Citations

Abstract Cholesterol has long been viewed as a structural component of cellular membranes, yet its role in DNA damage response remains poorly defined. Here, we show that ionizing radiation (IR) induces broad transcriptional upregulation of cholesterol biosynthesis, transport, and storage pathways, leading to sustained intracellular accumulation of cholesterol. BODIPY-cholesterol imaging, Filipin III staining, and quantitative subcellular fractionation confirmed selective nuclear enrichment of cholesterol following IR, coinciding with extensive chromatin remodeling. Proteomic profiling of cholesterol-interacting proteins revealed a strong enrichment of chromatin-associated factors, suggesting a previously unrecognized lipid-chromatin interface in irradiated cells. Functionally, cholesterol accumulation promoted chromatin compaction and repressive histone modification patterns, impairing DNA damage sensing and checkpoint activation despite increased underlying DNA lesions. These alterations facilitated aberrant mitotic entry, formation of cytoplasmic chromatin fragments (CCFs), and activation of cGAS-STING-NF-κB signaling. Cholesterol exposure ultimately diverted damaged cells toward a senescent fate, marked by Lamin B1 loss, p21 induction, and a robust senescence-associated secretory phenotype (SASP) enriched for IL-1 and TNF family cytokines. In vivo, dietary cholesterol exacerbated radiation-induced inflammation and weakened systemic anti-tumor immunity. Transcriptomic analyses of immunotherapy-treated patients revealed that tumors enriched for cholesterol import and senescence signatures were associated with poor response to PD-L1 blockade and worse survival. Together, these findings identify a cholesterol-chromatin-senescence axis that links metabolic remodeling to defective DNA damage signaling and immune suppression after radiation, highlighting cholesterol metabolism as a potential therapeutic vulnerability in cancer therapy. Citation Format: Yiqun Han, Yaobin Ouyang, Shouhai Zhu, Hangcheng Xu, Bin Chen, Ping Yin, Qin Zhou, Jinzhou Huang, Kuntian Luo, Zheming Wu, Huaping Xiao, Xinyi Tu, Jake A. Kloeber, Jiajun Jing, Xiaofeng Huang, Meng Xu Welliver, Zhenkun Lou, Robert Mutter. Cholesterol triggers chromatin stress to drive senescence and inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 539.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery is a popular intervention for small vestibular schwannomas in patients with preserved hearing. Gamma Knife radiosurgery (GKRS) and CyberKnife radiosurgery (CKRS) represent 2 alternative modalities, with CKRS potentially allowing for the delivery of higher doses over multiple sessions. However, the optimal dosing and hearing outcomes of CKRS remain unclear. This study systematically reviewed all literature describing outcomes following treatment of vestibular schwannomas with CKRS, with a focus on tumor control, hearing preservation, and dosing schema. METHODS: The PubMed, Scopus, and Embase databases were queried to identify primary retrospective studies reporting local tumor control and hearing preservation rates following CKRS for vestibular schwannoma. Studies were reviewed, and the systematic review and meta-analysis were performed according to PRISMA and meta-analysis guidelines. RESULTS: Fifteen studies with study periods ranging from 1998 to 2018 were included. These studies comprised 2018 patients (mean age, 60.2 years; range, 11-91 years; 52% female), of whom 64 had neurofibromatosis type 2. The mean follow-up was 40 (range, 6-120) months, and 309 patients had undergone prior treatment (surgery and/or stereotactic radiosurgery). In aggregate, local control at the last follow-up was 96% (95% CI, 95%-98%), and 73% (95% CI, 66%-81%) of patients had preserved hearing. The most common major complications after CKRS were facial neuropathy (1.4%), trigeminal neuralgia (1.3%), and hydrocephalus (0.5%). CKRS provides a high rate of short-term and mid-term tumor control with hearing preservation comparable with GKRS, but long-term outcomes remain under investigated. CONCLUSION: This systematic review and meta-analysis found that CKRS offers high rates of tumor control and hearing preservation in patients undergoing stereotactic radiosurgery for vestibular schwannomas. Current data suggest that CKRS is a reasonable, safe therapeutic option for patients with small tumors and preserved hearing. Further exploration in larger cohorts and direct comparison with GKRS is merited.

Abstract Background Adverse pregnancy outcomes (APO) are associated with increased maternal risk of cardiovascular disease (CVD) and mortality. Ischemia with no obstructive coronary artery disease (INOCA) is predominant in women, however the association of APO history with INOCA is poorly understood. Purpose To compare clinical characteristics, symptoms, cardiac structure and function and coronary microvascular dysfunction in women suspected to have INOCA with or without a history of APO. Methods Women’s Ischemia Syndrome Evaluation (WISE) CVD (NCT00832702) and WISE pre-HFpEF (NCT02582021) prospective cohorts of women with suspected INOCA were merged and utilized to determine among women with at least 1 prior pregnancy whether a history of APO was associated with ischemic symptoms, and to characterize CMRI measured left ventricle (LV) structure and function, myocardial deformation (systolic and diastolic strain) and coronary microvascular dysfunction on invasive coronary functional testing (CFT). Self-reported APO was defined as hypertensive disorder of pregnancy (HDP), gestational diabetes, preterm birth (<37-week gestation), low birth weight (<5lbs). Results In a cohort of 469 women with suspected INOCA, (mean average age 55 [SD 10.2] years) and at least 1 prior pregnancy, 138 (29%) had history of at least 1 APO. Among women with history of APO, 78 reported HDP, 50 gestational diabetes, 27 pre-term birth, 8 low birth weight. Women with a history of APO were younger, had higher rates of hypertension and diabetes, higher BMI and lower SAQ and DASI scores compared to those with no history of APO (Table). LV ejection fraction (EF) was lower and early diastolic strain rate/LVEDP was higher in women with APO history compared to those without APO history. Conclusion(s) In cohort of women with INOCA, history of APO was highly prevalent. Despite younger age, women with history of APO had higher rates of CVD risk factors, worse ischemic symptoms and functional capacity, lower EF, and higher filling pressures. Our findings suggest a potential for APO history to better identify women with worse prognosis that warrants further investigation and aggressive management.

Previous genome‐wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine‐mapping study across 2.06 Mb (chr8:127,561,724–129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93–0.97, conditional p = 5.8 × 10−6), rs7815245 (OR = 0.94, 95% CI = 0.91–0.96, conditional p = 1.1 × 10−6) and rs2033101 (OR = 1.05, 95% CI = 1.02–1.07, conditional p = 1.1 × 10−4) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r2 = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.

Abstract Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.