficient (ADC) map, and contrast-enhanced T1-weighted imaging (CE-T1). All textural features were obtained using open-source pyradiomics. After feature selection, logistic regression was used to build prediction models, and a nomogram was generated. Finally, the model was validated using validation cohort.

The CE-T1_Model (AUC 0.704) had a better predictive ability than the T2_Model (AUC 0.684) and ADC_Model (AUC 0.624). The MRI_Combined_Model (CE-T1, T2, and ADC texture features) (AUC 0.780) had a better predictive ability than the Clinical_Model (AUC 0.758). The Combined_Model (CE-T1, T2, ADC texture features, and clinical features) had the best predictive performance (AUC 0.871), with a sensitivity, specificity, and accuracy of 82.60 %, 83.30 %, and 80.18 %, respectively. The AUC, sensitivity, specificity, and accuracy in the validation cohort were 0.775, 86.70 %, 75.00 %, and 69.57 %, respectively.

Whole-tumor multi-sequence MRTA can be used as non-invasive quantitative parameters to assist in the preoperative clinical prediction of TERT promoter mutation status in IDHwt GB.

Malignant mesothelioma (MM) is a rare but aggressive cancer linked to asbestos exposure and characterized by advanced‑stage disease at presentation. Despite advances in treatment, prognosis remains abysmal, highlighting the imperative for the development of novel biomarkers and treatment approaches. Telomere biology plays a pivotal role in the tumorigenic process and has emerged as a key area in oncology research. Short telomeres have been associated with genomic instability, and substantially shorter telomere length (TL) has been identified in MM, showcasing the potential of TL in risk assessment, early detection, and disease progression monitoring. MM predominantly maintains TL through telomerase activity (TA), which in research has been identified in >90% of MM cases, underscoring the potential of TA as a biomarker in MM. Telomerase reverse transcriptase (TERT) polymorphisms may serve as valuable biomarkers, with research identifying associations between single nucleotide polymorphisms (SNPs) and the risk and prognosis of MM. Additionally, TERT promoter mutations have been associated with poor prognosis and advanced‑stage disease, with the non‑canonical functions of TERT hypothesized to contribute to the development of MM. TERT promoter mutations occur in ~12% of MM cases; C228T, C250T and A161C are the most common, while the distribution and frequency differ depending on histological subtype. Research reveals the promise of the various approaches therapeutically targeting telomerase, with favorable results in pre‑clinical models and inconclusive findings in clinical trials. The present review examines the role of telomere biology in MM and its implications in diagnosis, prognosis, and therapy.

Spontaneous regression of a neoplasm is a rare oncologic phenomenon. Certain neoplasms, such as melanomas and neuroblastomas, display this phenomenon. To date, spontaneous regression of oral cavity squamous cell carcinomas has been documented in only a handful of case reports. We present a novel case of spontaneous regression of an oral tongue squamous cell carcinoma following biopsy. We discuss the tumor's unique genetic profile, immune response to cancer, and review the literature on possible mechanisms of spontaneous regression. Small-volume persistent cancer in our patient reinforces that tissue confirmation remains crucial to avoid missing remaining tumor. Further investigation is required to understand mechanisms of spontaneous regression and how these may be exploited to improve head and neck squamous cell carcinoma treatment.

RNA interference (RNAi) represents a promising gene-specific therapy against tumors. However, its clinical translation is impeded by poor performance of lysosomal escape and tumor targeting. This challenge is especially prominent in glioblastoma (GBM) therapy, necessitating the penetration of the blood-brain barrier (BBB). Leveraging the intrinsic tumor-targeting and BBB traversing capability of human H-ferritin, we designed a series of ferritin variants with positively charged cavity and truncated carboxyl terminus, termed tHFn(+). These nanocarriers respond to weak acid and disassemble in endosomal compartments, exposing the internal positive charges to facilitate the lysosomal escape of loaded small interfering RNA (siRNA). Functioning as universal siRNA nanocarriers, tHFn(+) significantly enhanced the uptake of different siRNAs and suppressed gene expressions associated with GBM progression. Furthermore, tHFn(+) traversed the BBB and targeted glioma in vivo by binding to its receptors (e.g., transferrin receptor 1). tHFn(+)-delivered siRNAs exhibited exceptional therapeutic effects against glioma in vivo, advancing RNAi therapeutics beyond GBM for the treatment of various diseases.

