Using RNAseq data from the IMmotion 151 clinical trial (IM151), 7 RCC biologic clusters have been defined. Several groups have attempted to predict clusters on RCC datasets without observing the association with therapy response from IM151. We developed IRIS-RCC (Individual RNA-seq Intrinsic Subtyping for RCC; available at https://irisrcc.vindhyadatascience.com/), to predict molecular clusters using an individual-sample model. IRIS-RCC normalizes gene expression within a given sample using ratiometric gene expression values.
Germline heterozygous BAP1 pathogenic/likely pathogenic (P/LP) variants are associated with the BAP1-tumor predisposition syndrome (BAP1-TPDS). This study evaluated evidence for an association between ovarian cancers and BAP1-TPDS. We evaluated ovarian cancer incidence in two independent cohorts of female subjects with germline BAP1 P/LP variants. Additionally, we investigated whether the high incidence of spontaneous ovarian sex cord-stromal tumors (OSCSTs) in heterozygous Bap1-mutant FVB/N mice was strain-specific by examining their occurrence in several other Bap1-mutant mouse models with different genetic backgrounds. In the combined human cohort of 176 females with BAP1 P/LP variants, 7 (4%) had ovarian cancer, including 3 with OSCST. Another OSCST occurred in a patient with a germline BAP1 variant with conflicting pathogenesis, for which functional studies supported pathogenicity. OSCSTs were observed in all mouse strains with germline heterozygous Bap1 mutations (incidence: 32%–73%). Biallelic inactivation of BAP1 was observed in 3/3 human and 10/10 murine OSCSTs. OSCSTs from Bap1-mutant mice showed marked decreases in Bmpr1b, Erb, and Foxl2 expression, suggesting disruption of pathways involved in ovarian differentiation and homeostasis. In conclusion, ovarian cancers, particularly OSCSTs, represent a rarer phenotype of the BAP1-TPDS. Downregulation of Bmpr1b, Erb, and Foxl2 may reflect alterations in pathways amenable to therapeutic targeting in OSCSTs.
Immune checkpoint inhibitors (ICIs) and BRAF/MEK kinase inhibitors have substantially improved survival in advanced melanoma; however, therapeutic resistance and severe toxicities underscore the ongoing need for alternative strategies. Here, we evaluate the clinical utility of multi-omic profiling, biomarker-stratified recommendations, and survival outcomes within a prospective cohort of 98 patients with advanced cutaneous or uveal melanoma evaluated by the Molecular Tumor Board Freiburg (MTB-FR) between 2021 and 2024. Completed profiling revealed at least one potential actionable target beyond classical BRAF V600 mutations in 83.8% of cases. Alterations in NRAS, atypical BRAF variants, CDK4/6 pathway amplifications, and DNA-damage response (DDR) gene mutations most frequently guided board recommendations. Biomarker-stratified therapies were recommended for 68.4% of patients, and personalized immunotherapy combinations for 72.4%. The treatment implementation rate was 33.8% (n = 27), achieving an overall disease control rate (DCR) of 42.9% and an overall response rate (ORR) of 10.7%. These findings demonstrate that comprehensive molecular profiling in a real-world setting uncovers actionable alterations, providing viable subsequent treatment avenues that may optimize outcomes for heavily pretreated melanoma patients beyond established standards of care. Ultimately, prospective, randomized, biomarker-driven trials remain essential to validate whether these individualized diagnostic strategies translate into a reproducible survival benefit.
Tumor invasion and distant metastasis remain major causes of treatment failure in lung adenocarcinoma (LUAD), thereby elucidating the molecular mechanisms is critical for precise treatment of LUAD. Using bulk RNA-Seq and single cell transcriptome data, combining with multi-machine learning methods, we identified GOLM1 as a core gene associated with poor prognosis in LUAD, which is highly expressed in malignant epithelial cells characterized by increased extracellular matrix (ECM)-integrin signaling, glycosylation remodelling and invasion-related transcriptional programs. Mechanistically, we validated that STAT1 is an upstream transcription activator of GOLM1 that forms a STAT1-GOLM1 axis that triggers LUAD invasion. Candidate compounds were prioritized by computational molecular docking against STAT1 and subsequently evaluated in A549 cells. Experimental validation revealed that Compound 1 exhibited the strongest inhibitory effect on LUAD cells by regulating PI3K/AKT signaling, cell-cycle and apoptosis. Collectively, our results elucidated the significant role of STAT1-GOLM1 axis in LUAD and provided a promising AI-directed inhibitor for LUAD.
This study investigates the role of NDUFS2 in non-small cell lung cancer (NSCLC). The bioinformatics analysis of The Cancer Genome Atlas (TCGA) elucidated upregulation of NDUFS2 expression in NSCLC tissues relative to normal counterparts, correlating with unfavorable clinicopathological parameters. The single-cell RNA sequencing data further show NDUFS2 enrichment within malignant cancer cell populations across diverse primary NSCLC tumors and their metastatic sites. Validation studies employing local patient tissues and various NSCLC cell types corroborated the increased NDUFS2 expression observed in cancerous cells. NDUFS2 silencing or knockout induced profound mitochondrial dysfunction, and curtailed NSCLC cell viability, proliferation, migration, and invasion. These adverse cellular outcomes were partially mitigated by exogenous glucose or the antioxidant N-acetylcysteine. Conversely, forced overexpression of NDUFS2 enhanced mitochondrial function and augmented malignant characteristics. NDUFS2 was identified as a positive regulator of Akt-mTOR signaling pathway. The in vivo xenograft models showed that AAV-mediated NDUFS2 knockdown suppressed primary NSCLC cell xenograft growth in nude mice. Analysis of xenograft tissues confirmed the molecular consequences observed in vitro, including ATP depletion, oxidative damage, proliferation inhibition, Akt-mTOR inactivation, and apoptosis induction. Together, NDUFS2 acts as an oncogenic driver in NSCLC that supports mitochondrial function, enhances malignant phenotypes, and promotes the Akt-mTOR pathway.
