Citations

Abstract Background: Alternative lengthening of telomeres (ALT) is common in isocitrate dehydrogenase (IDH) mutant astrocytomas, but how telomere length variability contributes to genome instability remains unclear. We hypothesized that chromosome arm–specific telomere heterogeneity underlies distinct patterns of somatic structural variation (SV), copy-number alteration (CNA), and extrachromosomal DNA (ecDNA) formation. Methods: Oxford Nanopore long-read whole-genome sequencing (∼20–40x coverage) was performed in a clinical cohort of n = 20 IDH-mutant astrocytomas. Somatic SVs were called with Severus and filtered to a high-confidence tumor-specific set. CNAs were inferred by read-depth segmentation (DNAcopy) and further refined using a long-read CNA framework (Wakhan). Chromosome arm–specific telomere length was estimated with Telogator, and SV breakpoints were annotated for enrichment near subtelomeric and pericentromeric regions. Associations between arm-level telomere length and SV/CNA features (rate and proportion) were tested using linear mixed-effects models with patient as a random effect. High-level amplification regions were defined directly from CNA segments with high copy number, and ecDNA-like circular amplicons were subsequently reconstructed from amplified intervals using Decoil. Results: IDH-mutant astrocytomas displayed pronounced SV heterogeneity, with complex breakends (BNDs) dominating the somatic SV landscape. SVs were spatially patterned, as deletions and insertions preferentially accumulated near subtelomeric and pericentromeric domains, implicating chromosome ends and repeat-rich regions as recurrent substrates for rearrangement. At the tumor level, markedly shortened telomeres were associated with increased SV burden and CNA burden, consistent with telomere attrition as a correlate of genome-wide structural instability in highly rearranged genomes. At higher resolution, telomere length varied substantially across chromosome arms and classified distinct structural outcomes: arms with shorter telomeres were enriched for complex insertional SVs, whereas arms with relatively elongated telomeres more frequently carried focal high-level amplifications and ecDNA-like circular amplicons. Conclusions: These findings reveal a link between arm-specific telomere heterogeneity and the emergence of structural and amplification architectures in IDH-mutant astrocytomas. Telomere remodeling may influence where rearrangements and ecDNA structures arise, offering potential biomarkers of genome instability and tumor evolution. Generative AI was used to improve language clarity; all content was verified by the authors. Citation Format: Maryam Jehangir, Kristen Drucker, T. Rhyker Ranallo-Benavidez, Thomas M. Kollmeyer, Ayse Keskus, Daniel Lachance, Jeanette E. Eckel-Passow, Ofer Shoshani, Mikhail Kolmogorov, Robert B. Jenkins, Floris P. Barthel. Telomere length heterogeneity shapes structural and amplification landscapes in IDH-mutant astrocytoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr PR009.

Abstract Pediatric high-grade gliomas (pHGG) are aggressive primary brain neoplasms with a dismal prognosis, making them the leading cause of brain tumor-related deaths in children. pHGGs occur in specific anatomical locations at specific ages underscoring their origin in neurodevelopment and the critical importance of the brain tumor microenvironment. Many pHGGs originate from oligodendroglial precursor cells (OPC) and, like OPCs, neuronal activity promotes pHGG proliferation. Neuronal activity drives pHGG growth through the secretion of activity-regulated mitogens and electrochemical communication with pHGG cells that integrate into neural circuits. In turn, pHGG increases neuronal excitability and remodels functional neural circuits. The interconnected network of glioma cells and neurons is fundamental to pHGG progression. We developed a two-color in vivo imaging method to study neuron-glioma cell interactions over time in freely behaving mice enabling us to record the frequency, pattern, and synchronicity of calcium transients in neurons, glioma cells, and their coactivity, giving us a comprehensive view of the changes in neuron-glioma circuit dynamics over time. Our imaging paradigm offers a unique ability to study neuron-glioma interactions at the systems level. We have observed increasing neuronal activity and synchronicity throughout the disease. We have also observed that different gliomas exhibit unique patterns of calcium transients and show increased levels of activity and synchronicity as the tumor progresses. We verified our findings through longitudinal in vivo local field potential recordings, finding an increase in all power bands, especially in high-gamma activity over time. Using single nuclei RNA sequencing of mice harboring murine H3K27M-­altered DMG, we observed gene expression changes indicating an increase in synaptogenesis and axonogenesis processes in glioma-associated neurons. Performing in vitro neurite outgrowth assays, we observed increased axonogenesis in hiPSC-derived neurons in the presence of pHGGs compared to other neurons, confirming our snRNA-seq findings. Based on this data, we hypothesize that as gliomas progress, the neuron-glioma malignant circuitry evolves through synaptogenesis and axonogenesis to promote glioma progression.

