Citations

Abstract Pancreatic adenocarcinoma remains one of the most lethal malignancies, primarily due to its robust resistance to genotoxic therapies, such as chemotherapy and radiotherapy. Understanding the mechanisms underlying this resistance is essential to improve clinical outcomes. In this study, we identified trimethylguanosine synthase 1 (TGS1), previously known for its role in RNA modification, as a critical mediator of homologous recombination (HR) repair that specifically contributes to resistance in pancreatic adenocarcinoma. TGS1 was significantly overexpressed in pancreatic adenocarcinoma tissues, correlating strongly with advanced disease stages, therapy resistance, and poor patient prognosis. Following DNA damage, ATM kinase phosphorylated TGS1 at serine residues S389 and S531, which mediated its direct interaction with BRCA1 and subsequent recruitment of BRCA1 to DNA damage sites. The phosphorylation-dependent interaction enhanced HR repair efficiency, enabling cancer cells to survive genotoxic stress. Depletion or pharmacologic inhibition of TGS1 induced HR deficiency and markedly enhanced sensitivity to DNA-damaging agents, particularly PARP inhibitors, in pancreatic adenocarcinoma cell lines in vitro and in both cell line– and patient-derived xenograft models in vivo. Collectively, these findings uncover an ATM–TGS1–BRCA1 signaling axis that promotes DNA repair and resistance to genotoxic therapies in pancreatic cancer, positioning TGS1 as a promising predictive biomarker and therapeutic target to enhance treatment efficacy. Significance: The ATM–TGS1–BRCA1 signaling axis is a critical regulator of DNA repair that can be targeted to overcome genotoxic therapy resistance, providing a promising therapeutic strategy that could transform pancreatic cancer treatment.

Background Postoperative atrial fibrillation occurs in ~40% after cardiac surgery. Mineralocorticoid receptor antagonists (MRA) are known to reduce chronic atrial fibrillation (AF) development and burden. We evaluated the association of preoperative MRA use with postoperative atrial fibrillation and investigated atrial cell types modulated by MRAs during cold preservation. Methods We studied 19 042 cardiac surgery patients at Mayo Clinic. Propensity 1:3 matching identified 298 MRA users and 894 non‐users. A subgroup analysis of patients on any preoperative diuretic was performed to isolate cardiac‐specific effects of MRAs, matching 298 MRA users to 894 non‐MRA diuretic users. AF recurrence was assessed for up to 6‐years. Single‐nucleus RNA sequencing (snRNA‐seq) was performed on human donor atria exposed to canrenone (a water‐soluble MRA) during cold preservation with ex‐vivo reperfusion, and expression profiles were compared with atria from patients with AF. Results After matching, preoperative MRA use was associated with a lower incidence of postoperative atrial fibrillation (19.8% versus 31.8%, P <0.001). In the diuretic‐only subgroup, MRA users also had lower postoperative atrial fibrillation (19.8% versus 33.2%, P <0.001). MRA use was associated with a reduced incidence of paroxysmal and chronic AF at 6‐years. snRNA‐seq identified a cardiomyocyte subpopulation, CM2, with high mineralocorticoid receptor expression where canrenone suppressed cold preservation‐induced mineralocorticoid receptor target gene expression, which was conversely elevated in chronic AF. Canrenone also attenuated stress‐response in atrial macrophages and pericytes. Conclusions Preoperative MRAs were associated with reduced postoperative and long‐term AF after cardiac surgery. Mechanistically, our ex‐vivo human atrial model revealed that MRAs suppress mineralocorticoid receptor ‐driven atrial stress responses, particularly in conduction‐relevant cardiomyocytes.

