Using genomic analysis of metastatic clear cell renal cell carcinoma (ccRCC), Miao et al. found that patients with biallelic loss of PBRM1, a gene encoding part of the PBAF chromatin remodeling complex, experienced sustained tumor reduction and had significantly prolonged overall and progression-free survival following immune checkpoint blockade therapy. PBRM1 deficiency was associated with enhanced expression of genes involved in JAK/STAT3/IFNγ and hypoxia pathways, providing a potential mechanism of ccRCC response to immunotherapy.
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 a SWI/SNF chromatin remodeling complex (the PBAF subtype). We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-(L)1 blockade therapy alone or in combination with anti-CTLA-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, hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor cell expression profiles to influence responsiveness to immune checkpoint therapy.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 0
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (4) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. 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) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (7) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (10) Bristol-Myers Squibb, New York, NY 10154, USA. (11) Bristol-Myers Squibb, New York, NY 10154, USA. (12) Bristol-Myers Squibb, New York, NY 10154, USA. (13) Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (16) Columbia University Medical Center, New York, NY 10032, USA. (17) James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (18) James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (19) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (20) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (21) Mayo Clinic, Scottsdale, AZ 85259, USA. (22) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (23) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (24) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (25) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. eliezerm_vanallen@dfci.harvard.edu toni_choueiri@dfci.harvard.edu. (26) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. eliezerm_vanallen@dfci.harvard.edu toni_choueiri@dfci.harvard.edu. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.
