Molecular analysis of renal cell carcinoma with unclassfied histology [copy number alterations]

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. Affymetrix Oncoscan arrays were performed according to the manufacturer's directions on DNA extracted from paraffin embedded formalin fixed tumor tissues from 15 unclassified renal cell carcinomas. Genome-wide DNA copy number alterations and allelic imbalances were analyzed.