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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\n                    <jats:italic>in situ<\/jats:italic>\n                    hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including\n                    <jats:italic>NF2<\/jats:italic>\n                    (18%),\n                    <jats:italic>SETD2<\/jats:italic>\n                    (18%),\n                    <jats:italic>BAP1<\/jats:italic>\n                    (13%),\n                    <jats:italic>KMT2C<\/jats:italic>\n                    (10%) and\n                    <jats:italic>MTOR<\/jats:italic>\n                    (8%). Integrated analysis reveals a subset of 26% uRCC characterized by NF2 loss, dysregulated Hippo\u2013YAP pathway and worse survival, whereas 21% uRCC with mutations of\n                    <jats:italic>MTOR<\/jats:italic>\n                    ,\n                    <jats:italic>TSC1<\/jats:italic>\n                    ,\n                    <jats:italic>TSC2<\/jats:italic>\n                    or\n                    <jats:italic>PTEN<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/ncomms13131","type":"journal-article","created":{"date-parts":[[2016,10,7]],"date-time":"2016-10-07T05:19:41Z","timestamp":1475817581000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":170,"title":["Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5207-3648","authenticated-orcid":false,"given":"Ying-Bei","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders Jacobsen","family":"Skanderup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5391-4936","authenticated-orcid":false,"given":"Yiyu","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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