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Sci Rep. 2020 Jan 20;10(1):701. doi: 10.1038/s41598-020-57534-5.

Molecular characterization of sarcomatoid clear cell renal cell carcinoma unveils new candidate oncogenic drivers.

Author information

1
Department of Medical Oncology, Hôpital Pitié Salpêtrière, APHP, Sorbonne Université, Paris, France. maloufg@igbmc.fr.
2
Department of Hematology and Oncology, Centre Hospitalier Universitaire Régional de Strasbourg, Institut de Cancérologie de Strasbourg, Strasbourg, France. maloufg@igbmc.fr.
3
Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, Illkirch, France. maloufg@igbmc.fr.
4
Department of Medical Oncology, Hôpital Pitié Salpêtrière, APHP, Sorbonne Université, Paris, France.
5
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7
Department of Biostatistics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8
Department of Pathology, Hôpital Tenon, APHP, Sorbonne Université, Paris, France.
9
Department of Urology, Hôpital Pitié Salpêtrière, APHP, Sorbonne Université, Paris, France.
10
Inserm UMRS 1136, Sorbonne Université, Paris, France.
11
Department of Urology, MD Anderson Cancer Center, Houston, TX, USA.
12
Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA.
13
Center for Individualized Medicine, Epigenomics Group, Mayo Clinic, Rochester, MN, USA.
14
Molecular Oncology, Department of Medicine, Siteman Cancer Center, Washington University, St. Louis, MO, USA.
15
Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ntannir@mdanderson.org.
16
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. hakimia@mskcc.org.

Abstract

Sarcomatoid clear-cell renal cell carcinomas (sRCC) are associated with dismal prognosis. Genomic alterations associated with sarcomatoid dedifferentiation are poorly characterized. We sought to define the genomic landscape of sRCC and uncover potentially actionable therapeutic targets. We assessed the genomic landscape of sRCC using targeted panel sequencing including patients with microdissected sarcomatoid and epithelial components. Along with common genomic alterations associated with clear-cell histology, we found that Hippo was one of the most frequently altered pathways in these tumours. Hippo alterations were differentially enriched in sRCC compared to non-sRCC. Functional analysis showed that Hippo members mutations were associated with higher nuclear accumulation of YAP/TAZ, core effectors of the Hippo pathway. In a NF2-mutant sRCC model, YAP1 knockdown and NF2 reconstitution suppressed cell proliferation, tumour growth and invasion, both in vitro and in vivo. Overall, we show that Hippo pathway alterations are a feature of sRCC, and enable the exploration of the Hippo pathway as a novel potential therapeutic target.

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