bims-midomi 2026-08-02 papers

Curr Oncol. 2026 Jul 22. pii: 438. [Epub ahead of print]33(7):

Transcriptomic Stratification Reveals an FRS2-Associated, Proliferation-Independent Phenotype in MDM2-High Sarcomas.

Takao Sakai, Hisaki Aiba, Makoto Yamaguchi, Koji Hagiwara, Hideki Murakami, Hiroaki Kimura.

Sarcomas with Murine Double Minute 2 (MDM2) amplification are considered potential candidates for MDM2-targeted therapy. However, the limited efficacy of MDM2 inhibitor monotherapy suggests that additional biological factors may influence tumor behavior and prognosis. This study investigated the relationship between MDM2 expression and the Complexity Index in SARComas (CINSARC) transcriptomic signature, a gene expression signature that reflects cell division and chromosomal instability in soft tissue sarcomas. In the public GSE21050 dataset comprising 310 soft tissue sarcomas, the MDM2-low/CINSARC-low subgroup showed the most favorable metastasis-free survival, whereas the MDM2-high/CINSARC-low subgroup had an unfavorable metastasis-free survival comparable to that of the MDM2-high/CINSARC-high group. Among the representative genes in the 12q13-15 region, fibroblast growth factor receptor substrate 2 (FRS2) showed a strong positive correlation with MDM2 expression, but no significant correlation with CINSARC, suggesting an association independent of proliferative capacity. These findings suggest that proliferation-based risk assessment alone may underestimate the metastatic risk of a subset of MDM2-high sarcomas, and FRS2 may present a biologically relevant marker of aggressive behavior independent of tumor proliferation.

Keywords: 12q13-15 amplicon; CINSARC; FRS2; MDM2; metastasis-free survival; soft tissue sarcoma; transcriptomic analysis

DOI: https://doi.org/10.3390/curroncol33070438

J Gastroenterol Hepatol. 2026 Jul 31.

E3 Ubiquitin Ligase MDM2 Promotes Growth and CD8+ T Cell Dysfunction in Gastric Cancer Through Degradation of SST.

Fang Yang, Xiaoling Zhang, Juanjuan Ji, Sujuan Li, Xiangjie Fang, Lu Yang, Xiaohe Guo.

AIM: To figure out the role and molecular mechanism of SST in the progression of GC.
METHODS: GC microarray data GSE118916 were downloaded from the GEO database. Then, the module-related genes and differentially expressed genes (DEGs) in GC were respectively screened by weighted gene co-expression network analysis (WGCNA) analysis and limma 3.62.2. The protein-protein interaction (PPI) network was constructed to identify the core genes. After ubibrowser1.0 prediction, interaction between MDM2 and SST was verified using co-immunoprecipitation (CoIP) assay and GST pull-down assay. The biological role of MDM2 and SST on GC tumor growth was measured using the xenograft tumor model in vivo.
RESULTS: A total of 250 overlapping DEGs were identified using 1673 module-related genes from WGCNA and 322 DEGs from the GSE118916 database. PPI network identified 17 candidate core genes of GC, which were mainly enriched in gastric acid secretion, collecting duct acid secretion, oxidative phosphorylation, histidine metabolism, fat digestion and absorption, metabolic pathways, and neuroactive ligand-receptor interaction. One hub gene, SST, was identified according to the machine learning algorithms. SST expression was decreased in GC patients and cells, and its overexpression repressed GC cell proliferation and CD8+ T cell apoptosis, and promoted GC cell apoptosis and CD8+ T cell proliferation. Mechanistically, MDM2 could mediate ubiquitination and destabilization of SST in GC cells. MDM2 knockdown suppressed tumor growth by regulating SST in vivo.
CONCLUSION: MDM2 could facilitate the growth and CD8+ T cell dysfunction in GC through advancing the ubiquitination degradation of SST, which provides a promising therapeutic target for GC treatment.

Keywords: CD8+ T cells; gastric cancer; murine double minute 2; proliferation; somatostatin

DOI: https://doi.org/10.1111/jgh.70613

Head Neck Pathol. 2026 Jul 27. pii: 87. [Epub ahead of print]20(1):

Pleomorphic Adenoma of the Palate with Bizarre Ductal and Myoepithelial Cells: A Case Image.

Katsutoshi Hirose, Masato Nakaguro, Kohei Kawamura, Taisuke Mori, Satoru Toyosawa.

