bims-midomi 2025-11-09 papers

bims-midomi

Biomed News

on MDM2 and mitochondria

Issue of 2025–11–09
twelve papers selected by
Gavin McStay, Liverpool John Moores University

Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status.
Developing a diagnostic model to differentiate the well-differentiated lipomatous tumors based on clinicopathological characteristics.
PROTAC repurposing uncovers a noncanonical binding surface that mediates chemical degradation of nuclear receptors.
Quercetin reverses β1-adrenoceptor autoantibody-induced heart failure by promoting MDM2-mediated ubiquitination and degradation of p53 in cardiomyocytes.
[Clinicopathological characteristics and genetic alterations of undifferentiated embryonal sarcoma of the liver in children].
Ferroptosis-related genes MDM2 and CDKN1A as potential biomarkers for COPD.
CircPTK2 enhances non-small cell lung cancer proliferation by inhibiting cellular senescence through stabilizing NFYA and elevating FOXM1.
Editor's Note: The MDM2/MDMX-p53 Antagonist PM2 Radiosensitizes Wild-Type p53 Tumors.
Low Grade Fibro-Osseous Lesions with Isolated Chromosome 12 Chromothripsis: A Distinct Entity or a Low-Grade Central Osteosarcoma with a Novel Driver?
Myoepithelial and epithelial-myoepithelial clinically advanced and metastatic carcinomas of salivary gland: A comparative comprehensive genomic profiling study.
Characterizing resistance in prostate cancer at a single cell level with hormonal treatment and epigenetic inhibitors.
High-grade uterine endometrial stromal sarcoma harboring GLI1 and MDM2/CDK4 co-amplifications.

Oncol Res. 2025 ;33(11): 3429-3446

Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status.

Chiao-Ping Chen, Yan-Jei Tang, You-Yan Cai, Yi-Ru Pan, Chun-Nan Yeh, Wen-Kuan Huang, Chih-Hong Lo, Yu-Tien Hsiao, Hsuan-Jen Shih, Chiao-En Wu.

   Background: KIT proto-oncogene, receptor tyrosine kinase (KIT, CD117) and platelet-derived growth factor-alpha (PDGFRA) are key drivers of gastrointestinal stromal tumors (GIST), but resistance to targeted therapy often arises from tumor protein p53 (p53) alterations and loss of cell cycle control. However, the role of p53 status in GIST therapeutic potential has rarely been studied, so this study aimed to employ both wild-type and mutant p53 GIST models to investigate how p53 dysfunction influences the efficacy of p53 pathway-targeted therapies.
Methods: The efficacy of the mouse double minute 2 homolog (MDM2) inhibitor (HDM201) and the Wee1 G2 checkpoint kinase (Wee1) inhibitor (adavosertib) was confirmed in both p53 wild-type (p53 WT) and p53 mutant (p53 MT) GIST cells. The anti-proliferative effects were assessed using the Cell Counting Kit-8 (CCK-8) assay. Flow cytometry (FACS) and immunoblotting were employed to evaluate apoptosis and the expression of proteins related to drug efficacy. These findings were further validated in a xenograft model.
Results: HDM201 selectively inhibited growth and triggered apoptosis in p53 WT GIST cells, while adavosertib was effective mainly in p53 MT cells. Western blot analysis revealed that HDM201 increased p53 and p21 levels in p53 WT cells, and adavosertib affected Wee1 and phospho-cdc2 expression in both p53 WT and p53 MT cells. In a xenograft mouse model, HDM201 significantly reduced the tumor volume and weight in p53 WT GIST cells, whereas p53 MT tumors showed only a moderate size reduction with adavosertib, without significant changes.
Conclusions: Our results highlight the importance of p53 status in guiding GIST treatment. p53 WT tumors respond to MDM2 inhibitors, while p53 MT tumors show greater sensitivity to Wee1 inhibitors, supporting p53 pathway targeting as a promising strategy for GIST patients.

