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

YB Chen, J Xu, AJ Skanderup, Y Dong… - Nature …, 2016 - nature.com
YB Chen, J Xu, AJ Skanderup, Y Dong, AR Brannon, L Wang, HH Won, PI Wang…
Nature communications, 2016nature.com
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 …
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.
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