BACKGROUND: Pleomorphic adenomas (PAs), the most common salivary gland tumors, are comprised of ductal epithelial and myoepithelial cells within a stromal background. A rare subset of PAs exhibits bizarre cells and 12q amplification involving HMGA2 and MDM2; in reported cases, bizarre cells have been confined to the myoepithelial component. We report the first case of a PA with bizarre-cytological features in both the ductal and myoepithelial components.
CASE PRESENTATION: A 75-year-old woman presented with a palatal mass. Histology revealed a well-circumscribed biphasic tumor with marked nuclear pleomorphism in both luminal ductal and non-luminal myoepithelial cells. Despite the alarming atypia, mitotic activity was low, and neither necrosis nor invasive growth was observed. Immunohistochemically, luminal bizarre cells exhibited ductal characteristics, whereas non-luminal bizarre cells exhibited myoepithelial characteristics. Tumor cells were negative for androgen receptor and HER2 and showed a p53 wild-type expression pattern. The Ki-67 labeling index was < 5%, and the bizarre cells rarely tested positive. Molecular analysis demonstrated amplification of HMGA2 and MDM2, whereas no other pathogenic variants related to salivary gland tumors were detected. Complete excision was performed; no evidence of recurrence or metastasis was observed after 10 months.
CONCLUSION: Marked cytological atypia of bizarre cells in PA, even when involving ductal cells, may not necessarily indicate malignancy. This case highlights the value of integrating clinicopathological and genetic findings to better define PAs with bizarre cells and prevent overdiagnosis of carcinoma based on atypia alone.

Keywords: HMGA2 ; MDM2 ; 12q; Pleomorphic adenoma; Salivary glands

DOI: https://doi.org/10.1007/s12105-026-01953-9

J Surg Oncol. 2026 Jul 29.

Routine MDM2 FISH Testing and Preoperative Biopsy Reduces Recurrence Rate of Atypical Lipomatous Tumours.

Samuel O H Ching, Anderson S M Leung, Raymond C H Yau, Albert Y L Lam, Tony W H Shek, Maximus C F Yeung.

BACKGROUND: Although MDM2 FISH test has been increasingly used to differentiate ALT and benign lipomatous tumours, its impact on clinical outcome remains underexplored. This study investigated whether routine MDM2 FISH testing on preoperative biopsy is associated with a reduction in the recurrence risk of ALT.
METHODS: A total of 336 patients with MDM2-verified well-differentiated lipomatous tumours (ALT, n = 67; lipoma, n = 269) treated at a tertiary sarcoma centre were retrospectively analysed. Clinicopathological parameters, histological-molecular concordance, pre-operative diagnostic approach and recurrence rates were compared.
RESULTS: Compared to benign lipomatous tumours, ALT patients were older (p = 0.002), had larger tumours (median 15.0 vs 7.0 cm, p < 0.001) and more frequently deep extremity lesions (p < 0.001). Up to 25% of biopsy specimens of ALT exhibit purely benign morphology. ALT patients who underwent preoperative biopsy with MDM2 FISH had a lower recurrence rate than those who did not (16.2% vs 56.7%, p < 0.001). This was associated with a higher rate of extracapsular excision (97.3% vs 71.4%-77.8%, p = 0.021).
CONCLUSION: Routine MDM2 FISH testing on preoperative biopsy provides a definitive diagnosis of ALT, especially for lipoma-like histology, enabling surgeons to plan extracapsular excision and thereby reducing local recurrence.

Keywords: ALT; FISH; MDM2; atypical lipomatous tumour; preoperative; recurrence

DOI: https://doi.org/10.1002/jso.70349

Cancer Metastasis Rev. 2026 Jul 30. pii: 52. [Epub ahead of print]45(3):

Tumorigenesis of well-differentiated and dedifferentiated liposarcoma: 12q amplicon architecture, oncogenic cargo, and evolutionary progression.

Aobo Zhuang, Xiao Zhou, Chengfei Xu, YangJu Chen, Xueling Wang, Runchun Li, Jiajing Hu, Yinxue Cheng, Yunyan Wan, Ting Wu, Wengang Li.

Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are characterized by recurrent MDM2-centered amplification of chromosome 12q13-15, yet this diagnostic label reduces a complex structural lesion to a binary result. An architecture-resolved 12q amplicon platform requires an MDM2-centered dosage anchor plus direct evidence of nontrivial topology or carrier state; cargo, regulatory, and functional data define progressively higher-resolution features. When only MDM2 amplification is documented, the lesion is best described as diagnostic 12q amplification rather than a fully resolved platform. This review presents an evidence-graded architecture-to-function framework that separates direct WDLPS/DDLPS observations from mechanisms inferred from broader amplification biology. Disease-specific evidence supports heterogeneous 12q carriers, including ring, giant marker, rod-shaped, discontinuous, and neochromosome-like structures, as well as enhancer coamplification or altered 3D contacts. In contrast, chromothripsis, telomere crisis/BFB remodeling, ecDNA-like dynamics, and enhancer hubs are treated as extrapolated or testable mechanisms unless directly validated in liposarcoma. Conclusions are weighted by methodological resolution: cytogenetics/FISH define diagnostic amplification and visible carrier classes; MLPA or array-based assays define dosage and discontinuity; WGS with long-read or optical mapping is needed for junction-level architecture; and single-cell/spatial assays mainly resolve cellular-state or ecosystem context unless paired with structural readouts. MDM2-p53 and CDK4-RB remain central outputs, whereas selected cargo, lineage state, metabolism, and tumor-microenvironment programs are interpreted as evidence-ranked cooperating or downstream modules. Clinically, architecture-aware interpretation is proposed as a prospective framework for sampling, model design, biomarker development, and trial stratification, not as an established basis for routine management.

Keywords: 12q amplification; Amplicon architecture; Enhancer hijacking; Liposarcoma; Neochromosome; Tumor evolution

DOI: https://doi.org/10.1007/s10555-026-10363-w

Curr Issues Mol Biol. 2026 Jul 10. pii: 700. [Epub ahead of print]48(7):

Between Chemical Simplicity and Biological Complexity: In Silico Profiling of Butyrolactones I and III as Potential Multi-Target Drug Candidates.

Tomasz Kowalczyk, Anna Merecz-Sadowska, Belma Konuklugil, İbrahim Seyda Uras, Radosław Zajdel, Patricia Rijo, Przemysław Sitarek.

The development of multi-targeted therapeutic agents is increasingly recognized as essential for treating multifactorial diseases. Butyrolactone I and butyrolactone III, γ-butyrolactone derivatives isolated from the marine fungus Aspergillus terreus, represent structurally related natural products with largely unexplored polypharmacological potential. This study employed a comprehensive in silico approach combining ADMET profiling, quantum chemical calculations, molecular docking, and molecular dynamics simulations to evaluate their therapeutic potential across multiple pharmacological targets. Physicochemical analysis revealed favorable drug-like properties for both compounds, with complete compliance with Lipinski's Rule of Five, high predicted gastrointestinal absorption (>80%), and acceptable toxicity profiles (toxicity class 4, LD50 = 2000 mg/kg). Neither compound showed hepatotoxic, neurotoxic, cardiotoxic, carcinogenic, or mutagenic liabilities. Frontier molecular orbital analysis (DFT/B3LYP/6-31G(d,p)) revealed comparable HOMO energies (-6.054 and -6.059 eV), with butyrolactone III exhibiting enhanced kinetic stability based on a larger HOMO-LUMO gap (4.662 eV vs. 4.443 eV) and higher chemical hardness (η = 2.331 eV vs. 2.222 eV). Molecular docking against four therapeutic targets revealed target-selective binding profiles: butyrolactone III demonstrated binding affinity toward acetylcholinesterase exceeding donepezil (-9.0 vs. -8.3 kcal/mol), while butyrolactone I exhibited MDM2 binding affinity slightly exceeding nutlin-3a (-7.8 kcal/mol). Both compounds showed moderate interactions with COX-2 and topoisomerase IV. Molecular dynamics simulations validated the stability of AChE complexes (RMSD < 2.0 Å) and the MDM2-butyrolactone I complex (RMSD: 0.69 ± 0.09 Å), while the MDM2-butyrolactone III complex exhibited significant instability (RMSD up to 3.55 Å), highlighting the critical role of the prenyl group in MDM2 recognition. These findings, consistent with, though not a direct experimental validation of, previously published in vitro data, support the evaluation of butyrolactone III as a scaffold for neuroprotective agents and butyrolactone I as a p53 pathway modulator for cancer therapy, illustrating the potential value of fungal metabolites in multi-target drug discovery and the role of integrated computational approaches in prioritizing candidates for subsequent experimental testing.

Keywords: ADMET; Aspergillus terreus; MDM2; acetylcholinesterase; butyrolactone I; butyrolactone III; molecular docking; molecular dynamics; multitarget drug discovery; natural products

DOI: https://doi.org/10.3390/cimb48070700