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Nat Genet. 2015 Jan;47(1):13-21. doi: 10.1038/ng.3146. Epub 2014 Nov 17.

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

Author information

  • 11] Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA. [2] Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
  • 21] Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [3] Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 3Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
  • 41] Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 51] Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 6Structural Biology Department, Genentech, Inc., South San Francisco, California, USA.
  • 71] Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [3] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • 8Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
  • 91] Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 101] Kidney Cancer Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [3] Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 11Molecular Oncology Department, Genentech, Inc., South San Francisco, California, USA.

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.

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PMID:
25401301
[PubMed - indexed for MEDLINE]
PMCID:
PMC4489427
Free PMC Article
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