Keywords:  Tumor protein p53 (p53); Wee1 G2 checkpoint kinase (Wee1); adavosertib; gastrointestinal stromal tumors (GIST); mouse double minute 2 homolog (MDM2); mouse double minute 2 homolog inhibitor (HDM201)

DOI:  https://doi.org/10.32604/or.2025.066672
Sci Rep. 2025 Nov 05. 15(1): 38695

Developing a diagnostic model to differentiate the well-differentiated lipomatous tumors based on clinicopathological characteristics.

Jingjing Wu, Zhenzhen Zhang, Fangling Song, Xiangna Chen, Shanshan Huang.

  This study evaluated the diagnostic value of clinicopathological features and immunohistochemical markers for distinguishing lipomas from atypical lipomatous tumors/well-differentiated liposarcomas (ALT/WDLPS). An integrated diagnostic model for ALT/WDLPS was developed to guide diagnosis, treatment planning, and prognosis. This retrospective analysis included 216 patients with lipomatous tumors diagnosed between February 2018 and December 2024, including lipomas (n = 149), spindle cell lipomas (n = 3), ALTs/WDLPs (n = 62), and WDLPS with a low-grade de-differentiated component (n = 2). Immunohistochemical data for MDM2, CDK4, and p16 were available for 131 patients. MDM2 amplification was significantly more frequent in patients ≥ 55 years and in tumors of the lower limbs (the thigh) and retroperitoneum (p = 0.000). Larger tumor size and multiplicity were also associated with MDM2 amplification (p < 0.05). Immunohistochemistry sensitivities for ALT/WDLPS vs. lipomas: 65% (MDM2), 100% (CDK4), and 80.4% (p16); combined, the specificity was 100% and sensitivity 85.6%. The diagnostic model achieved 93.3% sensitivity and 72.2% specificity. Scores < 0.219 indicated a higher likelihood of lipoma, while scores > 0.652 indicated a higher likelihood of liposarcoma. Age ≥ 55 years, lower extremity/retroperitoneal location, tumor diameter ≥ 9.9 cm, and positive markers were independent risk factors. This model provides an effective tool for ALT/WDLPS identification.

Keywords:  Clinicopathological factors; Diagnostic prediction model; Double minute homologue 2 (MDM2); Fluorescence in situ hybridization (FISH); Well-differentiated lipomatous tumors

DOI:  https://doi.org/10.1038/s41598-025-22547-5
Nat Commun. 2025 Nov 06. 16(1): 9805

PROTAC repurposing uncovers a noncanonical binding surface that mediates chemical degradation of nuclear receptors.

Andrew D Huber, Wenwei Lin, Young-Hwan Jung, Shyaron Poudel, Guangwei Yang, Jing Wu, Annalise G Carrigan, Vishwajeeth Pagala, Wei Wang, Yingxue Fu, Zuo-Fei Yuan, Stephanie D Byrum, Ka Yang, Rebecca R Florke Gee, Elizabeth D Arnold, Allister J Loughran, Jingheng Wang, Shondra M Pruett-Miller, Junmin Peng, Taosheng Chen.

Proteolysis-targeting chimeras (PROTACs) containing a target protein ligand linked to an E3 ubiquitin ligase ligand induce target protein degradation through E3 recruitment. Most PROTACs bind a surface cleft of the protein of interest rather than a buried pocket. Using the nuclear receptor PXR, we previously described the inherent difficulties of PROTAC targeting via a deep solvent-inaccessible ligand binding pocket. Here, we discover that the CRBN-dependent MDM2 PROTAC MD-224 is a potent PXR degrader that achieves its activity from binding adjacent to the ligand-binding pocket. Furthermore, because the proximal region is a structural feature common among nuclear receptors, MD-224 also targets additional receptors for proteasomal degradation. Using structure- and activity-guided medicinal chemistry, we ablated MDM2 degradation and generated MD-224 analogs with activities skewed toward different receptors. Thus, we describe (1) PROTAC repurposing as a potential route of degrader discovery and (2) nuclear receptor-targeted degradation through a noncanonical binding site.

