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 LeeMichael F. Berger, Satish K. Tickoo, Victor E. Reuter, James J. Hsieh

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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.

Original languageEnglish
Article number13131
JournalNature communications
Volume7
DOIs
StatePublished - Oct 7 2016
Externally publishedYes

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