Cancer Cell
Volume 38, Issue 6, 14 December 2020, Pages 803-817.e4
Journal home page for Cancer Cell

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

https://doi.org/10.1016/j.ccell.2020.10.011Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Genomics of 823 RCC tumors, including 134 sarcomatoid tumors, reveals 7 subtypes

  • Subtype specific angiogenesis, immune, metabolic, stromal, and cell-cycle profiles

  • Differential prevalence of PBRM1, KDM5C, CDKN2A/2B, and TP53 alterations in subsets

  • Differential outcomes to VEGF blockade alone or in combination with anti-PD-L1

Summary

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

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

Cited by (0)

11

These authors contributed equally

12

These authors contributed equally

13

Lead Contact