DOI: https://doi.org/10.1038/s41467-025-64773-5
Front Nutr. 2025 ;12 1674507

Quercetin reverses β1-adrenoceptor autoantibody-induced heart failure by promoting MDM2-mediated ubiquitination and degradation of p53 in cardiomyocytes.

Mingxia Ma, Xintai Jiang, Weiqian Liu, Jin Xue, Yuan Yuan, Xiaoyan Zhi, Jiayan Feng, Yaolin Long, Yang Li, Zhijun Zhang, Xiaohui Wang, Li Wang.

   Introduction: Cardiomyocyte autophagy is essential for preserving cardiac homeostasis. Previous studies revealed that β1-adrenergic receptor autoantibody (β1-AA) suppressed cardiomyocyte autophagy, triggering cell death and heart failure (HF). Qiliqiangxin capsule enhances autophagy and mitigates HF through multiple pathways, but its complex composition complicates mechanistic clarity. Network pharmacology identified quercetin as a pivotal autophagy-inducing component in Qiliqiangxin, yet its role in counteracting β1-AA-induced autophagy impairment remains unvalidated. In this study, quercetin's therapeutic potential and mechanisms in restoring autophagy in β1-AA-associated HF were investigated.
Methods: Bioinformatics methods, including a STRING database analysis, PPI network construction, and Cytoscape-based pathway mapping, were used to delineate quercetin's autophagy-related targets. The in vivo efficacy was assessed in β1-AA-positive mice treated with quercetin (100 mg/[kg·d], intraperitoneal). The in vitro validation used H9c2 cardiomyocytes pretreated with quercetin (100 μM) prior to β1-AA exposure. Autophagy markers, p53 signaling, and ubiquitination pathways were analyzed by immunoblotting and functional enrichment analysis using the GOrilla database. A p53 knockdown and overexpressing cardiomyocyte model confirmed pathway specificity.
Results: Quercetin administration significantly restored myocardial autophagy levels in β1-AA-positive mice, which improved cardiac function and survival rates. In H9c2 cells, quercetin pretreatment reversed β1-AA-induced autophagy suppression. Bioinformatics linked quercetin to p53 pathway modulation, with experimental validation showing quercetin downregulated p53 expression via MDM2-mediated ubiquitination. p53 knockdown enhanced autophagy, while its overexpression blocked quercetin's effect, indicating quercetin restores autophagy in a p53-dependent manner. GO enrichment highlighted the association between quercetin and ubiquitin-dependent protein degradation, which was corroborated by elevated MDM2 levels and accelerated p53 degradation in quercetin-treated cells.
Discussion: Quercetin rescues β1-AA-impaired cardiomyocyte autophagy by activating MDM2-dependent p53 ubiquitination and degradation, thereby attenuating HF progression. These findings establish quercetin as the mechanistic basis of the cardioprotective effects of Qiliqiangxin and provide preclinical evidence for targeting autophagy by regulating p53 in β1-AA-induced cardiac dysfunction.

Keywords:  autophagy; heart failure; quercetin; ubiquitination; β1-adrenoceptor autoantibody

DOI:  https://doi.org/10.3389/fnut.2025.1674507
Zhonghua Bing Li Xue Za Zhi. 2025 Nov 08. 54(11): 1156-1162

[Clinicopathological characteristics and genetic alterations of undifferentiated embryonal sarcoma of the liver in children].

J Y Zheng, C Zhao, J Liang, Y H Pan, W Hu, L Y Tang, C K Shao, J N Chen.

