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Science DOI:10.1126/science.aan5951

Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.

Publication TypeJournal Article
Year of Publication2018
AuthorsMiao, D, Margolis, CA, Gao, W, Voss, MH, Li, W, Martini, DJ, Norton, C, Bossé, D, Wankowicz, SM, Cullen, D, Horak, C, Wind-Rotolo, M, Tracy, A, Giannakis, M, Hodi, FStephen, Drake, CG, Ball, MW, Allaf, ME, Snyder, A, Hellmann, MD, Ho, T, Motzer, RJ, Signoretti, S, Kaelin, WG, Choueiri, TK, Van Allen, EM
Date Published2018 Jan 04

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.


Alternate JournalScience
PubMed ID29301960