The chromosome 5p15.33 region, which encodes telomerase reverse transcriptase (TERT), harbors multiple germline variants identified by genome-wide association studies (GWAS) as risk for some cancers but protective for others. Here, we characterize a variable number tandem repeat within TERT intron 6, VNTR6-1 (38-bp repeat unit), and detect a strong link between VNTR6-1 alleles (Short: 24-27 repeats, Long: 40.5-66.5 repeats) and GWAS signals rs2242652 and rs10069690 within TERT intron 4. Bioinformatics analyses reveal that rs10069690-T allele increases intron 4 retention while VNTR6-1-Long allele expands a polymorphic G-quadruplex (G4, 35-113 copies) within intron 6, with both variants contributing to variable TERT expression through alternative splicing and nonsense-mediated decay. In two cell lines, CRISPR/Cas9 deletion of VNTR6-1 increases the ratio of TERT-full-length (FL) to the alternative TERT-β isoform, promoting apoptosis and reducing cell proliferation. In contrast, treatment with G4-stabilizing ligands shifts splicing from TERT-FL to TERT-β isoform, implicating VNTR6-1 as a splicing switch. We associate the functional variants VNTR6-1, rs10069690, and their haplotypes with multi-cancer risk and age-related telomere shortening. By regulating TERT splicing, these variants may contribute to fine-tuning cellular longevity and replicative potential in the context of stress due to tissue-specific endogenous and exogenous exposures, thereby influencing the cancer risk conferred by this locus.

TERT promoter mutations are not infrequently encountered in thyroid carcinomas; however, it is unclear if additional molecular alterations may play a role in determining tumor behavior.

Fine-needle aspiration (FNA) specimens from 32 patients with TERT promoter mutations detected by ThyroSeq v3 from 4 institutions were included in the study. FNA diagnoses, molecular results, and surgical follow-up were retrospectively reviewed and analyzed.

There were 5 benign and 27 malignant neoplasms, including 7 high-grade thyroid carcinomas (HGCs) on histopathologic follow-up. Of 4 cases with an isolated TERT mutation, 3 (75%) cases were malignant. Of 17 cases harboring a co-occurring TERT mutation with 1 additional molecular alteration, 13 (76%) displayed malignancy on histopathologic follow-up. All 11 cases with TERT mutations plus 2 or more additional molecular alterations were malignant on follow-up. Furthermore, HGC was not seen in cases with an isolated TERT mutation, while 80% of cases harboring TERT mutations plus 3 additional molecular alterations showed HGC.

TERT promoter mutations are commonly associated with malignancy, particularly HGCs, when multiple co-occurring molecular alterations are present. However, TERT promoter mutations may occasionally be detected in benign thyroid neoplasms when encountered in isolation or with fewer than 2 additional molecular alterations.

Annotation of cis-regulatory elements that drive transcriptional dysregulation in cancer cells is critical to understanding tumor biology. Herein, we present matched chromatin accessibility (single-cell assay for transposase-accessible chromatin by sequencing [scATAC-seq]) and transcriptome (single-cell RNA sequencing [scRNA-seq]) profiles at single-cell resolution from human breast tumors and healthy mammary tissues processed immediately following surgical resection. We identify the most likely cell of origin for subtype-specific breast tumors and implement linear mixed-effects modeling to quantify associations between regulatory elements and gene expression in malignant versus normal cells. These data unveil cancer-specific regulatory elements and putative silencer-to-enhancer switching events in cells that lead to the upregulation of clinically relevant oncogenes. In addition, we generate matched scATAC-seq and scRNA-seq profiles for breast cancer cell lines, revealing a conserved oncogenic gene expression program between in vitro and in vivo cells. This work highlights the importance of non-coding regulatory mechanisms that underlie oncogenic processes and the ability of single-cell multi-omics to define the regulatory logic of cancer cells.

Myxoid liposarcomas (MLS) can exhibit a disseminated metastatic pattern, necessitating extensive diagnostics during follow-up. With no tumor markers available, early diagnosis of recurrences and tumor monitoring is difficult. The detection of circulating tumor DNA (ctDNA; liquid biopsy) in MLS with the characteristic translocations t(12;16) and t(12;22) can provide an additional diagnostic. However, due to the often very low tumor fraction, distinguishing actual tumor variants from sequencing artifacts remains a key challenge.

Using MLS as a model for translocation-driven tumors, this study evaluates a refined analytical approach for detecting both single nucleotide variants (SNVs) and structural variants (SVs) with the highest possible sensitivity and specificity. Different analysis pipelines using Unique Molecular Identifiers (UMIs) were compared in dilution series of tumor DNA from MLS patients (n = 11) and a cell line. The results were validated on plasma samples (n = 36) from two MLS patients and one patient with Synovial Sarcoma (SS).

In dilution series, the use of UMIs significantly reduced false positive events in SNV analysis while maintaining high sensitivity without significant differences. In SV analysis, the effect of UMIs was not consistently detectable, as some dilution series exhibited no false positive events even without UMI correction. Additional filter criteria further improved specificity without significantly compromising assay sensitivity. Validation on patient plasma samples confirmed these findings, demonstrating the advantages of the differentiated analytical approach.

