Molecular analysis of renal cell carcinoma with unclassfied histology [gene expression]

Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell RCC (nccRCC) that have no standard therapy. The oncogenic drivers in these tumors are unknown. We performed a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, Single Nucleotide Polymorphism array, fluorescence in-situ hybridization, immunohistochemistry, and cell-based assays. We identified recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%), and MTOR (8%). Integrated analysis revealed distinct molecular subsets, including a subset of 26% uRCC characterized by NF2-loss, dysregulated Hippo-YAP pathway and worse survival. Analysis of RNA from uRCC with or without NF2-loss