Parthanatos, a novel form of programmed cell death mediated by PARP1 and driven by DNA damage, has not been comprehensively characterized in breast cancer (BC). Given the widespread clinical use of PARP1 inhibitors for treating BRCA-mutant breast cancers, understanding the role of parthanatos is crucial. In this study, we systematically analyzed the role and clinical significance of parthanatos in BC by integrating genomic, transcriptomic, and clinical data. Our analysis revealed significant differential expression of parthanatos-related genes between BC and normal breast tissues, with frequent copy number variations (CNVs) affecting gene expression. At the single-cell level, parthanatos-related genes were primarily expressed in breast cancer cells and macrophages, and genomic instability scores were positively correlated with parthanatos pathway scores. Unsupervised clustering identified two BC subtypes based on parthanatos-related gene expression: C1 (parthanatos-high) and C2 (parthanatos-low). C1 exhibited a poorer prognosis, reduced immune infiltration, and potential resistance to PARP inhibitors compared to C2. This study represents the first comprehensive investigation of parthanatos in BC, offering insights into its role in tumor progression and highlighting its potential link to PARP inhibitor resistance and poor clinical outcomes.

Recent clinical trials have suggested that solid cancers with mismatch repair (MMR) deficiency are highly responsive to immunotherapy, regardless of cancer types. Previous MMR-related studies on breast cancer have predominantly focused on germline variants. However, the somatic MMR alterations have not been comprehensively characterized in breast cancer. In this study, we integrated genomic, transcriptomic, and clinical data from over 3000 breast cancer cases across six public cohorts. Our findings revealed that 1.2% of breast cancers harbored oncogenic somatic MMR alterations, with triple-negative breast cancer (TNBC) demonstrating the highest mutation rate at 3.1%. Additionally, somatic MMR alterations were significantly associated with microsatellite instability-high (MSI-H) and MMR-related mutational signatures, indicating that somatic MMR alterations led to impaired function of the MMR system. Biallelic inactivation of MMR genes resulted in a more pronounced loss of MMR function compared to monoallelic inactivation. Importantly, these MMR alterations significantly increased the tumor mutational burden (TMB) and neoantigen load in breast cancer, regardless of MSI-H status. These findings indicate that the frequency of MMR alterations is highest in TNBC and that MMR alterations in breast cancer can lead to MMR functional deficiencies, suggesting that some patients harboring such alterations may benefit from immunotherapy.

Malignant giant cell tumor of bone (GCTB) is a rare malignant bone tumor. This analysis was conducted on patients with malignant GCTB at our center. The clinical, demographic, and prognostic characteristics were evaluated and compared. During 1 January 2015 to 31 December 2022, fifty patients were included in the study, which made up 3.3% of the contemporary GCTB patients. The clinical characteristics were comparable between the 24 patients with primary malignant GCTB (PMGCTB) and 26 patients with secondary malignant GCTB (SMGTCB). The tumor location was mainly at the axial and pelvic region (70%) and differed between the two types (p = 0.040). H3F3A pathogenic variant presented frequently in SMGCTB (p = 0.020). Cox regression analysis showed the prognostic outcomes were poor in those with a tumor located in the axial bone and sacrum with invasion of other places. H3F3A mutation status is also a risk factor, while chemotherapy and denosumab failed to demonstrate prognostic benefits. Malignant GCTB is a rare condition with a poor prognosis, especially in SMGTCB. The location and H3F3A mutation status had an influence on prognosis, and systemic therapy should be taken into consideration for patients with unfavorable prognostic features.

This review aims to summarize the evolution of surgical techniques for periacetabular metastatic cancer, assess their strengths and limitations, and clarify the corresponding indications. We conducted a comprehensive literature review on periacetabular metastatic cancer, summarizing surgical techniques involving both open and minimally invasive approaches. Additionally, we evaluated the indications for different minimally invasive techniques and proposed potential combinations of these techniques. Our review underscores the benefits of minimally invasive surgery, including reduced surgical trauma, improved patient mobility, lower complication rates, and expedited recovery times, facilitating earlier initiation of systemic cancer therapies. These techniques show substantial potential for broader application in the future. Despite the historical reliance on open surgery as the standard treatment, minimally invasive approaches are emerging as a promising alternative, particularly for managing osteolytic metastases around the acetabulum. This review provides insights into the optimal integration of these techniques, aiming to support evidence-based clinical decision-making and improve patient outcomes.