Abstract Background Breast cancer genome-wide association studies (GWAS) have identified more than 200 susceptibility loci, but most studies are dominated by European and East Asian populations. Methods We analyzed breast cancer GWAS summary statistics from African (AFR), East Asian (EAS), European (EUR), and Hispanic/Latina (H/L) samples (159,297 cases and 212,102 controls). We estimated logit-scale SNP-based heritability, polygenicity, and cross-ancestry genetic correlation, partitioned heritability across functional annotations, and integrated GWAS results with the Tabula Sapiens single-cell atlas using scDRS+. Results The logit-scale heritability of breast cancer ranged from ℎ 2 =0.47 (SE = 0.07) in EAS to AFR ℎ 2 =0.61 (SE = 0.10), with no significant differences across ancestries (p=0.63). The estimated number of susceptibility markers in a sparse normal-mixture effects model also varied from 4,446 (SE = 3,100) in EAS to 8,308 (SE = 2,751) in AFR, but differences were not significant across ancestries (p=0.55). Cross-sample genetic correlations varied, with the strongest correlation between EUR and EAS (𝜌 = 0.79, SE = 0.08) and weakest between AFR and H/L (𝜌 = 0.26, SE = 0.24). Regulatory annotations were enriched for breast cancer heritability across samples. Integration with single-cell expression profiles implicated ancestry-shared associations with innate immune, secretory epithelial, and stromal cell types. Conclusion These results indicate substantial cross-ancestry sharing of breast cancer polygenic architecture, highlight a consistent contribution of regulatory variation, and identify convergent cellular contexts that motivate functional follow-up and inform expectations for the transferability and attainable performance of common-variant risk prediction across populations.

Importance The APOE ε4 variant is causally linked to cerebral amyloid angiopathy and is a risk factor for intracranial hemorrhage (ICH) among warfarin-treated patients with atrial fibrillation. Nevertheless, its impact on those treated with apixaban remains unknown. Objective To test the hypothesis that APOE ε4 allele carriership is associated with an increased risk of ICH in patients with atrial fibrillation taking apixaban. Design, Setting, and Participants This cohort study involved data from the All of Us Research Program, a longitudinal, population-based study in the United States. Inclusion criteria were age older than 50 years, history of atrial fibrillation, and anticoagulation with apixaban. Participants with a history of ischemic stroke or ICH were excluded. Up to 3 years of follow-up data were available. Data were collected from 2017 to 2022 and analyzed from November 2023 to December 2024. Exposure APOE ε2, ε3, and ε4 were ascertained using variants rs429358 and rs7412. APOE ε4 was modeled dichotomously (noncarriers [no alleles] vs carriers [1 or 2 alleles]). Main Outcomes and Measures Incident ICH, including any new intraparenchymal, subdural, or subarachnoid hemorrhage after initiation of apixaban therapy. Results Of 413 477 All of Us participants, 2038 were eligible. Their mean (SD) age was 71 (9) years; 918 (45%) were female, 1120 (55%) were male, and 1710 (83%) had European ancestry. Among these participants, 483 (23.7%) were carriers of at least 1 APOE ε4 allele. After a median follow-up of 2.9 years, 26 participants sustained an ICH (cumulative incidence, 1.5%; 95% CI, 1.0%-2.2%), of whom 12 (cumulative incidence, 3.1%; 95% CI, 1.7%-5.3%) were carriers and 14 (cumulative incidence, 1%; 95% CI, 0.6%-1.7%) were noncarriers ( P = .007). Multivariable Cox proportional hazard models confirmed this association: compared with noncarriership, APOE ε4 carriership was associated with a 3-fold increase in the risk of ICH (hazard ratio, 3.07; 95% CI, 1.42-6.65). APOE information improved the discrimination of risk prediction scores (C statistic of 0.74 and 0.68 for models with and without APOE , respectively; P = .03). Conclusions and Relevance Further research is needed to evaluate whether cerebral amyloid angiopathy mediates the observed association and whether APOE e4 information improves clinical decision-making about anticoagulation therapy in patients with atrial fibrillation. The latter is important now that APOE information is used in clinical settings to guide antiamyloid treatment for Alzheimer disease and has been returned to millions of persons by direct-to-consumer genotyping companies.

