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Miao, Diana; Margolis, Claire A; Gao, Wenhua; Voss, Martin H; Li, Wei; Martini, Dylan J; Norton, Craig; Bossé, 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, Jr, William G; Choueiri, Toni K; Van Allen, Eliezer M
Science (American Association for the Advancement of Science), 02/2018, Letnik: 359, Številka: 6377Journal Article
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 gene ( = 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 ( = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and -deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways. loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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