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Clin Cancer Res. 2017 Nov 1;23(21):6686-6696. doi: 10.1158/1078-0432.CCR-17-1057. Epub 2017 Jul 14.

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

Author information

1
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Department of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
4
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado.
6
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Castle Biosciences, Friendswood, Texas.
9
Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ksircar@mdanderson.org.

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 AACRSee related commentary by Bergerot et al., p. 6381.

Comment in

PMID:
28710314
PMCID:
PMC5683086
DOI:
10.1158/1078-0432.CCR-17-1057
[Indexed for MEDLINE]
Free PMC Article

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