By integrating a refined analytical approach for SNVs and SVs, we achieved reliable ctDNA detection that corresponded with the clinical course of the patients' disease. This method enables non-invasive tumor detection in translocation-driven tumors with low mutational burden and can easily be adapted into routine clinical diagnostics.

Head and neck squamous cell carcinomas (HNSCCs) represent a heterogeneous group of malignancies with multifactorial aetiologies. High-risk human papillomavirus (hrHPV) infections, particularly HPV16, and the dysregulation of telomerase activity, specifically through its catalytic subunit, telomerase reverse transcriptase (TERT) are among the key contributors to HNSCC development and progression. HPV promotes oncogenesis via the E6 and E7 oncoproteins, which inactivate tumour suppressors TP53 and RB1, leading to unchecked cellular proliferation. Concurrently, telomerase activation plays a critical role in HNSCC by maintaining telomere length, thus enabling cellular immortality, and facilitating tumour development and progression. The interplay between HPV and telomerase is significant; HPV oncoprotein E6 enhances telomerase activity through multiple regulatory mechanisms, including upregulating TERT expression. Beyond telomere maintenance, TERT influences signalling pathways, cellular metabolism, and the tumour microenvironment, contributing to aggressive tumour behaviour and poor prognosis. This review integrates the roles of HPV and telomerase in HNSCC, focusing on their molecular mechanisms and interactions that drive carcinogenesis and influence disease progression. Understanding the synergistic effects of HPV and TERT in HNSCC may be crucial for risk stratification, prognostic assessment, and the development of novel therapeutic strategies targeting these specific molecular pathways.

Telomerase reverse transcriptase (TERT), a critical player in cellular immortalization, has emerged as a focal point of investigation due to its frequent promoter mutations in various human malignancies. TERT promoter mutations exhibit a significant role in tumorigenesis, fostering unbridled cellular proliferation and survival. This comprehensive review delves into the landscape of TERT promoter mutations and their profound implications in cancer, particularly within the context of gliomas. This article meticulously examines the intricate interplay between TERT promoter mutations and the metastatic cascade, shedding light on their capacity to orchestrate invasive behavior in gliomas. Moreover, this review describes the recent trends in therapeutic targeting of the TERT and dissects the evolving landscape of drug resistance associated with TERT mutations, providing insights into potential therapeutic challenges. In addition, the diagnostic and prognostic implications of TERT promoter mutations in gliomas are scrutinized, unraveling their potential as robust biomarkers. It also discusses the recent advancements in molecular diagnostics, illustrating the promise of TERT mutations as diagnostic tools and prognostic indicators. This review collectively aims to contribute to a deeper understanding of TERT promoter mutations in gliomas, offering a foundation for future research endeavors and paving the way for innovative strategies in glioma management.

(1) Background/Objectives: Primary and secondary brain tumours often hold devastating prognoses and low survival rates despite the application of maximal neurosurgical resection, and state-of-the-art radiotherapy and chemotherapy. One limiting factor in their management is that several antineoplastic agents are unable to cross the blood-brain barrier (BBB) to reach the tumour microenvironment. Nanomedicine could hold the potential to become an effective means of drug delivery to overcome previous hurdles towards effective neuro-oncological treatments. (2) Methods: A scoping review following the PRISMA-ScR guidelines and checklist was conducted using key terms input into PubMed to find articles that reflect emerging trends in the utilisation of nanomedicine in drug delivery for primary and secondary brain tumours. (3) Results: The review highlights various strategies by which different nanoparticles can be exploited to bypass the BBB; we provide a synthesis of the literature on the ongoing contributions to therapeutic protocols based on chemotherapy, immunotherapy, focused ultrasound, radiotherapy/radiosurgery, and radio-immunotherapy. (4) Conclusions: The emerging trends summarised in this scoping review indicate encouraging advantageous properties of nanoparticles as potential effective drug delivery mechanisms; however, there are still nanotoxicity issues that largely remain to be addressed before the translation of these innovations from laboratory to clinical practice.

Telomeres and telomerase play crucial roles in the initiation and progression of cancer. As biomarkers, they aid in distinguishing benign from malignant tissues. Despite the promising therapeutic potential of targeting telomeres and telomerase for therapy, translating this concept from the laboratory to the clinic remains challenging. Many candidate drugs remain in the experimental stage, with only a few advancing to clinical trials. This review explores the relationship between telomeres, telomerase, and cancer, synthesizing their roles as biomarkers and reviewing the outcomes of completed trials. We propose that changes in telomere length and telomerase activity can be used to stratify cancer stages. Furthermore, we suggest that differential expression of telomere and telomerase components at the subcellular level holds promise as a biomarker. From a therapeutic standpoint, combining telomerase-targeted therapies with drugs that mitigate the adverse effects of telomerase inhibition may offer a viable strategy.

