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

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

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma, Oxyphilic / classification
  • Adenoma, Oxyphilic / genetics
  • Adenoma, Oxyphilic / pathology
  • Amino Acid Sequence
  • Base Sequence
  • Biomarkers, Tumor / genetics
  • Carcinoma, Renal Cell / classification*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / pathology
  • DNA, Neoplasm
  • Gene Dosage
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic*
  • Genomic Instability
  • Humans
  • Kidney Neoplasms / classification
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / pathology
  • Molecular Sequence Data
  • Mutation*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / physiology
  • Polymorphism, Single Nucleotide
  • Protein Conformation
  • Proto-Oncogene Proteins c-met / chemistry
  • Proto-Oncogene Proteins c-met / genetics
  • Translocation, Genetic

Substances

  • ACTG1-MITF fusion protein, human
  • Biomarkers, Tumor
  • DNA, Neoplasm
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • MET protein, human
  • Proto-Oncogene Proteins c-met

Supplementary concepts

  • Oncocytoma, renal