The genomic landscape of metastatic non-clear cell renal cell carcinoma.

Abstract

474 Background: Non-clear cell renal cell carcinoma (nccRCC) encompasses about 20% of RCC cases and includes a number of subtypes that vary clinically and molecularly. Compared to ccRCC, these tumors have more limited sensitivity to conventional anti-VEGF agents and mTOR inhibitors, and there is clear need for better therapies. Analysis of genomic alterations in potentially targetable pathways may lead to novel therapeutic development strategies. Methods: We retrospectively analyzed tumors from 112 patients with metastatic nccRCC with targeted next-generation sequencing (NGS) across a panel of >340 cancer-relevant genes. Matched tumor and normal was used to facilitate somatic calling. We report on recurrent alterations observed for nccRCC variants. Results: Median age was 53 years (range 12-77), 67% were male; 47% presented with metastatic disease and 53% with localized disease that later metastasized. NGS was performed on tissue from primary tumors (57%) or metastatic sites (43%). Subtype classifications included unclassified (44%), papillary (21%), chromophobe (13%), translocation (12%), and other (9%). The most frequently altered genes by subtype are included in table. 36% of unclassified or papillary tumors had a mutation in a putative driver gene amenable to targeted therapies, including MET, NOTCH1, SMARCB1, TSC1, TSC2, PIK3CA, and FGFR3. 3 chromophobe tumors and 1 translocation tumor had a mutation in a potentially targetable pathway. Conclusions: The mutation profiles of metastatic nccRCC vary by papillary, chromophobe, and translocation subtype, with unclassified tumors most approximating papillary subtype. Unclassified and papillary subtypes harbor frequent mutations in potentially targetable pathways that merit further investigation. [Table: see text]