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

Diana Miao, Claire A. Margolis, Wenhua Gao, Martin H. Voss, Wei Li, Dylan J. Martini, Craig Norton, Dominick Bossé, Stephanie M. Wankowicz, Dana Cullen, Christine Horak, Megan Wind-Rotolo, Adam Tracy, Marios Giannakis, Frank Stephen Hodi, Charles G. Drake, Mark W. Ball, Mohamad E. Allaf, Alexandra Snyder, Matthew D. HellmannThai Ho, Robert J. Motzer, Sabina Signoretti, William G. Kaelin, Toni K. Choueiri, Eliezer M. Van Allen

Research output: Contribution to journalArticlepeer-review

281 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)801-806
Number of pages6
JournalScience
Volume359
Issue number6377
DOIs
StatePublished - Feb 16 2018

ASJC Scopus subject areas

  • General

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