High telomerase activity has been detected in over 85 % of tumors, with the activation of hTERT being the most crucial mechanism for re-establishing telomerase activity. Activation of hTERT maintains telomere length in cells, enabling cancer cells to proliferate indefinitely. Nevertheless, the specific mechanism of telomerase activation in non-small cell lung cancer (NSCLC) remains unclear, and post-transcriptional regulation of hTERT could be a potential activation mechanism.

We explored the regulatory impact of CMSS1 on hTERT expression in NSCLC cells using several methods: Yeast three-hybrid system, Reporter gene assay, Western blot, RNA decay assay, and Telomere length measurement. Our analysis revealed significant overexpression of CMSS1 in NSCLC, which correlated with poor prognosis, as determined by bioinformatics and tissue microarray techniques. RNA sequencing analysis showed that CMSS1 knockdown influenced the adhesion capabilities of NSCLC cells. Additionally, potential interacting proteins with CMSS1 were identified through mass spectrometry and co-immunoprecipitation experiments.

We discovered that CMSS1 regulates hTERT expression in NSCLC cells by binding to the 5' UTR of hTERT mRNA, impacting its mRNA stability and thereby influencing NSCLC progression. RNA-Seq results and adhesion experiments indicated that CMSS1 knockdown disrupts cell adhesion. hTERT also affects cell adhesion in NSCLC, underscoring CMSS1's role as an upstream regulator of hTERT. Mass spectrometry and Co-IP studies suggest potential interactions between CMSS1, RBM34, and DDX5 that further modulate hTERT expression.

These findings indicate that CMSS1 plays a crucial role in NSCLC progression through its interaction with hTERT, making it a promising therapeutic target.

Glioblastoma is the most common primary brain tumor in adult patients, and despite standard-of-care treatment, median survival has remained less than two years. Advances in our understanding of molecular mutations have led to changes in the diagnostic criteria of glioblastoma, with the WHO classification integrating important mutations into the grading system in 2021. We sought to review the basics of the important genetic mutations associated with glioblastoma, including known mechanisms and roles in disease pathogenesis/treatment. We also examined new advances in image processing as well as less invasive and noninvasive diagnostic tools that can aid in the diagnosis and surveillance of those undergoing treatment for glioblastoma. Our review is intended to serve as an overview of the current state-of-the-art in the diagnosis and management of glioblastoma.

Apurinic/apyrimidinic (AP) sites are endogenous DNA lesions widespread in human cells. Having no nucleobases, they are noncoding and promutagenic. AP site repair is generally initiated through strand incision by AP endonuclease 1 (APE1). Although AP sites' repair in regular B-DNA has been studied extensively, their processing in G-quadruplexes (G4s) has received much less attention. Here, we used the hTERT promoter region that is capable of forming three stacked parallel G4s to understand how AP sites can influence higher-order quadruplex folding and stability and how a G4 affects the efficiency of human APE1-mediated AP site processing. We designed a series of synthetic single- and double-stranded DNA constructs of varying lengths containing a stable AP site analog in both G- and C-rich strands at positions corresponding to somatic driver mutations. Using circular dichroism, we studied the effect of the AP site on hTERT G4 structure and stability. Bio-layer interferometry and gel-based approaches were employed to characterize APE1 binding to the designed DNA substrates and AP site processing. It was shown that (i) an AP site leads to G4 destabilization, which depends on the lesion location in the G4 scaffold; (ii) APE1 binds tightly to hTERT G4 structure but exhibits greatly reduced cleavage activity at AP sites embedded in the quadruplex; and (iii) a clear correlation was revealed between AP site-induced hTERT G4 destabilization and APE1 activity. We can hypothesize that reduced repair of AP sites in the hTERT G4 is one of the reasons for the high mutation rate in this promoter region.

The 2021 WHO Classification of Central Nervous System Tumors introduces more molecular markers for glioma reclassification, including TERT promoter (TERTp) mutation as a key feature in glioblastoma diagnosis.

Given the changes in the entities included in each subtype under the new classification, this research investigated the distribution, prognostic value, and correlations with other molecular alterations of TERTp mutation in different subgroups under this latest classification.

All glioma patients admitted to Peking Union Medical College Hospital for surgical resection or biopsy from 2011 to 2022 were included. Samples were analyzed for TERTp mutation and 59 other gene alterations and chromosome copy number variations.

