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

Gabriel G. Malouf, Ronan Flippot, Yiyu Dong, Renzo G. Dinatale, Ying Bei Chen, Xiaoping Su, Eva Compérat, Morgan Rouprêt, Roy Mano, Kyle A. Blum, Hui Yao, Roger Mouawad, Jean Philippe Spano, David Khayat, Jose A. Karam, Thai H. Ho, Satish K. Tickoo, Paul Russo, James J. Hsieh, Nizar M. TannirAbraham A. Hakimi

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Article number701
JournalScientific reports
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

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    Malouf, G. G., Flippot, R., Dong, Y., Dinatale, R. G., Chen, Y. B., Su, X., Compérat, E., Rouprêt, M., Mano, R., Blum, K. A., Yao, H., Mouawad, R., Spano, J. P., Khayat, D., Karam, J. A., Ho, T. H., Tickoo, S. K., Russo, P., Hsieh, J. J., ... Hakimi, A. A. (2020). Molecular characterization of sarcomatoid clear cell renal cell carcinoma unveils new candidate oncogenic drivers. Scientific reports, 10(1), [701]. https://doi.org/10.1038/s41598-020-57534-5