Background: Next generation sequencing (NGS) for advanced tumors is becoming more routine. However, not all patients respond to precision matched treatments. We hypothesized that one potential reason for treatment failure with targeted therapy could be discrepancies between DNA alterations and RNA expression. Methods: Tumor samples from patients with metastatic kidney, bladder, and prostate cancer were analyzed by whole exome or whole genome NGS and RNA sequencing (CLIA-certified laboratory; NantOmics LLC, Santa Cruz, CA). Only known pathogenic driver alterations were analyzed in the current study. Results: Of 45 patients, 10 had kidney cancer, 18 had bladder cancer; and 17 had prostate cancer. Median age was 66 years (range, 28 - 86). The most commonly altered genes were TP53 (35.6% [16/45]), PIK3CA (15.6% [7/45]), FGFR3 (11.1% [5/45]), ALK (8.9% [4/45]), and ATM (8.9% [4/45]). In total, 86 pathogenic DNA alterations were identified; 17 of these (19.8%) were not observed at the RNA level. Among 45 patients, 31.1% (14/45) had ≥1 DNA alteration that was not expressed at the RNA level. Discordance between DNA and RNA was seen in 40% of patients with kidney cancer (4/10), 28% of patients with bladder cancer (5/18), and 29% with prostate cancer (5/17). Examples of genes that had pathogenic DNA alterations not seen at the RNA level included ALK (four discordant cases), KDR (three discordant cases) and GNAS (one discordant case). On the other hand, alterations involving certain genes showed 100% concordance between DNA and RNA: TP53 [N = 16], PIK3CA [N = 7], and FGFR3 [N = 5]). Conclusions: A significant number of patients with genitourinary tumors had DNA alterations that are silenced at the RNA level (19.8%). Transcriptomic silencing merits additional investigation as a mechanism that could mediate resistance to therapeutics targeted at cognate alterations.