Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets Academic Article uri icon


MeSH Major

  • Antineoplastic Combined Chemotherapy Protocols
  • Hematopoietic Stem Cell Transplantation
  • Neoplasms, Germ Cell and Embryonal
  • Testicular Neoplasms


  • 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.

publication date

  • October 7, 2016



  • Academic Article



  • eng

PubMed Central ID

  • PMC5059781

Digital Object Identifier (DOI)

  • 10.1038/ncomms13131

PubMed ID

  • 27713405

Additional Document Info

start page

  • 13131


  • 7