Aim: Osteosarcoma remains aggressive with poor prognosis, particularly in chemotherapy-resistant cases. This study aimed to characterize transcriptional features of chemoresistant osteosarcoma cells, establish a prognostic resistance signature, and identify therapeutic vulnerabilities. Methods: Single-cell RNA sequencing (scRNA-seq) was performed on paired pre- and post-neoadjuvant chemotherapy (NAC) specimens from three patients (6 samples; 16,272 cells). Resistance trajectories were reconstructed using Monocle 3 pseudotime analysis. A nine-gene resistance score was validated in the Peking University People’s Hospital (PKPH) bulk RNA-seq cohort (n = 70) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database (n = 87), with drug sensitivities predicted via oncoPredict. Results: Chemotherapy reduced the malignant cell fraction but triggered expansion of cancer-associated fibroblasts and endothelial cells, creating a stromal-dominant, immune-sparse residual niche. Surviving tumor cells upregulated a nine-gene module along the resistance trajectory: KCNMA1, KIF21A, MIR181A1HG, RPS27, PDPN, ADIRF, PRELP, PHEX, and COL9A2. In an independent unpaired scRNA-seq cohort (two pre- and three post-chemotherapy samples), this signature remained associated with features of chemotherapy resistance. Higher scores correlated with poorer histopathologic response (r = -0.35, P = 0.006) and shorter progression-free survival [PKPH: hazard ratio (HR) = 2.4, 95% confidence interval (CI) 1.2-4.8, P = 0.01; TARGET: HR = 2.1, 95%CI 1.1-4.0, P = 0.02]. Of 198 compounds screened, only Pictilisib, a phosphoinositide 3-kinase (PI3K) inhibitor, showed lower predicted IC50 in the high-score subset across both datasets. However, the paired discovery cohort warrant further validation. Conclusion: Our paired scRNA-seq approach identifies a nine-gene signature linking pre-treatment tumor biology to NAC response and outcome. The enhanced Pictilisib sensitivity in chemoresistant tumors positions PI3K blockade as a strategy meriting prospective testing in refractory osteosarcoma.

Immunoglobulin heavy chain ( IGH ) enhancer translocations drive multiple myeloma (MM), but routine diagnostics resolve only 32 to 38% of cases. Here, we introduce TransFinder, a multiomic pipeline integrating SMRT long-read sequencing (LRS), Hi-C, H3K27ac ChIP-seq/CUT&Tag, and RNA-seq to systematically resolve cryptic translocations and their hijacked oncogenes by deconvoluting enhancer-promoter neo-loops at rearrangement breakpoints. Applied to MM, TransFinder identified that t(16;22)(q23;q11), a canonical translocation known to activate MAF , also hijacks enhancers to activate RAB36 . It further uncovered previously unrecognized t(5;8)(q35;q24) and t(1;22)(q25;q13), which activate MYC and CBX7 , respectively, through chromatin topology rewiring. CRISPR-Cas9–engineered t(1;22)(q25;q13) recapitulated CBX7 induction, and pharmacological inhibition of CBX7 suppressed myeloma cell proliferation. Beyond MM, TransFinder identified enhancer hijacking in chronic myeloid leukemia, where t(9;22)(q34;q11) repositioned an enhancer to activate BCR-ABL1 , and pancreatic ductal adenocarcinoma, where t(2;12)(p24;q24) hijacked an enhancer to activate SDC1 . Linking 3D genome architecture to oncogene activation, TransFinder decodes oncogenic structural variants and their trans-activities, establishing clinically actionable dependencies of noncoding drivers in malignancies.