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

Zixing Wang, Tae Beom Kim, Bo Peng, Jose Karam, Chad Creighton, Aron Joon, Fumi Kawakami, Patricia Trevisan, Eric Jonasch, Chi Wan Chow, Jaime Rodriguez Canales, Pheroze Tamboli, Nizar Tannir, Christopher Wood, Federico Monzon, Keith Baggerly, Marileila Varella-Garcia, Bogdan Czerniak, Ignacio Wistuba, Gordon MillsKenna Shaw, Ken Chen, Kanishka Sircar

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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. Experimental Design: We interrogated the mutational, copy number, and transcriptional characteristics of SRCC and compared these data with those of nonsarcomatoid 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. 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 with 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. Conclusions: SRCC 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.

Original languageEnglish (US)
Pages (from-to)6686-6696
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number21
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Wang, Z., Kim, T. B., Peng, B., Karam, J., Creighton, C., Joon, A., Kawakami, F., Trevisan, P., Jonasch, E., Chow, C. W., Canales, J. R., Tamboli, P., Tannir, N., Wood, C., Monzon, F., Baggerly, K., Varella-Garcia, M., Czerniak, B., Wistuba, I., ... Sircar, K. (2017). Sarcomatoid renal cell carcinoma has a distinct molecular pathogenesis, driver mutation profile, and transcriptional landscape. Clinical Cancer Research, 23(21), 6686-6696. https://doi.org/10.1158/1078-0432.CCR-17-1057