Peroxisome Proliferator-Activated Receptor Gamma (PPARG) status defines the luminal lineage in molecular profiles of advanced urothelial cancers (UC)

Background: About 20 000 patients are diagnosed with muscle-invasive UC annually, where the five-year survival rate is approximately 5% in metastatic cases. The transcription factor PPARG associated luminal lineage subtype reflecting ∼65% of all advanced patients. Recurrent genetic alterations PPARG, including focal amplification, missense mutations, and fusions, as well hotspot mutations its obligate heterodimer, retinoid X receptor alpha (RXRA) characteristic this molecular subtype. Materials Methods: We analyzed tumor tissue collected from over 3000 sequenced using Tempus xT assay (DNA-seq 648 genes at 500x coverage; RNA-seq; 3262pt DNA, 2685pt both). Molecular classification (luminal papillary, luminal, infiltrated subtypes) or non-luminal (basal-squamous neuronal was performed non-negative matrix factorization (NMF) rank 5 following Robertson method, excluding gene set to eliminate inference bias. Mean expression reported Log2[TPM+1]. Mutations were single nucleotide variants insertion/deletions (SnvIndel). Results: determined that luminal-papillary (669pt), (449pt), luminal-infiltrated (621pt) subtypes comprised 65% real-world cohort, consistent distribution TCGA data set. Higher (7.78 Log2[TPM+1], p < 0.00001) compared (5.47 Log2[TPM+1]). prevalence RXRA, fibroblast growth 3 (FGFR3) also significantly higher subtype, frequency amp (copy number 4–7) 10% (p 0.05), SnvIndel 2.0% = 0.8), RXRA 3.3% 0.00005) FGFR3 14% 0.005). Collectively 1 a population harbored FGFR3. A threshold (7.75 Log2[TPM+1]) derived logistic regression comparing amplified diploid patients, gain even one copy overexpression. Many exhibit (7.49 comparable High sustained samples (7.55 Log2[TPM+1]), did not vary by site > 0.05). Conclusion: To best our knowledge, represents largest dataset evaluated date. Stratification based upon status defining feature phenotype supports targeting pathway novel agents under development. Conflict interest: Ownership: Flare-affiliated authors shareholders Flare Therapeutics.