期刊
SCIENCE
卷 359, 期 6377, 页码 801-805出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aan5951
关键词
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资金
- Bristol-Myers Squibb II-ON consortium
- American Association for Cancer Research KureIt Grant for Kidney Cancer Research
- Cancer Immunologic Data Commons [NIH U24CA224316]
- Dana-Farber/Harvard Cancer Center Kidney Specialized Program of Research Excellence (SPORE)
- Kohlberg chair at Harvard Medical School
- Trust Family
- Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at the Dana-Farber Cancer Institute
- Gerstner Family Career Development Award
- National Cancer Institute [K12CA90628]
- U.S. Department of Defense [W81XWH-17-1-0546]
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.
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