Background: Novel biomarkers are required to accurately assess response in renal cancer. Genomic alterations (GAs) in samples from primary (nephrectomy) (N) as compared distant metastases (M) in clear cell RCC (ccRCC) may have clinical implications as well as mutations in circulating tumour DNA (ctDNA). Methods: 237 primary ccRCC nephrectomy specimens and 156 samples from distant metastases were assayed by hybrid capture based comprehensive genomic profiling (CGP) in the course of clinical care to identify GAs suggesting benefit from targeted therapy. Tumor mutation burden (TMB) was assessed as the number of somatic coding point mutations per megabase of targeted territory. Aditionally, 17 patient-specific assays were developed to quantify ctDNA allele fraction (AF) in plasma of mRCC patients. Results: 1263 GAs and 34 clinically relevant GA (CRGAs) were identified. Most common GA identified were VHL (74%/72%), PBRM1 (40%/51%), SETD2 (28%/26%) in N and m respectively (Table). Additionally, most common CRGA identified were TP53 (8%/15%), PTEN (10%/10%), TSC1 (6%/6%), and TERT(5%/9%) in N and m respectively. No difference in TMB was seen between primary and metastatic samples. By site of metastases, soft tissue, and adrenal gland had the highest TMB and lymph node the lowest. In the 17 patients with available ctDNA, 15/17 (88.2%) have a maximum somatic AF < 1% (median 0.33% [0% - 22%]) suggesting generally low tumor content. Interestingly, ctDNA in 3 patients were successfully sequenced including a patient with an EML4-ALKfusion treated with alectinib. Conclusions: This data supports that both primary and metastatic RCC share the majority of common GA. Quantitation of ctDNA is a promising biomarker for response.