A total of 207 patients were included. The occurrence of TERTp mutations varied with percentages of 4.55%, 100%, and 77.92% in astrocytoma, oligodendroglioma, and glioblastoma, respectively. 65% of all adult-type glioma patients and 42.6% of IDH-wildtype histology grade 2 or 3 patients were TERTp-mutant. Survival analysis showed that TERTp mutation was a predictor of better prognosis in IDH-mutant grade 2 gliomas (median OS (mOS): not reached (NA) (95% CI: NA-NA) vs. 75.9 (95% CI: 55.4-NA) months, HR = 0.077 (95% CI: 0.01-0.64), p = 0.003), while poor OS was associated with all Grade 4 gliomas (mOS: 17.5 (95% CI: 12.6-24.2) vs. 40.5 (95% CI: 24.4-83.8) months, HR = 2.014 (95% CI: 1.17-3.47), p = 0.01) and all IDH-wildtype histology grade 2 or 3 gliomas (median OS: 12.6 (95% CI: 11-24.2) vs. 83.8 (95% CI: 35.2-NA) months, HR = 3.768 (95% CI: 1.83-7.78), p < 0.001). Moreover, TERTp mutation tended to co-occur with EGFR, KRAS, and MET in glioblastoma. In the IDH-mutant subgroup, it tended to co-occur with CIC and FUBP1 alterations, while being mutually exclusive with ATRX and TP53 alterations. These correlations may further refine prognostic predictions.

Aims of this study were to investigate the prevalence of TP53 and TERT mutations in Medullary Thyroid carcinoma (MTC) and their role in inducing aggressiveness in positive cases.

We performed a literature search in PubMed to identify studies investigating the prevalence of TERT and TP53 mutations in MTC. We also included data on MTC cases (n = 193) obtained at our center and unpublished. The in-silico pathogenicity of the TP53 mutations has been evaluated by predictor tools.

We identified a total of 25 and 11 published papers: all together 1280 cases have been investigated for the presence of TP53 mutations and 974 for TERT promoter mutation. Twenty-five out of 1280 (2%) cases had a TP53 mutation while only 3/974 MTC cases (0.3%) have been found to be positive for TERT promoter mutations. Among all, we identified 19 different TP53 mutations that in 12 cases were demonstrated to have an in silico predicted high pathogenic role and a high impact on protein function. Three non-sense and 4 probably not damaging mutations were also reported. The pathogenic role of the TERT promoter mutations has been previously in vitro determined. No correlation between TP53 and/or TERT mutations and aggressiveness of MTC has been demonstrated.

The prevalence of TP53 and TERT promoter mutations is very low in MTC. The reported mutations are pathogenic in the majority of cases. Because of their rarity it is not possible to clarify if they play or not a role in the pathogenesis and/or aggressiveness of this specific thyroid tumor.

Adult glioblastomas (GBMs) are associated with high recurrence and mortality. Personalized treatment based on molecular markers may help improve the prognosis. We aimed to evaluate whether apparent diffusion coefficient (ADC) histogram analysis can better predict MGMT and TERT molecular characteristics and to determine the prognostic relevance of genetic profile in patients with GBM.

MRI, clinical, and pathological data of 79 patients with GBM were retrospectively collected. The ADC values based on histogram analysis were described using 10th percentile (p10), 90th percentile (p90), mean, median, minimum, maximum, skewness, kurtosis, and entropy. The independent-sample t test, linear correlation analysis, receiver operating characteristics (ROC) curve analysis, Kaplan-Meier analysis, and Cox proportional hazard regression were performed.

MGMT promoter methylation and TERT promoter mutation were detected in 53.2% and 44.3% of GBM patients, respectively. The ADCp10 in MGMT promoter unmethylated group was significantly lower than that in the MGMT promoter methylated group (p = 0.005). There were significant differences in ADCmin, ADCp10, ADCmean, and entropy between TERT promoter mutant and wild-type groups. Entropy showed the best diagnostic performance in differentiating between positive and negative TERT groups (AUC = 0.722, p = 0.001). Overall survival (OS) showed a positive correlation with ADCmin. The TERT promoter mutation was the only independent prognostic factor for GBM.

ADC histogram analysis may be a potential noninvasive biomarker for differentiating MGMT and TERT molecular markers and providing prognostic information for GBM patients.

