Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes - Abstract

To further understand the molecular distinctions between kidney cancer subtypes, we analyzed exome, transcriptome and copy number alteration data from 167 primary human tumors that included renal oncocytomas and non-clear cell renal cell carcinomas (nccRCCs), consisting of papillary (pRCC), chromophobe (chRCC) and translocation (tRCC) subtypes.

We identified ten significantly mutated genes in pRCC, including MET, NF2, SLC5A3, PNKD and CPQ. MET mutations occurred in 15% (10/65) of pRCC samples and included previously unreported recurrent activating mutations. In chRCC, we found TP53, PTEN, FAAH2, PDHB, PDXDC1 and ZNF765 to be significantly mutated. Gene expression analysis identified a five-gene set that enabled the molecular classification of chRCC, renal oncocytoma and pRCC. Using RNA sequencing, we identified previously unreported gene fusions, including ACTG1-MITF fusion. Ectopic expression of the ACTG1-MITF fusion led to cellular transformation and induced the expression of downstream target genes. Finally, we observed upregulation of the anti-apoptotic factor BIRC7 in MiTF-high RCC tumors, suggesting a potential therapeutic role for BIRC7 inhibitors.

Written by:
Durinck S, Stawiski EW, Pavía-Jiménez A, Modrusan Z, Kapur P, Jaiswal BS, Zhang N, Toffessi-Tcheuyap V, Nguyen TT, Pahuja KB, Chen YJ, Saleem S, Chaudhuri S, Heldens S, Jackson M, Peña-Llopis S, Guillory J, Toy K, Ha C, Harris CJ, Holloman E, Hill HM, Stinson J, Rivers CS, Janakiraman V, Wang W, Kinch LN, Grishin NV, Haverty PM, Chow B, Gehring JS, Reeder J, Pau G, Wu TD, Margulis V, Lotan Y, Sagalowsky A, Pedrosa I, de Sauvage FJ, Brugarolas J, Seshagiri S.   Are you the author?
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Structural Biology Department, Genentech, Inc., South San Francisco, California, USA.
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Click HERE to read a press release from UT Southwestern Medical Center

Reference: Nat Genet. 2014 Nov 17. (Epub ahead of print)
doi: 10.1038/ng.3146


PubMed Abstract
PMID: 25401301

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