Sarcomatoid renal cell carcinoma has a distinct molecular pathogenesis, driver mutation profile and transcriptional landscape

Purpose: Sarcomatoid renal cell carcinoma (SRCC) ranks among the most aggressive clinicopathologic phenotypes of RCC. However, the paucity of high-quality, genome-wide molecular examinations of SRCC has hindered our understanding of this entity.<br /><br />Experimental Design: We interrogated the mutational, copy number, and transcriptional characteristics of SRCC and compared these data with those of non-sarcomatoid RCC (RCC). We evaluated whole exome sequencing, single nucleotide polymorphism, and RNA sequencing data from patients with SRCC (n=65) and RCC (n=598) across different parent RCC subtypes, including clear cell RCC, papillary RCC, and chromophobe RCC subtypes.  <br /><br />Results: SRCC was molecularly discrete from RCC and clustered according to its parent RCC subtype, though with upregulation of TGFβ signaling across all subtypes.  The epithelioid (E-) and spindled (S-) histologic components of SRCC did not show differences in mutational load among cancer related genes, despite a higher mutational burden in S-.  Notably, sarcomatoid clear cell RCC (SccRCC) showed significantly fewer deletions at 3p21-25, a lower rate of two-hit loss for VHL and PBRM1, and more mutations in PTEN, TP53, and RELN compared to clear cell RCC (ccRCC).  A two-hit loss involving VHL predicted for ccRCC and a better prognosis whereas mutations in PTEN, TP53, or RELN predicted for SccRCC and worse prognosis.  <br /><br />Conclusions: Sarcomatoid RCC segregates by parent subtype and SccRCC has a fundamentally different early molecular pathogenesis, usually lacking the classic 3p21-25 deletion and showing distinctive mutational and transcriptional profiles.  These features prompt a more precise molecular classification of RCC with diagnostic, prognostic, and therapeutic implications.

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