Telomerase reverse transcriptase gene promoter (TERT) mutations are biomarkers that predict survival and responses to immune checkpoint inhibitors in various malignancies. However, their prevalence and clinicopathologic characteristics in biliary tract carcinomas are largely unknown. We performed a comprehensive genomic profiling of formalin-fixed paraffin-embedded tumor tissue from 485 carcinomas, including intrahepatic (n = 220), perihilar (n = 54), distal biliary tract (n = 110), and gallbladder (n = 101) cancers, using next-generation sequencing. TERT mutations were observed in 50 out of 485 biliary tract cancers (10.3 %) consisting of 39 C228T (78.0 %) and 11 C250T (22.0 %) variants. Among the different anatomic locations, TERT mutations were most frequent in the gallbladder (20.8 %), followed by perihilar (9.3 %), intrahepatic (7.7 %), and distal bile ducts (6.4 %) (p < 0.01). Genetically, TERT mutations were significantly associated with TP53 mutations (p = 0.04), ERBB2 amplification (p < 0.01), and high tumor mutational burdens (TMB) (p < 0.01); moreover, they were negatively correlated with KRAS (p < 0.01), SMAD4 (p = 0.01), and PBRM1 mutations (p = 0.01). In addition, TERT mutations were associated with a poor progression-free survival (PFS, p = 0.01). Specifically, in cases of intrahepatic cholangiocarcinoma, TERT mutations were more frequent in patients with cirrhosis (p = 0.01), hepatitis B virus infection (p = 0.04), and advanced disease stages (p < 0.01). In gallbladder carcinoma, TERT mutations were also associated with poor PFS. In conclusion, TERT mutations in biliary tract carcinomas had unique clinicopathologic and genetic characteristics. Despite its poor PFS, the concomitant presence of ERBB2 amplification and a high TMB indicated a potential for targeted therapy and immunotherapy in this specific subtype.

Most cancers re-activate telomerase to maintain telomere length and thus acquire immortality. Activating telomerase promoter mutations are found in many cancers, including melanoma. However, it is unclear when and if telomerase is strictly required during tumorigenesis. We combined the telomerase mutant (tert-/-) with two established zebrafish melanoma models. We show that tert-/- melanomas initially develop with similar incidence and invasiveness to tert+/+ tumors. However, they eventually decline in growth and regress. Late tert-/- tumors exhibit reduced cell proliferation, increased apoptosis, and melanocyte differentiation. Notably, these tumors show enhanced immune cell infiltration and can resume growth when transplanted into immunocompromised hosts. We propose that telomerase is required for melanoma in zebrafish, albeit at later stages of progression, to sustain tumor growth while avoiding immune rejection and regression. Thus, the absence of telomerase restricts melanoma through tumor-autonomous mechanisms (cell-cycle arrest, apoptosis, and melanocyte differentiation) and a non-tumor-autonomous mechanism (immune rejection).

Gliomas are a heterogeneous group of brain tumors, among which the most aggressive subtype is glioblastoma, accounting for 60% of cases in adults. Available systemic treatment options are few and ineffective, so new approaches to therapies for glioblastoma are in high demand. In total, 131 patients with diffuse glioma were studied. Paired tumor–normal samples were sequenced on the Illumina platform; the panel included 812 genes associated with cancer development. Molecular profiles in clinically distinct groups were investigated. In low-grade glioma (LGG) patients (n = 18), the most common mutations were IDH1/2 (78%), ATRX (33%), TP53 (44%), PIK3CA (17%), and co-deletion 1p/19q (22%). In high-grade glioma (HGG) patients (n = 113), more frequently affected genes were CDKN2A/B (33%), TERTp (71%), PTEN (60%), TP53 (27%), and EGFR (40%). The independent predictors of better prognosis were tumor grade and IDH1/2 mutations. In IDH—wildtype glioblastoma patients, a history of other precedent cancer was associated with worse overall survival (OS), while re-operation and bevacizumab therapy increased OS. Also, among genetic alterations, TERTp mutation and PTEN deletion were markers of poor prognosis. Nine patients received molecular targeted therapy, and the results were evaluated. The search for molecular changes associated with tumor growth and progression is important for diagnosis and choice of therapy.

Cancer remains a leading cause of death worldwide and although prognosis and survivorship after therapy have improved significantly, current cancer treatments have long-term health consequences. For decades telomerase-mediated telomere maintenance has been an attractive anti-cancer therapeutic target due to its abundance and role in telomere maintenance, pathogenesis, and growth in neoplasms. Telomere maintenance-specific cancer therapies, however, are marred by off-target side effects that must be addressed before they reach clinical practice. Regular exercise training is associated with telomerase-mediated telomere maintenance in normal cells, which is associated with healthy aging. A single bout of endurance exercise training dynamically, but temporarily, increases TERT mRNA and telomerase activity, as well as several molecules that control genomic stability and telomere length (i.e., shelterin and TERRA). Considering the epidemiological findings and accumulating research highlighting that exercise significantly reduces the risk of many types of cancers and the anti-carcinogenic effects of exercise on tumor growth in vitro, investigating the governing molecular mechanisms of telomerase control in context with exercise and cancer may provide important new insights to explain these findings. Specifically, the molecular mechanisms controlling telomerase in both healthy cells and tumors after exercise could reveal novel therapeutic targets for tumor-specific telomere maintenance and offer important evidence that may refine current physical activity and exercise guidelines for all stages of cancer care.