Abstract Introduction: Breast cancer genome-wide association studies (GWAS) have identified over 200 susceptibility loci, many replicated in diverse populations. However, cross-ancestry evaluation of breast cancer genetic architecture remains limited. We examined breast cancer genetic architecture using GWAS summary results from European (EUR; cases (ca) = 188,474, controls (co) = 96,201), East Asian (EAS; ca = 20,393, co = 86,329), African American (AA; ca = 9,235, co = 10,184), and US Hispanic/Latina and Latin American (H/L; ca = 2,396, co =7,468) studies. Methods: GWAS results were derived from the Breast Cancer Association Consortium, the African Ancestry Breast Cancer Genetics Consortium (AABCG), Biobank Japan, and a meta-analysis of five studies of H/L women with breast cancer. Linkage disequilibrium (LD) scores were generated for EUR, EAS, and AMR using the 1000 Genomes Project, while AA LD scores were derived from a subset of AABCG controls. Heritability was estimated for each ancestry group using LD score regression. Genetic correlations between populations were assessed via Popcorn. Polygenicity was analyzed using GENESIS; however, due to the limited sample size in the H/L studies, these estimates were restricted to AA, EAS, and EUR. Enrichment of heritability across regulatory elements was evaluated using stratified LD score regression across all populations. Results: The logit-scale heritability and corresponding standard error (SE) were 0.466 (0.066) for EAS, 0.501 (0.050) for EUR, 0.588 (0.360) for H/L, and 0.614 (0.095) for AA. The estimated number of independent susceptibility loci was 4,446 for EAS, 5,235 for EUR, and 8,308 for AA. Using a clumping and thresholding approach, an optimal set of common variants were projected to explain 38.6% (EUR), 39.4% (EAS), and 26.2% (AA) of genetic variance for samples of 100,000 cases and 100,000 controls with AUCs from corresponding estimated polygenic risk scores (PRSs) of 0.621 (EUR), 0.634 (EAS), and 0.611 (AA). Genetic correlations were strongest between EUR and EAS (ρ = 0.79, SE = 0.08) and EUR and H/L (ρ = 0.68, SE = 0.21), and weakest between AA and EAS (ρ = 0.42, SE = 0.14) and AA and H/L (ρ = 0.26, SE = 0.24). Among 73 genomic features, we found significant (P &lt; 0.05/73) enrichment in heritability in EUR for ‘ancient promoter’ regions, transcription factor binding sites, H3K4me3, ‘super-enhancers’, H3K4me1, H3K27ac; in EAS for ‘super-enhancers’; and in AA for H3K27ac. No genomic features were significantly enriched in H/L, likely due to limited power. Conclusion: These findings suggest a shared breast cancer genetic architecture across diverse populations, as well as the potential for a similar level of breast cancer risk stratification by PRS in these populations. Expanding GWAS in underrepresented populations is essential to improve genetic risk predictions and foster equitable cancer prevention. Citation Format: James L. Li, Maria Zanti, Jacob Williams, Om Jahagirdar, Guochong Jia, Qiang Hu, Jean-Tristan Brandenburg, Li Yan, Weang-Kee Ho, Jingmei Li, José P. Miranda, Devika Godbole, Julie-Alexia Dias, Leila Dorling, Wenlong C. Chen, Nicholas Boddicker, Ying Wang, Alicia Martin, Martin J. Zhang, Yan Zhang, Joe Dennis, Esther M. John, Gabriela Torres-Mejia, Larry Kushi, Jeffrey Weitzel, Susan L. Neuhausen, Luis Carvajal-Carmona, Christopher Haiman, Elad Ziv, Laura Fejerman, Wei Zheng, Dezheng Huo, Douglas Easton, Nilanjan Chatterjee, Peter Kraft, Montserrat Garcia-Closas, Wendy Wong, Kyriaki Michailidou, Qianqian Zhu, Diptavo Dutta, Thomas U. Ahearn, Haoyu Zhang. Genetic architecture of breast cancer across diverse populations: Assessing heritability, genetic correlation, and polygenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2282.