Abstract Diffuse hemispheric glioma, H3 G34‐mutant (DHG‐H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high‐resolution copy number profiling of a series of 60 DHG‐H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187‐gene mutation and fusion targeted neuro‐oncology next‐generation sequencing panel ( n = 60) and Oncoscan chromosomal microarray ( n = 26) by a single laboratory (2018–2022). A subset of cases had immunohistochemical results for OLIG2 ( n = 42), p53 ( n = 48), and ATRX ( n = 46), and methylation array data ( n = 8). Median age at testing was 21 years (range, 12–50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3‐3A G34 mutations included G34R ( n = 56; 94%), G34V ( n = 3), and a non‐canonical G34E ( n = 1). Concurrent mutations most often involved TP53 ( n = 55; 92%), ATRX ( n = 50; 83%), and PDGFRA ( n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy‐neutral loss of heterozygosity (cnLOH) encompassing TP53 . This copy number profile was reminiscent of that seen in Grade 4 IDH‐mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high‐resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG‐H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH—a copy number abnormality that has been largely unrecognized—for this new 2021 World Health Organization central nervous system tumor type.

Abstract Background Common genetic variation has been linked to an increased risk of developing dilated cardiomyopathy (DCM) in case-control studies. However, the phenotypic profile and biological mechanisms by which genetic background may predispose individuals to DCM and outcomes in the general population remain unclear. Aim The primary objectives of this study were twofold: (1) to validate a DCM polygenic score (PRS-1) based on a prior meta-analysis of case–control genetic association studies [Tadros R et al. Nat Genet (2021)]; and (2) To apply this PRS, along with two recently developed PRSs for DCM [PRS-2 from Zheng SL et al. Nat Genet (2024) and PRS-3 from Jurgens SJ et al. Nat Genet (2024)] to a general population that underwent comprehensive longitudinal phenotypic assessments and had long-term outcomes available. Methods While the PRS-1 was derived from only 13 SNPs, PRS-2 and PRS-3 were generated from 709,534 and 1,072,247 SNPs, respectively with significant overlap between them. These DCM-PRSs were applied to an unselected community-based cohort (n=1897) aged >45 years, who underwent a physical examination, echocardiogram, and blood sample at baseline. Subsequent clinical outcomes were collected over a median 16 year follow-up (IQR: 15-17). Results No significant differences between the quartiles were present in terms of age, sex (48% male), and cardiovascular risk factors (CV-RF) (such as hypertension, diabetes, and coronary artery disease). However, linear regression models demonstrated a significant correlation between all DCM-PRSs and left ventricular (LV) parameters, including LV ejection fraction, LV end-systolic diameter, and LV end-diastolic diameter (Table). Multivariable regression analysis confirmed that these correlations were independent of age, sex, CV-RF, and population stratification (adjusted for the first 10 principal components [PCs]). During follow-up, 47 individuals developed DCM. A logistic regression analysis, using a 3:1 matched cohort of non-DCM vs. DCM individuals based on age and sex and adjusted for the same 10 PCs, found a significant correlation between DCM development and both PRS-1 [OR=2.27 (1.06–4.85), p=0.03] and PRS-3 [OR=2.63 (1.20–5.75), p=0.02], while PRS-2 did not show a significant association [OR=1.85 (0.84–4.06), p=0.12]. No association was found between the DCM-PRSs and heart failure (HF) biomarkers (aldosterone, natriuretic peptides, ST2, Galectin-3) or HF outcomes (all-cause mortality/HF hospitalization). Conclusion PRS-1 for DCM despite being derived from only 13 risk alleles, performs at least as well as the newer and more extensive PRSs, in its correlation with LV function, dimensions, and DCM development (except for PRS-2) in a general population. The absence of correlation between these DCM-PRSs and the renin-angiotensin-aldosterone system or natriuretic peptides suggests that genetic background influences LV traits through mechanisms independent of these biological pathways.

Abstract In adult-type diffuse gliomas CDKN2A and/or CDKN2B (CDKN2A/B) deletions often co-occur with deletion of MTAP, suggesting that MTAP immunohistochemistry (IHC) may be a surrogate marker of CDKN2A/B status. However, the association between CDKN2A/B and MTAP deletion at the genomic level remains unknown. We assessed CDKN2A/B and MTAP deletions by chromosomal microarray in 333 adult-type diffuse gliomas and performed MTAP IHC on a subset (n = 63). CDKN2A/B and MTAP deletions were detected in 216 and 215 cases, respectively, and were concurrent in 99.5% (215/216). While most tumors with CDKN2A/B homozygous deletion (n = 148) showed concurrent MTAP homozygous deletion (108/148; 73.0%), a subset harbored MTAP heterozygous deletion (39/148; 26.4%). By analyzing the size of the chromosomal alterations, we demonstrate that initial large chromosomal 9p losses result in concurrent heterozygous deletion of CDKN2A/B and MTAP whereas smaller “second hit” deletions leading to homozygous CDKN2A/B deletion do not always encompass the MTAP locus. Discordant CDKN2A/B and MTAP tumors affect the association between MTAP IHC and copy number status of MTAP and CDKN2A/B. These findings suggest that adult-type diffuse gliomas, regardless of IDH status, follow a stereotypic pathway involving concurrent CDKN2A/B and MTAP heterozygous deletion but may diverge for CDKN2A/B and MTAP homozygous deletion.

