학술논문
Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma
Document Type
Author abstract
Author
Miao, Diana; Margolis, Claire A.; Gao, Wenhua; Voss, Martin H.; Li, Wei; Martini, Dylan J.; Norton, Craig; Bosse, Dominick; Wankowicz, Stephanie M.; Cullen, Dana; Horak, Christine; Wind-Rotolo, Megan; Tracy, Adam; Giannakis, Marios; Hodi, Frank Stephen; Drake, Charles G.; Ball, Mark W.; Allaf, Mohamad E.; Snyder, Alexandra; Hellmann, Matthew D.; Ho, Thai; Motzer, Robert J.; Signoretti, Sabina; Kaelin, William G., Jr.; Choueiri, Toni K.; Van Allen, Eliezer M.
Source
Science. Feb 16, 2018, Vol. 359 Issue 6377, p801, 6 p.
Subject
Language
English
ISSN
0036-8075
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 antiCTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies (P = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and PBRMl-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. 10.1126/science.aaq5951