Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma Journal Article
| Authors: | Miao, D.; Margolis, C. A.; Gao, W.; Voss, M. H.; Li, W.; Martini, D. J.; Norton, C.; Bossé, D.; Wankowicz, S. M.; Cullen, D.; Horak, C.; Wind-Rotolo, M.; Tracy, A.; Giannakis, M.; Hodi, F. S.; Drake, C. G.; Ball, M. W.; Allaf, M. E.; Snyder, A.; Hellmann, M. D.; Ho, T.; Motzer, R. J.; Signoretti, S.; Kaelin, W. G. Jr; Choueiri, T. K.; Van Allen, E. M. |
| Article Title: | Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma |
| 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. © 2018 American Association for the Advancement of Science. All Rights Reserved. |
| Journal Title: | Science |
| Volume: | 359 |
| Issue: | 6377 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2018-02-16 |
| Start Page: | 801 |
| End Page: | 806 |
| Language: | English |
| DOI: | 10.1126/science.aan5951 |
| PROVIDER: | scopus |
| PUBMED: | 29301960 |
| PMCID: | PMC6035749 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2018 -- Source: Scopus |
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