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Science. 2018 Feb 16;359(6377):801-806. doi: 10.1126/science.aan5951. Epub 2018 Jan 4.

Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
2
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.
3
Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Weill Cornell Medical College, New York, NY 10065, USA.
5
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
6
Bristol-Myers Squibb, New York, NY 10154, USA.
7
Columbia University Medical Center, New York, NY 10032, USA.
8
James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
9
Mayo Clinic, Scottsdale, AZ 85259, USA.
10
Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
11
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. eliezerm_vanallen@dfci.harvard.edu toni_choueiri@dfci.harvard.edu.

Abstract

Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene (P = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies (P = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.

Comment in

PMID:
29301960
PMCID:
PMC6035749
DOI:
10.1126/science.aan5951
[Indexed for MEDLINE]
Free PMC Article

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