|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Miao, 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 Published||2018 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.