This study uncovers a previously unrecognized role for NAV3 in TGF-β1-driven cardiac fibroblast activation. We show that NAV3 facilitates profibrotic remodeling through noncanonical signaling and cell cycle arrest, independently of SMAD2/3. These findings position NAV3 as a novel regulator of fibroblast phenotype and a potential modulator of cardiac fibrosis.

Abstract Background Current literature suggestsisocitrate dehydrogenase (IDH)-mutant astrocytoma contains several molecular subgroups. In this study, we are interested in determining the connection between different molecular subgroups with grade and/or survival. Methods A cohort of 470 Mayo Clinic adult patients (≥18 years, 56.2% male) with primary IDH-mutant astrocytoma diagnosed by World Health Organization (WHO) 2021 criteria were examined. Results were validated in an independent cohort of 614 Mayo Clinic Neuropathology consult patients and 235 The Cancer Genome Atlas (TCGA) patients. Results The Mayo Clinic Practice cohort confirmed the association of CDKN2A/B deletion with overall survival (OS, homozygous vs hemizygous vs intact, 2.7 vs 9.6 vs 17.2 years, P < .001). Phosphatase and tensin homolog (PTEN) deletion was also associated with poor OS (7.3 vs 17.4 years, P < .001). Increased number of copy number alterations was associated with OS (continuous variable, HR = 1.027, P < .001). Carrying one or more copies of the germline risk allele at rs55705857 was associated with earlier age of onset (median age 33 vs 35 years, P = .01), and a shorter OS after adjusting for age, grade, sex and treatment (HR = 1.81, P = .007). The Mayo Clinic Neuropathology Consult cohort and TCGA were utilized to validate age of onset and survival, respectively. Unsupervised clustering of the copy number alterations identified several clinically significant groups that may define pathways to disease progression. Losses of chromosomes 11p, 13q, 1p, and 10q were all associated with reduced overall survival in the Mayo Clinic cohort. Conclusions Patients with hemizygous loss of CDKN2A/B, loss of PTEN, increased number of copy number alterations, specific chromosomal arm losses or rs55705857 germline risk allele have reduced overall survival.

Abstract Background To date, no scoring system has adequately defined clinical efficacy of erectile dysfunction (ED) therapies when evaluating differences between cohorts or in meta-analytic studies. Aim To outline the minimal criteria required for any therapy to be considered clinically effective in the treatment of ED. Methods An analytic review was performed of standardized ED questionnaires, with a particular emphasis placed on the International Index of Erectile Function, Erectile Function Domain (IIEF-EFD), and the minimally clinically important difference (MCID) concept. The data were used to create a societal position statement and recommendations on best practices within clinical trials to determine treatment efficacy. Outcomes The SMSNA provided 6 key statements and recommendations to suggest best practices and define minimal thresholds for improvements required for an ED therapy to be considered clinically effective. Results The IIEF-EFD currently represents the preferred standardized questionnaire to evaluate for changes in erectile function post-treatment and is the only questionnaire adequate to assess primary outcomes. To claim efficacy, investigational treatments must demonstrate MCID between cohorts (eg, 2-, 5-, or 7-point median improvements between groups among mild, moderate, or severe ED cohorts) in prospective, randomized, placebo-controlled, and adequately powered studies. In studies employing mixed-severity ED populations, a method of calculating an adjusted MCID was proposed based on statistical weighting principles. Similarly, a novel method for analyzing differences between cohorts in meta-analytic studies was presented to incorporate the concept of MCID. Based on these principles, the SMSNA would not support efficacy of a therapy based on statistical significance in a meta-analytic study alone. Similarly, studies claiming efficacy utilizing responder approaches (ie, statistically higher percentage of men achieving MCID between cohorts) would not be acceptable unless the median difference between groups on the IIEF-EFD achieved MCID. Clinical Implications The current position statement provides important, evidence-based data and scientific principles to help define what may be considered as an effective therapy in the treatment of ED. This framework provides a basis that decision-makers, clinicians, and patients may use to help differentiate clinically effective therapies. Strengths & Limitations The published literature is limited by a lack of validated instruments and data defining MCID for ED therapies between cohorts and with meta-analytic studies. The current position statement provides important guidance on these areas of ambiguity pending further, definitive data. Conclusion The current position statement provides detailed guidance on key criteria required to conclude efficacy of therapies used to treat ED.