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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
JournalScience
Volume359
Issue6377
Pages801-806
Date Published2018 Feb 16
ISSN1095-9203
KeywordsB7-H1 Antigen, Carcinoma, Renal Cell, Chromosomal Proteins, Non-Histone, Cohort Studies, CTLA-4 Antigen, Exome, Gene Expression Profiling, Genomics, Humans, Immunotherapy, Kidney Neoplasms, Mutation, Programmed Cell Death 1 Receptor, Transcription Factors
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 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.

DOI10.1126/science.aan5951
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/29301960?dopt=Abstract

Alternate JournalScience
PubMed ID29301960
PubMed Central IDPMC6035749
Grant ListKL2 TR001100 / TR / NCATS NIH HHS / United States
K08 CA188615 / CA / NCI NIH HHS / United States
K12 CA090628 / CA / NCI NIH HHS / United States
U24 CA224316 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States