Objective: To investigate the clinicopathological characteristics and genetic alterations of undifferentiated embryonal sarcoma of the liver (UESL). Methods: Three cases of UESL diagnosed in the Department of Pathology, the Third Affiliated Hospital of Sun Yat-sen University from 2020 to 2023 were retrospectively collected. The clinical, histomorphological, immunohistochemical, and genetic profiles were reviewed and analyzed. Results: The cohort comprised of three patients, including one male and two females, aged 7, 9, and 15 years, respectively. Tumor locations were in the right lobe of the liver in two cases, and in both the right and left lobes in one case. One case exhibited tumor rupture with hemorrhage. Gross examination revealed solid tumors in gray-red fleshy appearance, with areas of hemorrhage and necrosis. Microscopically, the tumor was composed of irregularly shaped spindle and polygonal cells arranged in bundles or sheets with varying density, scattered within a myxoid matrix containing giant tumor cells and eosinophilic globules. The tumor cells were positive for Vimentin, CD56, CD68, and bcl-2, with a Ki-67 index of 30%-80%. INI1 expression was retained, while p53 exhibited a mutant pattern. CKpan, CK7, CK19, EMA, HepPar-1, Arginase-1, AFP, CD34, S-100, Myogenin, and MyoD1 were negative. All three cases harbored TP53 missense mutations. Case 1 also showed MDM2 copy number amplification (class Ⅰ mutation), and case 2 exhibited a frameshift mutation in exon 10 of TSC2 (class Ⅱ mutation). Additionally, several class Ⅲ mutations were identified in all three cases. Germline testing for tumor-related genetic variants in case 2 revealed a missense mutation in exon 12 of DICER1, an in-frame insertion mutation in exon 8 of MSH2, and a missense mutation in exon 30 of TSC2. Conclusion: UESL is a rare malignant mesenchymal tumor of the liver, predominantly affecting children, with distinctive clinicopathological features and genetic alterations. TP53 mutations may play a key role in the pathogenesis of this tumor.

DOI: https://doi.org/10.3760/cma.j.cn112151-20250805-00537
J Inflamm (Lond). 2025 Nov 07. 22(1): 49

Ferroptosis-related genes MDM2 and CDKN1A as potential biomarkers for COPD.

Rui Shi, Lueli Wang, Chunyun Bai, Fang Wang, Chaozhong Li, Chuang Xiao, Alex F Chen, Weimin Yang.

   OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is characterized by inflammation and an immune response. However, the relationship between ferroptosis and COPD remains unknown. We aim to identify pivotal ferroptosis-related biomarkers in COPD and explore their roles in immune infiltration landscapes.
METHODS: Differentially expressed genes (DEGs) were obtained from all current datasets of peripheral blood and lung tissues associated with COPD. DEGs were intersected with ferroptosis-related genes (FRGs) from FerrDb database to obtain FRDEGs. Hub FRDEGs were evaluated using WGCNA, GO, and KEGG enrichment, PPI network analysis, LASSO-COX, and ROC curve analysis, and validated in blood of COPD patients. The association between hub FRDEGs and COPD was investigated. The role of hub FRDEGs in 17 types of respiratory tract diseases was analyzed, and potential drugs targeting these FRDEGs were predicted via CMAP drug database. Importantly, MDM2 and CDKN1A expressions were identified and verified by H&E and Masson staining, and Western blot analysis in the CS and LPS-induced COPD mice.
RESULTS: MDM2 and CDKN1A were identified as hub genes in all COPD patients, and their expressions were significantly upregulated in the lung tissues of COPD mice. 17 types of respiratory tract diseases were markedly associated with MDM2 and CDKN1A. The 2 genes were correlated with neutrophils. MDM inhibitor (AMG-232) was screened as a potentially key drug affecting MDM2.
CONCLUSION: MDM2 and CDKN1A could be potential targets for COPD by regulating neutrophil-involving inflammation. One drug with potential clinical application value was identified.

Keywords:  CDKN1A; COPD; Ferroptosis; Immune infiltration; MDM2

DOI:  https://doi.org/10.1186/s12950-025-00468-4
Br J Pharmacol. 2025 Nov 07.

