Comprehensive genomic analysis of translocation renal cell carcinoma reveals copy number variations as drivers of disease progression.

PURPOSE: Translocation renal cell carcinoma (tRCC) is a rare, aggressive RCC subtype. There is currently limited understanding on the role of molecular alterations in the pathogenesis and progression of these tumors. We investigated the association between somatic alterations and clinical outcomes in two independent cohorts profiled using DNA-sequencing. EXPERIMENTAL DESIGN: Twenty-two tRCCs underwent targeted sequencing (MSK-IMPACT); a subset was profiled using exome-sequencing and combined with exome data from The Cancer Genome Atlas (TCGA) for analysis. The prognostic value of specific somatic aberrations, tumor mutation burden (TMB) and fraction of copy-number altered genome (FCNAg) was explored. In TCGA cases, neoantigen prediction and immune cell deconvolution were performed using RNA-seq and exome data. Overall survival estimates were computed using the Kaplan-Meier method; time-on-treatment (TOT) was calculated for 14 MSK-IMPACT patients who underwent systemic therapy. Associations between molecular features and outcomes were evaluated using non-parametric testing. RESULTS: Copy-number aberrant tRCCs were associated with poor overall survival (p=0.03). Pediatric patients had tumors with lower FCNAg (p=0.01). In one adult case with two chronologically distinct tumor samples sequenced, we confirmed that copy-number events occurred early during evolution. TERT promoter mutations were found exclusively in high-stage tumors. We found that tRCCs displayed distinct angiogenesis and PD-L1 gene expression profiles compared to other RCC subtypes. CONCLUSIONS: Tumors molecularly defined by increased CNVs were associated with aggressive disease in tRCC. A higher burden of genomic events in adults compared to pediatric cases likely reflects a more aggressive clinical course. The unique immunophenotypic characteristics of tRCC merit further exploration.