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Figures S1-S10 from Sarcomatoid Renal Cell Carcinoma Has a Distinct Molecular Pathogenesis, Driver Mutation Profile, and Transcriptional Landscape

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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

Figure S1. Biphasic histologic components of sarcomatoid renal cell carcinoma. The macrodissected paired epithelioid or carcinomatous (E) and spindled or sarcomatoid (S) components of clear cell RCC (upper panel), Papillary RCC (middle panel), and chromophobe RCC (lower panel). H&E stain, scale bar 200 �m. Figure S2. Sarcomatoid ccRCC shows fewer VHL deletions. (A) Clear cell RCC (H&E stain, scale bar 100 µm) with (B) Fluorescence in situ hybridization (FISH) image showing paired CEN3q signals (green) and a single VHL signal (red). (C) Sarcomatoid ccRCC (H&E stain, scale bar 100 µm) with (D) FISH image showing balanced CEN3q (green) and VHL (red) signals. (E) Box plot showing significantly higher VHL/3q ratios associated with sarcomatoid histology, P<0.008. Figure S3: The smooth scatter plot of signal B versus signal A. Figure S4a: 3p21 and 3p21.1 copy number versus chromosome position. Figure S4b: 3p25 copy number versus chromosome position. Figure S5: Kernel density plots. Each sample per row; left three columns: 3p21; middle three columns: 2q37; and right three columns: 1p1. Figure S6a: Example of more than one peak in the summed signal. Figure S6b: Example of 4 peaks in signals A and B. Figure S7: Density plots of TCGA samples with copy-neutral LOH. Figure S8. VHL and PBRM1 show fewer 2-hit inactivation in sarcomatoid ccRCC. Sarcomatoid ccRCC and ccRCC cases shown in terms of the inactivating "hits" on 3p21-25 genes (VHL, PBRM1, SETD2, BAP1) consisting of mutations or methylation (mutually exclusive for VHL) and deletions. Figure S9. Top activated and inhibited pathways of sarcomatoid samples. Pathways altered by differentially expressed genes between non-sarcomatoid and sarcomatoid samples. The genes selected were differentially expressed in both the TCGA and MD Anderson samples. Figure S10. S- component shows a higher mutational load in sarcomatoid RCC. The total number of non-synonymous mutations in the E- and S- components of sarcomatoid RCC, across all parent RCC subtypes (A) and in clear cell RCC (B).

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NIH

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University of Texas MD Anderson Cancer Center

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