Meningiomas are the most frequent brain tumors, typically benign and curable by surgery. However, some patients experience repeated recurrences from residual tumors. To address such cases, the development of novel therapeutic options is crucial. For this purpose, the availability of cell lines that possess the characteristics of benign meningiomas is essential. Here, we established a benign meningioma cell line under 3% O2 hypoxic conditions without the induction of immortalization genes. This cell line, named TKB-MEN2, has been stably grown for over two years with more than 20 passages. There were no hotspot telomerase reverse transcriptase (TERT) promoter mutations or cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) homozygous deletions, which are genetic features typical of malignant meningiomas. Cultured under hypoxic conditions, this cell line showed fewer characteristics of cellular senescence, such as morphological changes, IL-6 secretion, and lower senescence-associated b-galactosidase activity, compared to the same cell line cultured under 20% O2 conditions. This immortalized non-transgenic cell line appears to reflect the characteristics of a genuine benign meningioma, potentially allowing the identification of new therapeutic targets and the development of novel therapies for benign meningiomas.

Non-coding mutations in the TERT promoter (TERTp), typically at one of two bases -124 and -146 bp upstream of the start codon, are among the most prevalent driver mutations in human cancer. Several additional recurrent TERTp mutations have been reported but their functions and origins remain largely unexplained. Here, we show that atypical TERTp mutations arise secondary to canonical TERTp mutations in a two-step process. Canonical TERTp mutations create de novo binding sites for ETS family transcription factors that induce favourable conditions for DNA damage formation by UV light, thus creating a hotspot effect but only after a first mutational hit. In agreement, atypical TERTp mutations co-occur with canonical driver mutations in large cancer cohorts and arise subclonally specifically on the TERTp driver mutant chromosome homolog of melanoma cells treated with UV light in vitro. Our study gives an in-depth view of TERTp mutations in cancer and provides a mechanistic explanation for atypical TERTp mutations.

The screening of TERT promoter (TERTp) mutations is essential in cancer research and diagnostics, due to its prevalence in tumours associated with low self-renewal rates. TERTmonitor is a diagnosis kit primarily designed for real-time qPCR qualitative detection of -124C>T and -146C>T TERTp mutations, which are highly prevalent in several malignancies, particularly in bladder carcinoma.

This study aims to investigate TERTmonitor performance in droplet digital PCR (ddPCR) in urine samples from bladder cancer patients.

A total of 45 urine samples were examined by real-time qPCR and ddPCR techniques, and their performances were compared.

TERTmonitor had similar performance in both real-time qPCR and ddPCR platforms. Specifically, the methods exhibited a concordance rate of 95.45% and 90% for -124C>T and -146C>T mutations, respectively. Importantly, an enhanced sensitivity in certain scenarios was exhibited by ddPCR when compared to real-time qPCR, detecting mutations that the latter failed to identify in approximately 4.55% and 10% of the samples for -124C>T and -146C>T mutations, respectively. This enhanced sensitivity of ddPCR was particularly evident in samples with low-frequency mutations.

The findings highlight the usefulness of TERTmonitor for cancer surveillance either in real-time qPCR or ddPCR platforms.

In 2021, the World Health Organization classified isocitrate dehydrogenase (IDH) mutant gliomas as a distinct subgroup of tumors with genetic changes sufficient to enable a complete diagnosis. Patients with an IDH mutant glioma have improved survival which has been further enhanced by the advent of targeted therapies. IDH enzymes contribute to cellular metabolism, and mutations to specific catalytic residues result in the neomorphic production of D-2-hydroxyglutarate (D-2-HG). The accumulation of D-2-HG results in epigenetic alterations, oncogenesis and impacts the tumor microenvironment via immunological modulations. Here, we summarize the molecular, cellular, and clinical implications of IDH mutations in gliomas as well as current diagnostic techniques.

The transcriptional regulator ATRX, a genetic factor, is associated with a range of disabilities, including intellectual, hematopoietic, skeletal, facial, and urogenital disabilities. ATRX mutations substantially contribute to the pathogenesis of ATRX syndrome and are frequently detected in gliomas and many other cancers. These mutations disrupt the organization, subcellular localization, and transcriptional activity of ATRX, leading to chromosomal instability and affecting interactions with key regulatory proteins such as DAXX, EZH2, and TERRA. ATRX also functions as a transcriptional regulator involved in the pathogenesis of neuronal disorders and various diseases. In conclusion, ATRX is a central protein whose abnormalities lead to multiple diseases.