CircPTK2 enhances non-small cell lung cancer proliferation by inhibiting cellular senescence through stabilizing NFYA and elevating FOXM1.

Qiuhui Li, Kun Zhao, Yili Shen, Qian Ying, Boyi Chen, Jianhui Zhang, Bin Wang, Shunli Dong, Xuefei Shi.

   BACKGROUND AND PURPOSE: Cellular senescence, a stress-induced cell cycle arrest state, plays a dual role in cancer. Circular RNAs (circRNAs), endogenous noncoding RNAs, regulate physiological processes and are linked to diseases including cancer. This study investigates the role and mechanism of circPTK2 in non-small cell lung cancer (NSCLC).
EXPERIMENTAL APPROACH: Lentivirus-mediated knockdown or overexpression of circPTK2 were used to assess effects on proliferation and senescence. circPTK2 expression in NSCLC tissues was examined using tissue microarrays and in situ hybridization. RNA-seq identified circPTK2-regulated signalling pathways and downstream targets. Transcriptional regulation of FOXM1 by NFYA was investigated using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. Co-immunoprecipitation (Co-IP) was conducted to assess the interaction between NFYA and MDM2, as well as NFYA ubiquitination.
KEY RESULTS: circPTK2 was highly expressed in NSCLC tissues and was associated with poor prognosis. Knockdown of circPTK2 significantly inhibited cancer cell growth and enhanced cellular senescence. RNA-seq analysis identified FOXM1 as a downstream target of circPTK2. Database predictions suggested that NFYA could transcriptionally regulate FOXM1. Knockdown of circPTK2 induced NFYA degradation. circPTK2 was found to bind to the E3 ubiquitin ligase MDM2 in the cytoplasm, thereby preventing MDM2 from interacting with the transcription factor NFYA. This interaction blocked MDM2-mediated ubiquitylation and degradation of NFYA. Additionally, NFYA bound to the FOXM1 gene promoter, ultimately leading to the up-regulation of FOXM1 and suppression of cellular senescence.
CONCLUSIONS AND IMPLICATIONS: Elevated circPTK2 expression correlates with poorer survival, representing a potential therapeutic target in NSCLC.

Keywords:  FOXM1; MDM2; NFYA; cell proliferation; cell senescence; circPTK2

DOI:  https://doi.org/10.1111/bph.70220
Cancer Res. 2025 Nov 03. 85(21): 4286

Editor's Note: The MDM2/MDMX-p53 Antagonist PM2 Radiosensitizes Wild-Type p53 Tumors.

Diana Spiegelberg, Anja C Mortensen, Sara Lundsten, Christopher J Brown, David P Lane, Marika Nestor.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4015
Mod Pathol. 2025 Nov 05. pii: S0893-3952(25)00229-7. [Epub ahead of print] 100931

Low Grade Fibro-Osseous Lesions with Isolated Chromosome 12 Chromothripsis: A Distinct Entity or a Low-Grade Central Osteosarcoma with a Novel Driver?

Carla Saoud, Yanming Zhang, Jamal Benhamida, Liliana Villafania, Gunes Gundem, Robert Cimera, Hwang Sinchun, Neerav N Shukla, Damon Reed, Elli Papaemmanouil, Narasimhan P Agaram, Konstantinos Linos, Marc Ladanyi, Carol D Morris, Meera R Hameed.

