Dsai-01 Tumor Evolution of Brain-Specific Tropism in Metastatic Renal Cell Carcinoma

Abstract BACKGROUND Herein, we describe the molecular landscape of renal cell carcinoma (RCC) brain metastases (BrMs). METHODS Panel-based DNA (DNAseq) and whole-transcriptome sequencing (RNAseq) were used to assess BrM, non-BrM and matched primary renal tumors (PRT) from RCC patients who underwent resection. RESULTS 95samples (BrM=54, nBrM=14, PRT=27) from 53patients were included (85% clear-cell histology). DNAseq of 85 samples (50pts) identified common mutations in VHL (18pts, 36%), TP53 (24%), PBRM1 (24%), SETD2 (24%), and BAP1 (8%). MTOR-pathway mutations were enriched, with 25pts (50%) having at least one mutation in PTEN (12pts, 24%), TSC1 (8%), TSC2 (10%), or MTOR (18%). Copy number analyses revealed frequent deletions in chr14q21(34pts, 68%) and chr9p21 (70%) and gains in chr20q13 (62%) and chr7p15 (62%). At the sample-level, PTEN mutations were more common in BrM (11pts, 22.9%) versus non-BrM (0) and PRT (12%, p=0.124), as were deletions in chr13q22 (BrM=26.5% 13pts, non-BrM=8.3%, PRT=4%; p=0.036) and gains in chr20q13 (BrM=61.2% 30pts, non-BrM=33.3%, PRT=32%; p=0.03). Chr9p21 deletions were enriched in BrM (32pts, 65.3%) and non-BrM (66.7%) relative to PRTs (28%, p=0.006). Other copy number alterations and somatic mutations had similar distribution across sites. Analysis of 86 samples (51pts) identified 806 genes expressed differentially between BrM and PRT (adjusted p0.05), 399 between BrM and non-BrM (adj. p0.05). Gene set enrichment analysis of MSigDB Hallmark gene sets revealed upregulation of MTORC1 signaling, glycolysis, and MYC targets in BrM comparted to PRT and non-BrM (adj. p0.0001). Immune-related gene sets, e.g. interferon-alpha, interferon-gamma, TNF-alpha, were enriched in PRT relative to BrM (adj. p0.0001), but not non-BrM (adj. p 0.05). CIBERSORT cellular deconvolution analysis comparing BrM with PRT revealed increased proportions of M2 (p=0.0009), but decreased M1 macrophages (p=0.0003) and CD8+T-cells (p=0.0106). CONCLUSIONS RCC with BrM exhibit distinct MTOR-pathway enrichment and hyperactivation. The immunosuppressive milieu in BrM may be steroid-related. Further analyses are underway.