Abstract Approximately two-thirds of hypopharyngeal squamous cell carcinoma (HPSCC) are diagnosed in advanced stage, with the worst prognosis among head and neck squamous cell carcinomas (HNSCCs). Identifying biomarkers for high-risk patients who need aggressive treatment is crucial. We present mutational, transcriptomic and proteomic studies of 103 Chinese HPSCC patients, observing a higher prevalence and poorer prognosis in males comparing to females. Genes in estrogen response pathways are up-regulated and proteins phosphorylated by protein kinase C (PKC) and Cyclin-dependent kinases (CDKs) are aberrantly regulated. We identify aberrant copy number regions including SOX2 (3q26.33), FGFR (8p11.23), CCND1 (11q13.3), CDKN2A/2B (9p21.3), and MYC (8q24.21). HPV status combined with highly mutated genes as predictive markers was assessed, including SYNE1 in HPV(-), MUC4 in HPV(+) patients. We confirm the presence of four known gene expression (GE) subtypes of HNSCC in our HPSCC cohort and present the genomic alterations, patient characteristics and survival status of each subtype. A predictive model involving clinical factors and transcriptomic expression of six genes was established and cross-site validated. The findings open new opportunities for stratifying high-risk patients and molecular targets for novel therapeutic strategies. Citation Format: Yanxin Ren, Wei Xiong, Chun Feng, Dan Yu, Xiaoyan Wang, Qing Yang, Siting Yu, Hongjiang Zhang, Bangyun Huo, Honglu Jiang, Zuli Li, Junlin Wang, Yu-Xiong Su, Ping Yang, Yong Liao, Qi Zhong, Junwen Wang. Multi-omics insights into the molecular signature and prognosis of hypopharyngeal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4999.

Abstract Background New postoperative atrial fibrillation (POAF) occurs in about 40% after cardiac surgery. Mineralocorticoid receptor antagonists (MRA) are known to reduce chronic atrial fibrillation (AF) development and burden. We examined the impact of preoperative MRA use on POAF and also examine the atrial cell type impacted by MRA treatment during cold cardiac preservation. Methods Retrospective study of 19,042 patients who underwent cardiac surgery at Mayo Clinic in Minnesota, and performed 1:3 propensity matching to obtain 298 patients on preoperative MRA matched to 894 who were not. We also separately matched patients using preoperative diuretics. Single-nuclei RNA sequencing (snRNA-seq) examined MRA’s effects on different atrial cell types in canrenone (water soluble MRA) treated human donor hearts undergoing cold preservation followed by ex-vivo reperfusion and compared gene expression to the atria of patients with AF. Results Propensity matched preoperative MRA group had less new onset POAF (19.8% vs 31.5%, P<0.001). To account for the possibility that preoperative diuretic use and volume reduction may impact POAF, we propensity matched 298 preop diuretic users that included MRA use to another 894 patients who used a non-MRA diuretic preoperatively. Those who used preoperative MRA similarly had a lower incidence of POAF (19.8% vs 33.2%, P<0.001). No survival difference was present between the propensity matched groups that used preoperative diuretics (P=0.079). Preoperative MRA use also reduced the development of paroxysmal and chronic AF at 6 years of follow up. From our snRNA-seq data, we identified a subpopulation of atrial cardiomyocytes (CM2) that had high MR expression where canrenone suppressed the increase in MR target gene expression associated with cold preservation-reperfusion. These MR targets were conversely elevated in patients with chronic AF. Canrenone also suppressed other cardiac preservation associated genes that show elevated expression in atrial macrophages and pericytes from chronic AF atria. Conclusions Our studies show that preoperative MRA use is associated with 40% reduction in POAF as well as lowering long standing AF development by about 41%. Our cold cadiac preservation-reperfusion model showed that canrenone reduced expression of MR target genes associated with chronic AF, particular in cardiomyocytes with important roles in electrical conduction. Clinical Perspective What is New? This study shows that preoperative use of mineralocorticoid receptors antagonists (MRA) is associated with a reduced incidence of new onset perioperative atrial fibrillation after cardiac surgery utilizing cardiopulmonary bypass. We show that preoperative MRA use is associated with a lower incidence of developing more chronic paroxymal or sustained atrial fibrillation. Addition of canrenone, a clinically utilized water soluble MRA, to cardioplegia solution used during cardiac preservation can attenuate atrial inflammatory reponses and reduce signaling through molecular pathways that promote atrial fibrillation. What are the clinical implications? Perioperative use of MRAs may be considered to reduce early postoperative atrial fibrillation as well as lowering the risk of developing more chronic atrial arrhythmias. These findings support pursuing a clinical trial to determine the impact of MRA use on atrial arrhythmias following cardiac surgery in the setting of cardiopulmonary bypass with cold cardiac preservation.

