Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade

Cancer Cell. 2020 Dec 14;38(6):803-817.e4. doi: 10.1016/j.ccell.2020.10.011. Epub 2020 Nov 5.


Integrated multi-omics evaluation of 823 tumors from advanced renal cell carcinoma (RCC) patients identifies molecular subsets associated with differential clinical outcomes to angiogenesis blockade alone or with a checkpoint inhibitor. Unsupervised transcriptomic analysis reveals seven molecular subsets with distinct angiogenesis, immune, cell-cycle, metabolism, and stromal programs. While sunitinib and atezolizumab + bevacizumab are effective in subsets with high angiogenesis, atezolizumab + bevacizumab improves clinical benefit in tumors with high T-effector and/or cell-cycle transcription. Somatic mutations in PBRM1 and KDM5C associate with high angiogenesis and AMPK/fatty acid oxidation gene expression, while CDKN2A/B and TP53 alterations associate with increased cell-cycle and anabolic metabolism. Sarcomatoid tumors exhibit lower prevalence of PBRM1 mutations and angiogenesis markers, frequent CDKN2A/B alterations, and increased PD-L1 expression. These findings can be applied to molecularly stratify patients, explain improved outcomes of sarcomatoid tumors to checkpoint blockade versus antiangiogenics alone, and develop personalized therapies in RCC and other indications.

Keywords: CDKN2A/B; PBRM1; PD-L1; VHL; atezolizumab; bevacizumab; checkpoint blockade; integrated genomics; renal cell carcinoma; sarcomatoid; sunitinib.

Publication types

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

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use*
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bevacizumab / pharmacology
  • Bevacizumab / therapeutic use
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / genetics
  • Clinical Trials, Phase III as Topic
  • Computational Biology / methods
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / genetics
  • Prognosis
  • Randomized Controlled Trials as Topic
  • Sequence Analysis, RNA
  • Sunitinib / pharmacology
  • Sunitinib / therapeutic use
  • Treatment Outcome
  • Unsupervised Machine Learning


  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal, Humanized
  • Biomarkers, Tumor
  • Immune Checkpoint Inhibitors
  • Bevacizumab
  • atezolizumab
  • Sunitinib