Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets

Ying-Bei Chen (), Jianing Xu, Anders Jacobsen Skanderup, Yiyu Dong, A. Rose Brannon, Lu Wang, Helen H. Won, Patricia I. Wang, Gouri J. Nanjangud, Achim A. Jungbluth, Wei Li, Virginia Ojeda, A. Ari Hakimi, Martin H. Voss, Nikolaus Schultz, Robert J. Motzer, Paul Russo, Emily H. Cheng, Filippo G. Giancotti, William Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter and James J. Hsieh ()
Additional contact information
Ying-Bei Chen: Memorial Sloan Kettering Cancer Center
Jianing Xu: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Anders Jacobsen Skanderup: Computational Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center
Yiyu Dong: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
A. Rose Brannon: Memorial Sloan Kettering Cancer Center
Lu Wang: Memorial Sloan Kettering Cancer Center
Helen H. Won: Memorial Sloan Kettering Cancer Center
Patricia I. Wang: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Gouri J. Nanjangud: Molecular Cytogenetics Laboratory, Memorial Sloan Kettering Cancer Center
Achim A. Jungbluth: Memorial Sloan Kettering Cancer Center
Wei Li: Cell Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center
Virginia Ojeda: Cell Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center
A. Ari Hakimi: Urology Service, Memorial Sloan Kettering Cancer Center
Martin H. Voss: Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center
Nikolaus Schultz: Computational Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center
Robert J. Motzer: Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center
Paul Russo: Urology Service, Memorial Sloan Kettering Cancer Center
Emily H. Cheng: Memorial Sloan Kettering Cancer Center
Filippo G. Giancotti: Cell Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center
William Lee: Computational Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center
Michael F. Berger: Memorial Sloan Kettering Cancer Center
Satish K. Tickoo: Memorial Sloan Kettering Cancer Center
Victor E. Reuter: Memorial Sloan Kettering Cancer Center
James J. Hsieh: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%). Integrated analysis reveals a subset of 26% uRCC characterized by NF2 loss, dysregulated Hippo–YAP pathway and worse survival, whereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are associated with better clinical outcome. FH deficiency (6%), chromatin/DNA damage regulator mutations (21%) and ALK translocation (2%) distinguish additional cases. Altogether, this study reveals distinct molecular subsets for 76% of our uRCC cohort, which could have diagnostic and therapeutic implications.

Date: 2016
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DOI: 10.1038/ncomms13131

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