  Chromothripsis, a catastrophic genomic event causing extensive chromosomal fragmentation and rearrangement, has been identified in conventional osteosarcoma, contributing to karyotypic heterogeneity. Chromothripsis was also detected in a subset of parosteal osteosarcomas, primarily involving chromosome 12, but not well-documented in low-grade central osteosarcoma (LGCOS). Here, we report two cases of low-grade fibro-osseous lesions with isolated chromosome 12 chromothripsis, aiming to characterize them by comparing their genomic and epigenetic profiles to those of other bone neoplasms. Case 1 was a 12-year-old male with a destructive lesion involving the proximal left tibia and case 2 was a 13-year-old female with expansile lucent bone lesion involving the distal tibia with cortical breakthrough. Both cases consisted of hypocellular bland fibroblastic proliferation. Areas of thin trabeculae of woven bone surrounded by osteoblasts were present. In addition, case 1 showed areas of atypical cartilaginous islands and areas reminiscent of LGCOS. By single nucleotide polymorphism array, both cases showed extremely complex and numerous genomic alterations involving chromosome 12. Whole genome sequencing and optical genome sequencing confirmed the chromothriptic event involving chromosome 12. Using the DKFZ sarcoma methylation classifier (v12.3), both cases matched to fibrous dysplasia methylation class. Dimensionality reduction using UMAP (Uniform Manifold Approximation and Projection) demonstrated that the two index cases clustered primarily with low-grade osteosarcomas lacking MDM2 amplification and with fibrous dysplasia, while remaining separate from parosteal osteosarcomas and MDM2-amplified low-grade osteosarcomas. Our findings suggest that chromothripsis of chromosome 12 may represent an early and/or an alternate mechanism in fibro-osseous lesions progressing to LGCOS instead of or before the development of the well-recognized CDK4/MDM2 amplification. Larger cohorts with long-term follow ups and integrative molecular studies are needed to clarify the biological significance and clinical implications, including recurrence, dedifferentiation, and survival.

Keywords:  CDK4; MDM2; chromosome 12; chromothripsis; fibro-osseous lesions; fibrous dysplasia; low grade central osteosarcoma

DOI:  https://doi.org/10.1016/j.modpat.2025.100931
Hum Pathol. 2025 Oct 31. pii: S0046-8177(25)00256-4. [Epub ahead of print]166 105969

Myoepithelial and epithelial-myoepithelial clinically advanced and metastatic carcinomas of salivary gland: A comparative comprehensive genomic profiling study.

Céline S C Hardy, Kevin M Lin, Dean Pavlick, Richard S P Huang, Jeffrey S Ross, Daniel J Zaccarini.

  Myoepithelial carcinoma (MECA) and Epithelial-myoepithelial carcinomas (EMC) are rare salivary gland carcinomas (SGCA) that may arise de novo or in the background of a prior pleomorphic adenoma (carcinoma ex pleomorphic adenoma CAEXPLA). Despite being clinically distinct entities, MECA and EMC share morphologic similarities which can make them difficult to distinguish on histologic examination. Further, there is a currently an evolving understanding of the characteristic genomic and immunohistochemical biomarkers for these tumors. In this study, we characterize the genomic profiles of a relatively large cohort of clinically advanced MECA (n = 52) and EMC (n = 26) cohorts. Both tumor types demonstrated single copy number changes, short variant mutations, and gene rearrangements. The most common alterations in MECA were in CDKN2A and CDKN2B. In EMC, HRAS mutations were the most common alteration, while both PIK3CA and MDM2 mutations were also common. Although not significantly different, CDKN2A and CDKN2B alterations were more frequent in MECA, while PIK3CA alterations were more frequent in EMC. Overall, EMC and MECA had both overlapping and unique molecular alterations that have potential for targeted therapies.

Keywords:  Epithelial-myoepithelial carcinoma; Genomic profiling; Myoepithelial carcinoma

DOI:  https://doi.org/10.1016/j.humpath.2025.105969
J Pharm Pharmacol. 2025 Nov 03. pii: rgaf100. [Epub ahead of print]

Characterizing resistance in prostate cancer at a single cell level with hormonal treatment and epigenetic inhibitors.

Morgan Howells, Priyadarsini Gangadharannambiar, Calum McMullen, Francesco Crea, Wendi Bacon, Colette Christiansen.