Diffuse gliomas in adults are highly infiltrative and largely incurable. Whole exome sequencing (WES) has been demonstrated very useful in genetic analysis. Here WES was performed to characterize genomic landscape of adult-type diffuse gliomas to discover the diagnostic, therapeutic and prognostic biomarkers. Somatic and germline variants of 66 patients with adult-type diffuse gliomas were detected by WES based on the next-generation sequencing. TCGA and CGGA datasets were included to analyze the integrated diagnosis and prognosis. Among 66 patients, the diagnosis of 9 cases was changed, in which 8 cases of astrocytoma were corrected into IDH-wildtype glioblastoma (GBM), and 1 oligodendroglioma without 1p/19q co-deletion into astrocytoma. The distribution of mutations including ATRX/TP53 differed in three cohorts. The genetic mutations in GBM mainly concentrated on the cell cycle, PI3K and RTK pathways. The mutational landscape of astrocytoma was more similar to that of GBM, with the highest frequency in germline variants. Patients with IDH-mutant astrocytoma harboring SNVs of PIK3CA and PIK3R1 showed a significantly worse overall survival (OS) than wild-type patients. AEBP1 amplification was associated with shorter OS in GBM. Our study suggests that clinical sequencing can recapitulate previous findings, which may provide a powerful approach to discover diagnostic, therapeutic and prognostic markers for precision medicine in adult-type diffuse gliomas.

Molecular profiling in upper tract urothelial carcinoma (UTUC) with synchronous or metachronous urothelial bladder cancer (UBC) is scarce. We intended to assess immunohistochemical (IHC) and genetic differences between UTUC-only and UTUC with synchronous or metachronous UBC (UTUC + UBC) and evaluate the effect of subsequent UBC on the outcome of UTUC patients stratified by luminal-basal subtypes.

A retrospective cohort of UTUC was divided into UTUC-only (n = 71) and UTUC + UBC (n = 43). IHC expression of cytokeratin 5/6 (CK5/6), CK20, GATA3, and p53 was evaluated to assess relevant subtypes. Genetic characterization comprised TERTp, FGFR3, RAS, and TP53 status. Kaplan-Meier and Cox regression analyses estimated the effect of clinicopathological variables and molecular profiles on progression-free survival (PFS) and overall survival (OS) of UTUC patients.

No meaningful differences were detected among both subgroups according to luminal-basal stratification and genetic analysis. UTUC + UBC was independently associated with a worse PFS when stratified by luminal-basal phenotype (HR 3.570, CI 95% 1.508-8.453, p = 0.004) but with no impact in OS (HR 1.279, CI 95% 0.513-3.190, p = 0.597).

This study reveals that both subgroups exhibited equivalent genomic features and luminal-basal subtypes. The involvement of the bladder relates to shorter PFS but does not seem to influence the survival outcome of UTUC, independently of the IHC phenotype.

Over 30,000 point mutations are associated with debilitating diseases, including many cancer types, underscoring a critical need for targeted genomic solutions. CRISPR base editors, like adenine base editors (ABEs) and cytosine base editors (CBEs), enable precise modifications by converting adenine to guanine and cytosine to thymine, respectively. Challenges in efficiency and safety concerns regarding viral vectors used in delivery limit the scope of base editing. This study introduces non-viral minicircles, bacterial-backbone-free plasmids, as a delivery vehicle for ABEs and CBEs. The research uses cells engineered with the "Gene On" (GO) reporter gene systems for tracking minicircle-delivered ABEs, CBEs, or Cas9 nickase (control), using green fluorescent protein (GFPGO), bioluminescence reporter firefly luciferase (LUCGO), or a highly sensitive Akaluciferase (AkalucGO) designed in this study. The results show that transfection of minicircles expressing CBE or ABE resulted in significantly higher GFP expression and luminescence signals over controls, with minicircles demonstrating the most substantial editing. This study presents minicircles as a new strategy for base editor delivery and develops an enhanced bioluminescence imaging reporter system for tracking ABE activity. Future studies aim to evaluate the use of minicircles in preclinical cancer models, facilitating potential clinical applications.

Telomerase is associated with cellular aging, and its presence limits cellular lifespan. Telomerase by preventing telomere shortening can extend the number of cell divisions for cancer cells. In adult pancreatic cells, telomeres gradually shorten, while in precancerous lesions of cancer, telomeres in cells are usually significantly shortened. At this time, telomerase is still in an inactive state, and it is not until before and after the onset of cancer that telomerase is reactivated, causing cancer cells to proliferate. Methylation of the telomerase reverse transcriptase (TERT) promoter and regulation of telomerase by lactate dehydrogenase B (LDHB) is the mechanism of telomerase reactivation in pancreatic cancer. Understanding the role of telomeres and telomerase in pancreatic cancer will help to diagnose and initiate targeted therapy as early as possible. This article reviews the role of telomeres and telomerase as biomarkers in the development of pancreatic cancer and the progress of research on telomeres and telomerase as targets for therapeutic intervention.