Introduction: Coagulation factor XI (FXI) inhibitors have shown a better safety profile than other anticoagulants, offering similar reductions in ischemic stroke (IS) risk with a lower risk of intracerebral hemorrhage (ICH). The APOE ε4 genotype is associated with increased risks of both IS and ICH, likely due to its effects on lipid levels, intracranial atherosclerosis, and cerebral amyloid angiopathy. We hypothesized that APOE ε4 carriers would gain greater therapeutic benefit from genetically reduced FXI levels compared to non-carriers. Methods: We conducted a two-stage Mendelian randomization (MR) analysis using the random-effects, inverse-variance weighted method. First, we estimated the effect of genetically proxied FXI inhibition on IS and ICH risk in the general population using summary data from genome-wide association studies of FXI levels (16,169 participants), IS (1,503,898 controls and 110,182 cases), and ICH (3,745 controls and 3,226 cases). Second, we performed stratified analyses to estimate the effect of genetically determined FXI levels on IS (10,343 cases and 476,838 controls) and ICH (2,236 cases and 484,945 controls) risk across APOE ε4 carriership strata (0, 1, or 2 alleles) using UK Biobank data. Results: In the general population, random-effects, inverse-variance weighted MR analyses showed that every 1 unit decrease in natural log-transformed FXI levels was associated with a 37% reduction in IS risk (OR:0.63; 95%CI:0.52–0.77; p <0.001) without a significant increase in ICH risk (OR:0.86; 95%CI:0.37–2.00; p =0.73). Stratified MR analyses indicated that genetically determined reductions in FXI levels had varying protective effects on IS risk based on APOE ε4 status: 31% in non-carriers (OR:0.69, 95%CI:0.53–0.91; p =0.008), 43% in carriers of 1 allele (OR:0.57, 95%CI:0.36–0.91; p =0.02), and 75% in carriers of 2 alleles (OR:0.25, 95%CI:0.06–1.06; p =0.06). Similar MR analyses showed no significant increase in ICH risk with genetically determined reductions in FXI levels in any APOE ε4 strata (all p >0.38, Figure 1). Conclusion: This two-stage genetic study provides causal evidence that lower FXI levels reduce IS risk in the general population, with an even stronger effect among APOE ε4 carriers, while not increasing ICH risk. These results indicate that FXI inhibitors might be a safer and more effective alternative to other anticoagulants among APOE ε4 carriers, who are known to be at higher risk for both ischemic and hemorrhagic events.

Abstract Background Prolonged and recurrent fevers in pediatric outpatients often require specialist consultations, presenting a challenge in accurately triaging to the correct pediatric subspecialty. This study aims to develop an artificial intelligence (AI)-based model to accurately direct pediatric patients to appropriate subspecialties.Table 1.Patient characteristics and the department confirming the final diagnosis Table 1. Patient characteristics and the department confirming the final diagnosis Methods A retrospective study was conducted at the Mayo Clinic, Rochester, from December 1, 2020, to January 1, 2023, involving pediatric patients aged 0 to 18 referred for recurrent fever or fever of unknown origin. Six machine learning models, including gradient boosting, random forest, support vector machines (SVM), k-Nearest Neighbor (KNN), logistic regression (LR) and decision tree, were developed using 7 variables (demographics, chief complaints, referral sources, departments of same-day initial visit, and lab tests results within 30 days before initial visits). Data were extracted from external electronic health records (EHR) using Mayo Data Explorer and Lab Information Management Systems. Precision, Recall, F1 Score, and area under the curve (AUROC) were selected to measure the performance.Table 2.Performance of six machine learning models Table 2. Performance of six machine learning models Results The study evaluated 87 pediatric patients with a median age of 10.2 years (IQR: 4.6-13.8), including 43 (49%) females (Table 1). External provider referrals were noted in 40 (46%) patients. Musculoskeletal pain was the most common chief complaint, identified in 29 (33%) patients, in addition to prolonged or recurrent fever. Infectious disease and rheumatology divisions jointly saw 43 (49%) patients during the initial visit. Sub-optimal performance was observed in six machine learning models (Table 2). The random forest model showed the best results (Accuracy=0.39, Precision=0.34, Recall=0.39, F1 Score=0.35, AUROC=0.60) (Figure).Figure.ROC curves for various models Figure. ROC curves for various models Conclusion This study demonstrates the potential of AI-based models for outpatient triage prediction in pediatric patients with recurrent fever, using EHR data to optimize health resource utilization. This data serves as the groundwork to expand and refine this AI triage tool. Disclosures All Authors: No reported disclosures