Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma

Cell. 2019 Oct 31;179(4):964-983.e31. doi: 10.1016/j.cell.2019.10.007.

Abstract

To elucidate the deregulated functional modules that drive clear cell renal cell carcinoma (ccRCC), we performed comprehensive genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic characterization of treatment-naive ccRCC and paired normal adjacent tissue samples. Genomic analyses identified a distinct molecular subgroup associated with genomic instability. Integration of proteogenomic measurements uniquely identified protein dysregulation of cellular mechanisms impacted by genomic alterations, including oxidative phosphorylation-related metabolism, protein translation processes, and phospho-signaling modules. To assess the degree of immune infiltration in individual tumors, we identified microenvironment cell signatures that delineated four immune-based ccRCC subtypes characterized by distinct cellular pathways. This study reports a large-scale proteogenomic analysis of ccRCC to discern the functional impact of genomic alterations and provides evidence for rational treatment selection stemming from ccRCC pathobiology.

Keywords: CPTAC; ccRCC; chromosomal translocation; drug targets; immune infiltration; phosphoproteomics; proteogenomics; proteomics; renal carcinoma; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / immunology
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / pathology
  • Disease-Free Survival
  • Exome / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Genome, Human / genetics
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / immunology
  • Oxidative Phosphorylation
  • Phosphorylation / genetics
  • Proteogenomics*
  • Signal Transduction / genetics
  • Transcriptome / genetics*
  • Transcriptome / immunology
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • Whole Exome Sequencing

Substances

  • Biomarkers, Tumor
  • Neoplasm Proteins