   BACKGROUND: Late-stage prostate cancer is treated with hormonal therapy. While initially effective, development of drug resistance is common. Hypoxia, a local-environmental occurrence in tumours, is known to trigger hormone-independence and concurrent drug resistance in cancer cells.
METHODS: Here we analyse single-cell transcriptomes of LNCaP cells throughout drug treatment. These cells were exposed to chronic hypoxia and treated with Enzalutamide, a hormonal drug which inhibits the androgen receptor, both with and without Tazemetostat, an epigenetic drug that inhibits EZH2 catalytic activity, which renders Enzalutamide-resistant clones partially sensitive to hormonal therapies. We identify genes characterizing the resistant clone and assess clinical relevance.
RESULTS: We characterize a resistant cluster present with Enzalutamide treatment but not with combination therapy. The top 10 upregulated genes in this cluster included genes previously linked to resistance: DDIT3, MDM2, and CDKN1A, and one previously proposed as a pan-cancer hallmark (HSP90B1). Analysis of clinical databases showed expression of CDKN1A, POLH, and GADD54 to be significantly upregulated in association with neuroendocrine prostate cancer.
CONCLUSION: This work characterizes at a single-cell level the Enzalutamide resistant clone and the impact of epigenetic inhibitors on resistance development. This characterization may enable the identification of resistant and non-resistant cells by their gene expression profile.

Keywords:  cancer; drugs; epigenetic; genes; hormonal; resistance

DOI:  https://doi.org/10.1093/jpp/rgaf100
Diagn Pathol. 2025 Nov 06. 20(1): 125

High-grade uterine endometrial stromal sarcoma harboring GLI1 and MDM2/CDK4 co-amplifications.

Lili Zhang, Lijuan Luan, Lei Zhang, Yufeng Huang, Wenyi Gu, Shui Yu, Licheng Shen, Jie Huang, Yang Shao, Jieakesu Su, Yingyong Hou, Chen Xu.

GLI1 gene alterations including fusions and amplifications compromise a subset of malignant mesenchymal tumors exhibiting characteristic monomorphic nested morphology and frequent S100 positivity, which mimic glomus tumors or well differentiated neuroendocrine tumors. We report four high-grade uterine endometrial stromal sarcomas (ESS) harboring GLI1 and MDM2/CDK4 co-amplifications with a median age of 51.5 years (range 43 ~ 72 years). Histologically, tumors showed a heterogenous morphology, including ovoid to spindle cells, showing nested/nodular arrangement (4/4). Myxoid background was observed at least partially in 4 tumors with prominent capillary networks. Mitoses index was 2 to 20/10 HPF (median 9.5/10 HPF). Immunochemically, tumors showed diffuse staining of CD10 (3/4) with frequently positive CyclinD1(2/4 tested) and mostly negative S100 protein (3/4). Next-generationsequencing (NGS) studies revealed GLI1 and MDM2/CDK4 co-amplification in all cases (4/4) and GLI1 fusion in 1 case (1/4), which were validated by fluorescence in situ hybridization (FISH) analysis. BCOR fusions were firstly identified with GLI1 and MDM2/CDK4 co-amplification in 2 cases (2/4). Copy number (CN) segmentation data showed GLI1 co-amplified cases present generally a single peak at the 12q13.3-15 locus. Follow-up (range:3 to 112 months; median 37.5 months) showed recurrence and/or metastasis in all cases (4/4), in which 1 patient developed lungs and liver metastasis. Relapse-free survival (RFS) analysis showed similar median RFS between GLI1 co-amplified HGESS and GLI1 non-amplified HGESS groups, which were shorter than LGESS group. Unusual clinicopathologic features of these HGESS with GLI1 and MDM2/CDK4 co-amplification mimicked other neoplasms, which caused significant diagnostic challenge and pitfalls. However, identification of GLI1 alterations in these tumors is beneficial for diagnosis and potential use of targeted GLI1 inhibitors.

DOI: https://doi.org/10.1186/s13000-025-01716-0