American Association for Cancer Research
10780432ccr171057-sup-181839_2_supp_4126853_cs7tld.docx (60.65 kB)

Supplementary Methods from Sarcomatoid Renal Cell Carcinoma Has a Distinct Molecular Pathogenesis, Driver Mutation Profile, and Transcriptional Landscape

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journal contribution
posted on 2023-03-31, 20:24 authored by 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 Mills, Kenna Shaw, Ken Chen, Kanishka Sircar

Supplemental Methods 1. Exome sequencing pipeline Supplemental Methods 2. RNA seq pipeline Supplemental Methods 3. DNA methylation profiling pipeline Supplemental Methods 4. Fluorescence in situ hybridization Supplemental Methods 5. TCGA samples with possible copy neutral loss of heterozygosity in 3p21 and 3p25 regions





University of Texas MD Anderson Cancer Center



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. Clin Cancer Res; 23(21); 6686–96. ©2017 AACR.See related commentary by Bergerot et al., p. 6381